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Zhang J, Ju T, Qin Y, Hou M, Gao L, Wu LA. Therapeutic targeting of P2X receptors for orofacial pain. Brain Res Bull 2025; 224:111301. [PMID: 40086763 DOI: 10.1016/j.brainresbull.2025.111301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Revised: 02/16/2025] [Accepted: 03/10/2025] [Indexed: 03/16/2025]
Abstract
P2X receptors (P2XRs), membrane ion channels activated by extracellular adenosine 5' -triphosphate (ATP), play a pivotal role in nociception by directly promoting pain signaling. Currently, antagonists targeting P2XRs have taken effect in alleviating various pain. The therapeutic potential of the P2X receptor family has become a central focus. Consequently, numerous research groups and pharmaceutical companies are actively engaged in developing novel P2XR antagonists. Furthermore, an increasing number of clinical trials on P2XR antagonists have obtained encouraging results. This review provides an overview of the structural characteristics and cellular localization of P2XRs, their molecular mechanisms and signaling pathways implicated in orofacial pain. Additionally, it explores the development of P2XR antagonists and their therapeutic application for managing orofacial pain. In conclusion, this review highlights the promising role of P2XRs as therapeutic targets for orofacial pain treatment.
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Affiliation(s)
- Jing Zhang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Diseases, Department of Pediatric Den-tistry, School of Stomatology, The Fourth Military Medical University, Xi'an 710032, China.
| | - Tianjuan Ju
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Diseases, Department of Pediatric Den-tistry, School of Stomatology, The Fourth Military Medical University, Xi'an 710032, China.
| | - Yaru Qin
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Diseases, Department of Pediatric Den-tistry, School of Stomatology, The Fourth Military Medical University, Xi'an 710032, China.
| | - Ming Hou
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Diseases, Department of Pediatric Den-tistry, School of Stomatology, The Fourth Military Medical University, Xi'an 710032, China.
| | - Lei Gao
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Diseases, Department of Pediatric Den-tistry, School of Stomatology, The Fourth Military Medical University, Xi'an 710032, China.
| | - Li-An Wu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Diseases, Department of Pediatric Den-tistry, School of Stomatology, The Fourth Military Medical University, Xi'an 710032, China.
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Butenas ALE, Baranczuk AM, Carroll RJ, Parr SK, Ade CJ, Hageman KS, Musch TI, Copp SW. Novel role for purinergic 2× subtype 4 (P2X4) receptors in the exercise pressor reflex and mechanoreflex: Effect of heart failure. Auton Neurosci 2025; 260:103277. [PMID: 40233602 DOI: 10.1016/j.autneu.2025.103277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Revised: 02/06/2025] [Accepted: 04/01/2025] [Indexed: 04/17/2025]
Abstract
We investigated the role played by ATP-sensitive purinergic 2 × 4 (P2X4) receptors on the sensory endings of thin fibre muscle afferents in exercise pressor reflex and mechanoreflex activation in healthy/SHAM rats and rats with heart failure with reduced ejection fraction (HF-rEF). We hypothesized that infusion of the P2X4 receptor antagonist 5-BDBD (8 μg) into the hindlimb arterial supply would reduce the mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) responses to 30s of electrically-induced hindlimb skeletal muscle contraction (model of exercise pressor reflex activation) and 30s of hindlimb skeletal muscle stretch (model of mechanoreflex activation) in decerebrate, unanesthetized HF-rEF rats but not SHAM rats. Ejection fraction was significantly lower in HF-rEF (46 ± 3 %) compared to SHAM (83 ± 2 %; P < 0.001) rats. In SHAM rats, P2X4 receptor blockade had no effect on the pressor response to hindlimb muscle contraction (n = 8) or the pressor and RSNA response to muscle stretch (n = 4). However, in SHAM rats we found that P2X4 receptor blockade significantly reduced the RSNA response to muscle contraction. In HF-rEF rats, P2X4 receptor blockade reduced the pressor and RSNA response to hindlimb muscle contraction (n = 7) as well as the pressor, but not the RNSA, response to hindlimb muscle stretch (n = 8). Collectively, the data suggest that P2X4 receptors on thin fibre muscle afferent sensory endings play a role in the evoking the exercise pressor reflex in healthy subjects that is limited to RSNA, and that in HF-rEF this expands to a significant role in mechanoreflex and exercise pressor reflex-mediated blood pressure control.
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Affiliation(s)
- Alec L E Butenas
- Department of Kinesiology, Kansas State University, Manhattan, KS, United States of America
| | - Ashley M Baranczuk
- Department of Kinesiology, Kansas State University, Manhattan, KS, United States of America
| | - Raimi J Carroll
- Department of Kinesiology, Kansas State University, Manhattan, KS, United States of America
| | - Shannon K Parr
- Department of Kinesiology, Kansas State University, Manhattan, KS, United States of America
| | - Carl J Ade
- Department of Kinesiology, Kansas State University, Manhattan, KS, United States of America
| | - K Sue Hageman
- Department of Anatomy and Physiology, Kansas State University, Manhattan, KS, United States of America
| | - Timothy I Musch
- Department of Kinesiology, Kansas State University, Manhattan, KS, United States of America; Department of Anatomy and Physiology, Kansas State University, Manhattan, KS, United States of America
| | - Steven W Copp
- Department of Kinesiology, Kansas State University, Manhattan, KS, United States of America.
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Hui SE, Westlund KN. Role of HDAC5 Epigenetics in Chronic Craniofacial Neuropathic Pain. Int J Mol Sci 2024; 25:6889. [PMID: 38999998 PMCID: PMC11241576 DOI: 10.3390/ijms25136889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Revised: 06/08/2024] [Accepted: 06/16/2024] [Indexed: 07/14/2024] Open
Abstract
The information provided from the papers reviewed here about the role of epigenetics in chronic craniofacial neuropathic pain is critically important because epigenetic dysregulation during the development and maintenance of chronic neuropathic pain is not yet well characterized, particularly for craniofacial pain. We have noted that gene expression changes reported vary depending on the nerve injury model and the reported sample collection time point. At a truly chronic timepoint of 10 weeks in our model of chronic neuropathic pain, functional groupings of genes examined include those potentially contributing to anti-inflammation, nerve repair/regeneration, and nociception. Genes altered after treatment with the epigenetic modulator LMK235 are discussed. All of these differentials are key in working toward the development of diagnosis-targeted therapeutics and likely for the timing of when the treatment is provided. The emphasis on the relevance of time post-injury is reiterated here.
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Affiliation(s)
| | - Karin N. Westlund
- Department of Anesthesiology & Critical Care Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
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Zhang J, Gao L, Zhang Y, Wang H, Sun S, Wu L. Involvement of microglial P2X7 receptor in pain modulation. CNS Neurosci Ther 2024; 30:e14496. [PMID: 37950524 PMCID: PMC10805404 DOI: 10.1111/cns.14496] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 08/23/2023] [Accepted: 10/02/2023] [Indexed: 11/12/2023] Open
Abstract
BACKGROUND Pain is a rapid response mechanism that compels organisms to retreat from the harmful stimuli and triggers a repair response. Nonetheless, when pain persists for extended periods, it can lead to adverse changes into in the individual's brain, negatively impacting their emotional state and overall quality of life. Microglia, the resident immune cells in the central nervous system (CNS), play a pivotal role in regulating a variety of pain-related disorders. Specifically, recent studies have shed light on the central role that microglial purinergic ligand-gated ion channel 7 receptor (P2X7R) plays in regulating pain. In this respect, the P2X7R on microglial membranes represents a potential therapeutic target. AIMS To expound on the intricate link between microglial P2X7R and pain, offering insights into potential avenues for future research. METHODS We reviewed 140 literature and summarized the important role of microglial P2X7R in regulating pain, including the structure and function of P2X7R, the relationship between P2X7R and microglial polarization, P2X7R-related signaling pathways, and the effects of P2X7R antagonists on pain regulation. RESULTS P2X7R activation is related to M1 polarization of microglia, while suppressing P2X7R can transfer microglia from M1 into M2 phenotype. And targeting the P2X7R-mediated signaling pathways helps to explore new therapy for pain alleviation. P2X7R antagonists also hold potential for translational and clinical applications in pain management. CONCLUSIONS Microglial P2X7R holds promise as a potential novel pharmacological target for clinical treatments due to its distinctive structure, function, and the development of antagonists.
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Affiliation(s)
- Jing Zhang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Department of Pediatric Dentistry, School of StomatologyThe Fourth Military Medical UniversityXi'anShaanxiChina
| | - Lei Gao
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Department of Pediatric Dentistry, School of StomatologyThe Fourth Military Medical UniversityXi'anShaanxiChina
| | - Yaoyuan Zhang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Department of Pediatric Dentistry, School of StomatologyThe Fourth Military Medical UniversityXi'anShaanxiChina
| | - Haozhen Wang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Department of Pediatric Dentistry, School of StomatologyThe Fourth Military Medical UniversityXi'anShaanxiChina
| | - Shukai Sun
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Department of Pediatric Dentistry, School of StomatologyThe Fourth Military Medical UniversityXi'anShaanxiChina
| | - Li‐an Wu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Department of Pediatric Dentistry, School of StomatologyThe Fourth Military Medical UniversityXi'anShaanxiChina
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Zhang WJ, Li MY, Wang CY, Feng X, Hu DX, Wu LD, Hu JL. P2Y12 receptor involved in the development of chronic nociceptive pain as a sensory information mediator. Biomed Pharmacother 2023; 164:114975. [PMID: 37267639 DOI: 10.1016/j.biopha.2023.114975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2023] [Revised: 05/24/2023] [Accepted: 05/30/2023] [Indexed: 06/04/2023] Open
Abstract
Direct or indirect damage to the nervous system (such as inflammation or tumor invasion) can lead to dysfunction and pain. The generation of pain is mainly reflected in the activation of glial cells and the abnormal discharge of sensory neurons, which transmit stronger sensory information to the center. P2Y12 receptor plays important roles in physiological and pathophysiological processes including inflammation and pain. P2Y12 receptor involved in the occurrence of pain as a sensory information mediator, which enhances the activation of microglia and the synaptic plasticity of primary sensory neurons, and reaches the higher center through the ascending conduction pathway (mainly spinothalamic tract) to produce pain. While the application of P2Y12 receptor antagonists (PBS-0739, AR-C69931MX and MRS2359) have better antagonistic activity and produce analgesic pharmacological properties. Therefore, in this article, we discussed the role of the P2Y12 receptor in different chronic pains and its use as a pharmacological target for pain relief.
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Affiliation(s)
- Wen-Jun Zhang
- Department of Rehabilitation Medicine, the Second Affiliated Hospital, Nanchang University, Nanchang City, Jiangxi Province 343000, China
| | - Mei-Yong Li
- Department of Laboratory medicine, the Second Affiliated Hospital, Nanchang University, Nanchang City, Jiangxi Province 343000, China
| | - Cheng-Yi Wang
- Department of Rehabilitation Medicine, the Second Affiliated Hospital, Nanchang University, Nanchang City, Jiangxi Province 343000, China
| | - Xiao Feng
- Department of Rehabilitation Medicine, the Second Affiliated Hospital, Nanchang University, Nanchang City, Jiangxi Province 343000, China
| | - Dong-Xia Hu
- Department of Rehabilitation Medicine, the Second Affiliated Hospital, Nanchang University, Nanchang City, Jiangxi Province 343000, China.
| | - Li-Dong Wu
- Department of Emergency Medicine, the Second Affiliated Hospital, Nanchang University, Nanchang City, Jiangxi Province 343000, China.
| | - Jia-Ling Hu
- Department of Emergency Medicine, the Second Affiliated Hospital, Nanchang University, Nanchang City, Jiangxi Province 343000, China.
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Shi Y, Wen H, Cui J, Qin W. Ulinastatin inhibits microglia activation in spinal cord via P2Y12 receptor in a rat neuropathic pain model. J Histotechnol 2023; 46:39-53. [PMID: 36637388 DOI: 10.1080/01478885.2022.2163792] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2022] [Accepted: 12/26/2022] [Indexed: 01/14/2023]
Abstract
Ulinastatin, a broad spectrum of serine protease inhibitor, has been found to alleviate neuropathic pain (NPP). However, its mechanism is not completely clear. Here, a sciatic nerve ligation rat model and BV2 microglial cells were used to investigate the effect of Ulinastatin on the activation of microglia and P2Y12 receptors in vivo and in vitro. Levels of P2Y12 receptor and NF-κB (P65) expression in the dorsal horn of the lumbar enlargement region of the spinal cord and BV2 cells were assessed by immunohistochemistry and double-label immunofluorescence assays. Levels of IL-1β and TNF-α in cell culture medium and cerebrospinal fluid (CSF) were examined by ELISA. The results showed that Ulinastatin reduced the release of inflammatory IL-1β and TNF-α by inhibiting the activation of spinal microglia. Ulinastatin down-regulated P2Y12 receptor and NF-κB (P65) expression in the spinal microglia of the chronic constrictive injury model. The results indicated that Ulinastatin may attenuate the activation of spinal microglia after peripheral nerve injury by inhibiting the activation of P2Y12 receptor signal pathway in microglia. NF-kB may play a key role in the mechanism of Ulinastatin.
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Affiliation(s)
- Ying Shi
- Department of Pain Care, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Huizhong Wen
- Department of Neurobiology, Army Medical University, Chongqing, China
| | - Jian Cui
- Department of Pain Care, Southwest Hospital, Army Medical University, Chongqing, China
| | - Wanxiang Qin
- Department of Pain Care, Southwest Hospital, Army Medical University, Chongqing, China
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Hu QQ, He XF, Ma YQ, Ma LQ, Qu SY, Wang HZ, Kang YR, Chen LH, Li X, Liu BY, Shao XM, Fang JF, Liang Y, Fang JQ, Jiang YL. Dorsal root ganglia P2X4 and P2X7 receptors contribute to diabetes-induced hyperalgesia and the downregulation of electroacupuncture on P2X4 and P2X7. Purinergic Signal 2023; 19:29-41. [PMID: 35218450 PMCID: PMC9984662 DOI: 10.1007/s11302-022-09844-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Accepted: 01/11/2022] [Indexed: 12/11/2022] Open
Abstract
Diabetic neuropathic pain (DNP) is highly common in diabetes patients. P2X receptors play critical roles in pain sensitization. We previously showed that elevated P2X3 expression in dorsal root ganglion (DRG) contributes to DNP. However, the role of other P2X receptors in DNP is unclear. Here, we established the DNP model using a single high-dose streptozotocin (STZ) injection and investigated the expression of P2X genes in the DRG. Our data revealed elevated P2X2, P2X4, and P2X7 mRNA levels in DRG of DNP rats. The protein levels of P2X4 and P2X7 in DNP rats increased, but the P2X2 did not change significantly. To study the role of P2X4 and P2X7 in diabetes-induced hyperalgesia, we treated the DNP rats with TNP-ATP (2',3'-O-(2,4,6-trinitrophenyl)-adenosine 5'-triphosphate), a nonspecific P2X1-7 antagonist, and found that TNP-ATP alleviated thermal hyperalgesia in DNP rats. 2 Hz electroacupuncture is analgesic against DNP and could downregulate P2X4 and P2X7 expression in DRG. Our findings indicate that P2X4 and P2X7 in L4-L6 DRGs contribute to diabetes-induced hyperalgesia, and that EA reduces thermal hyperalgesia and the expression of P2X4 and P2X7.
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Affiliation(s)
- Qun-Qi Hu
- Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, People's Republic of China
| | - Xiao-Fen He
- Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, People's Republic of China
| | - Yi-Qi Ma
- Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, People's Republic of China
| | - Li-Qian Ma
- Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, People's Republic of China
| | - Si-Ying Qu
- Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, People's Republic of China
| | - Han-Zhi Wang
- Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, People's Republic of China
| | - Yu-Rong Kang
- Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, People's Republic of China
| | - Lu-Hang Chen
- Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, People's Republic of China
| | - Xiang Li
- Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, People's Republic of China
| | - Bo-Yu Liu
- Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, People's Republic of China
| | - Xiao-Mei Shao
- Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, People's Republic of China
| | - Jun-Fan Fang
- Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, People's Republic of China
| | - Yi Liang
- Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, People's Republic of China
| | - Jian-Qiao Fang
- Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, People's Republic of China.
| | - Yong-Liang Jiang
- Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, People's Republic of China.
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Wang Y, Li C, Xing J, Zhu Y, Sun M, Yin S, Liu J, Zou L, Liang S, Liu S. Neohesperidin Alleviates the Neuropathic Pain Behavior of Rats by Downregulating the P2X4 Receptor. Neurochem Res 2023; 48:781-790. [PMID: 36331667 DOI: 10.1007/s11064-022-03805-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 08/31/2022] [Accepted: 10/20/2022] [Indexed: 11/06/2022]
Abstract
Neuropathic pain (NP) is a type of chronic pain affecting 6-8% of human health as no effective drug exists. The purinergic 2X4 receptor (P2X4R) is involved in NP. Neohesperidin (NH) is a dihydroflavonoside compound, which has anti-inflammatory and antioxidative properties. This study aimed to investigate whether NH has an effect on P2X4R-mediated NP induced by chronic constriction injury (CCI) of the sciatic nerve in rats. In this study, the CCI rat model was established to observe the changes of pain behaviors, P2X4R, and satellite glial cells (SGCs) activation in dorsal root ganglion (DRG) after NH treatment by using RT-PCR, immunofluorescence double labeling and Western blotting. Our results showed CCI rats had mechanical and thermal hyperalgesia with an increased level of P2X4R. Furthermore, SGCs were activated as indicated by increased expression of glial fibrillary acidic protein and increased tumor necrosis factor-alpha receptor 1and interleukin-1β. In addition, phosphorylated extracellular regulated protein kinases and interferon regulatory factor 5 in CCI rats increased. After NH treatment in CCI rats, the levels of above protein decreased, and the pain reduced. Overall, NH can markedly alleviate NP by reducing P2X4R expression and SGCs activation in DRG.
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Affiliation(s)
- Yueying Wang
- Department of Physiology, Basic Medical School of Nanchang University, Nanchang, People's Republic of China
| | - Chenxi Li
- Department of Physiology, Basic Medical School of Nanchang University, Nanchang, People's Republic of China
| | - Jingming Xing
- Department of Basical Medicine, Medical School of Nanchang University, Nanchang, People's Republic of China
| | - Yan Zhu
- Department of Endocrine, The First Hospital of Nanchang, Nanchang, People's Republic of China
| | - Minghao Sun
- Department of Clinical Medicine, The Second Clinical Medical School of Nanchang University, Nanchang, People's Republic of China
| | - Sui Yin
- Department of Physiology, Basic Medical School of Nanchang University, Nanchang, People's Republic of China
| | - Jianming Liu
- Department of Pharmacology, Pharmacy School of Nanchang University, Nanchang, People's Republic of China
| | - Lifang Zou
- Center of Hematology, The First Affiliated Hospital of Nanchang University, Nanchang, People's Republic of China.,Institute of Hematology, Academy of Clinical Medicine of Jiangxi Province, Nanchang, People's Republic of China
| | - Shangdong Liang
- Department of Physiology, Basic Medical School of Nanchang University, Nanchang, People's Republic of China
| | - Shuangmei Liu
- Department of Physiology, Basic Medical School of Nanchang University, Nanchang, People's Republic of China.
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9
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Yang H, Zhang Y, Duan Q, Ni K, Jiao Y, Zhu J, Sun J, Zhang W, Ma Z. Dehydrocorydaline alleviates sleep deprivation-induced persistent postoperative pain in adolescent mice through inhibiting microglial P2Y 12 receptor expression in the spinal cord. Mol Pain 2023; 19:17448069231216234. [PMID: 37940138 DOI: 10.1177/17448069231216234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2023] Open
Abstract
During adolescence, a second period of central nervous system (CNS) plasticity that follows the fetal period, which involves sleep deprivation (SD), becomes apparent. SD during adolescence may result in abnormal development of neural circuits, causing imbalance in neuronal excitation and inhibition, which not only results in pain, but increases the chances of developing emotion disorders in adulthood, such as anxiety and depression. The quantity of surgeries during adolescence is also consistently on the rise, yet the impact and underlying mechanism of preoperative SD on postoperative pain remain unexplored. This study demonstrates that preoperative SD induces upregulation of the P2Y12 receptor, which is exclusively expressed on spinal microglia, and phosphorylation of its downstream signaling pathway p38Mitogen-activated protein/Nuclear transcription factor-κB (p38MAPK/NF-κB)in spinal microglia, thereby promoting microglia activation and microglial transformation into the proinflammatory M1 phenotype, resulting in increased expression of proinflammatory cytokines that exacerbate persisting postoperative incisional pain in adolescent mice. Both intrathecal minocycline (a microglia activation inhibitor) and MRS2395 (a P2Y12 receptor blocker) effectively suppressed microglial activation and proinflammatory cytokine expression. Interestingly, supplementation with dehydrocorydaline (DHC), an extract of Rhizoma Corydalis, inhibited the P2Y12/p38MAPK/NF-κB signaling pathway, microglia activation, and expression of pro-inflammatory cytokines in the model mice. Taken together, the results indicate that the P2Y12 receptor and microglial activation are important factors in persistent postoperative pain caused by preoperative SD in adolescent mice and that DHC has analgesic effects by acting on these targets.
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Affiliation(s)
- Haikou Yang
- Department of Anesthesiology, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- Department of Anesthesiology, Affiliated Hospital of Yang Zhou University Medical College, Huai'an Maternal and Child Health Care Center, Huai'an, China
| | - Yufeng Zhang
- Department of Anesthesiology, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- Department of Anesthesiology, Affiliated Hospital of Yang Zhou University Medical College, Huai'an Maternal and Child Health Care Center, Huai'an, China
| | - Qingling Duan
- Department of Anesthesiology, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Kun Ni
- Department of Anesthesiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Yang Jiao
- Department of Anesthesiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Jixiang Zhu
- Department of Anesthesiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Jian Sun
- Department of Anesthesiology, Affiliated Hospital of Yang Zhou University Medical College, Huai'an Maternal and Child Health Care Center, Huai'an, China
| | - Wei Zhang
- Department of Anesthesiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Zhengliang Ma
- Department of Anesthesiology, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
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Chen Z, Huang Q, Song X, Ford NC, Zhang C, Xu Q, Lay M, He SQ, Dong X, Hanani M, Guan Y. Purinergic signaling between neurons and satellite glial cells of mouse dorsal root ganglia modulates neuronal excitability in vivo. Pain 2022; 163:1636-1647. [PMID: 35027518 PMCID: PMC9771604 DOI: 10.1097/j.pain.0000000000002556] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Accepted: 11/24/2021] [Indexed: 10/19/2022]
Abstract
ABSTRACT Primary sensory neurons in dorsal root ganglia (DRG) are wrapped by satellite glial cells (SGCs), and neuron-SGC interaction may affect somatosensation, especially nociceptive transmission. P2-purinergic receptors (P2Rs) are key elements in the two-way interactions between DRG neurons and SGCs. However, because the cell types are in such close proximity, conventional approaches such as in vitro culture and electrophysiologic recordings are not adequate to investigate the physiologically relevant responses of these cells at a population level. Here, we performed in vivo calcium imaging to survey the activation of hundreds of DRG neurons in Pirt-GCaMP6s mice and to assess SGC activation in GFAP-GCaMP6s mice in situ. By combining pharmacologic and electrophysiologic techniques, we investigated how ganglionic purinergic signaling initiated by α,β-methyleneadenosine 5'-triphosphate (α,β-MeATP) modulates neuronal activity and excitability at a population level. We found that α,β-MeATP induced robust activation of small neurons-likely nociceptors-through activation of P2X3R. Large neurons, which are likely non-nociceptive, were also activated by α,β-MeATP, but with a delay. Blocking pannexin 1 channels attenuated the late phase response of DRG neurons, indicating that P2R stimulation may subsequently induce paracrine ATP release, which could further activate cells in the ganglion. Moreover, ganglionic α,β-MeATP treatment in vivo sensitized small neurons and enhanced responses of spinal wide-dynamic-range neurons to subsequent C-fiber inputs, suggesting that modulation via ganglionic P2R signaling could significantly affect nociceptive neuron excitability and pain transmission. Therefore, targeting functional P2Rs within ganglia may represent an important new strategy for pain modulation.
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Affiliation(s)
- Zhiyong Chen
- Department of Anesthesiology and Critical Care Medicine, the Johns Hopkins University, School of Medicine, Baltimore, MD, United States
| | - Qian Huang
- Department of Anesthesiology and Critical Care Medicine, the Johns Hopkins University, School of Medicine, Baltimore, MD, United States
| | - Xiaodan Song
- Department of Anesthesiology and Critical Care Medicine, the Johns Hopkins University, School of Medicine, Baltimore, MD, United States
| | - Neil C. Ford
- Department of Anesthesiology and Critical Care Medicine, the Johns Hopkins University, School of Medicine, Baltimore, MD, United States
| | - Chi Zhang
- Department of Anesthesiology and Critical Care Medicine, the Johns Hopkins University, School of Medicine, Baltimore, MD, United States
| | - Qian Xu
- The Solomon H. Snyder Department of Neuroscience, Center for Sensory Biology, Johns Hopkins University, School of Medicine, Baltimore, MD, United States
- Howard Hughes Medical Institute, Johns Hopkins University, School of Medicine, Baltimore, MD, United States
| | - Mark Lay
- The Solomon H. Snyder Department of Neuroscience, Center for Sensory Biology, Johns Hopkins University, School of Medicine, Baltimore, MD, United States
| | - Shao-Qiu He
- Department of Anesthesiology and Critical Care Medicine, the Johns Hopkins University, School of Medicine, Baltimore, MD, United States
| | - Xinzhong Dong
- The Solomon H. Snyder Department of Neuroscience, Center for Sensory Biology, Johns Hopkins University, School of Medicine, Baltimore, MD, United States
- Howard Hughes Medical Institute, Johns Hopkins University, School of Medicine, Baltimore, MD, United States
| | - Menachem Hanani
- Laboratory of Experimental Surgery, Hadassah-Hebrew University Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Mount Scopus, Jerusalem, Israel
| | - Yun Guan
- Department of Anesthesiology and Critical Care Medicine, the Johns Hopkins University, School of Medicine, Baltimore, MD, United States
- Department of Neurological Surgery, Johns Hopkins University, School of Medicine, Baltimore, MD, United States
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11
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Long L, Zhong W, Guo L, Ji J, Nie H. Effect of Bufalin-PLGA Microspheres in the Alleviation of Neuropathic Pain via the CCI Model. Front Pharmacol 2022; 13:910885. [PMID: 35770074 PMCID: PMC9234216 DOI: 10.3389/fphar.2022.910885] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 04/25/2022] [Indexed: 11/20/2022] Open
Abstract
The treatment of neuropathic pain (NPP) is considered challenging, while the search for alternative medication is striving. NPP pathology is related with the expression of both the purinergic 2X7 (P2X7) receptor and the transient receptor potential vanilloid 1 receptor (TRPV1). Bufalin is a traditional Chinese medication derived from toad venom with pronounced antitumor, analgesic, and anti-inflammatory properties. However, poor solubility, rapid metabolism, and the knowledge gap on its pain alleviation mechanism have limited the clinical application of bufalin. Hence, the purpose of this study is to illustrate the NPP alleviation mechanism of bufalin via chronic constriction injury (CCI). To address the concern on fast metabolism, bufalin-PLGA microspheres (MS) were prepared via membrane emulsification to achieve prolonged pain-relieving effects. Western blot, real-time PCR, immunofluorescence, and molecular docking were employed to demonstrate the therapeutic action of bufalin on NPP. The results showed enhanced thermal withdrawal latency (TWL) and mechanical withdrawal threshold (MWT) after the administration of both bufalin and bufalin-PLGA MS in the CCI rats. Prolonged pain-relieving effects for up to 3 days with reduced dose frequency was achieved via bufalin-PLGA MS. In the CCI rats treated with bufalin-PLGA MS, the expression levels of protein and mRNA in TRPV1 and P2X7, both localized in the dorsal root ganglion (DRG), were reduced. Moreover, bufalin-PLGA MS effectively reduced the levels of IL-1β, IL-18, IL-6, and TNF-α in the CCI group. The results from molecular docking suggested a possible mechanism of NPP alleviation of bufalin through binding to P2X7 receptors directly. The administration of bufalin-PLGA MS prepared by membrane emulsification demonstrated promising applications for sustained effect on the alleviation of NPP.
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Affiliation(s)
- Lina Long
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, China
- International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), College of Pharmacy, Jinan University, Guangzhou, China
| | - Wenwei Zhong
- School of Chinese Medicinal Resource, Guangdong Pharmaceutical University, Yunfu, China
- Guangzhou Nansha Information Technology Park Post-Doctoral Scientific Research Station, Guangzhou, China
- *Correspondence: Wenwei Zhong, ; Hong Nie,
| | - Liwei Guo
- Guangzhou Bio-Green Biotechnology Co., Ltd., Guangzhou, China
- National Engineering Research Center of Pharmaceutical Processing Technology of Traditional Chinese Medicine and Drug Innovation, Guangzhou, China
- Guangzhou Dayuan Studio of Membrane Science and Technology for Traditional Chinese Medicine, Guangzhou, China
| | - Jing Ji
- Guangzhou Nansha Information Technology Park Post-Doctoral Scientific Research Station, Guangzhou, China
| | - Hong Nie
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, China
- International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), College of Pharmacy, Jinan University, Guangzhou, China
- *Correspondence: Wenwei Zhong, ; Hong Nie,
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12
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Zou L, Liu S, Li L, Yang R, Xu X, Li G, Zhang C, Li G, Liang S. Implication of P2Y 12 receptor in uc.48+-mediated abnormal sympathoexcitatory reflex via superior cervical ganglia in myocardial ischemic rats. Eur J Pharmacol 2022; 927:175049. [PMID: 35644421 DOI: 10.1016/j.ejphar.2022.175049] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 05/19/2022] [Accepted: 05/19/2022] [Indexed: 12/28/2022]
Abstract
Purinergic 2Y12 (P2Y12) receptor antagonists are used as platelet aggregation inhibitors. Long non-coding RNAs (lncRNAs) play an important role in neuropathological events. Satellite glial cells (SGCs) in the superior cervical ganglia (SCGs) encircle the somata of neurons. This study explored if the upregulated P2Y12 receptor in SCGs was relevant to lncRNA uc.48+ during myocardial ischemia (MI). The results showed that upregulation of P2Y12 receptor was accompanied by increased expression of uc.48+ in the SCGs of MI rats which displayed abnormal changes in cervical sympathetic nerve activity, blood pressure, heart rate, electrocardiograms and cardiac tissue structure. The P2Y12 antagonist clopidogrel improved abnormal alterations in cardiac function and tissue structure in MI rats. Short hairpin RNA (shRNA) against uc.48+ significantly inhibited P2Y12 receptor upregulation and its co-expression with glial fibrillary acidic protein (GFAP) in SCGs, and ameliorated the cardiac dysfunction in MI rats. By contrast, overexpression of uc.48+ increased the expression of P2Y12 in SCGs and enhanced cervical sympathetic nerve activity in control rats. Direct interaction between uc.48+ and the P2Y12 receptor was predicted using the bioinformatic tool CatRAPID and confirmed by RNA immunoprecipitation. Moreover, overexpression of the P2Y12 receptor reversed the protective effect of uc.48+ shRNA on cardiac dysfunction in MI rats. Uc.48 shRNA treatment also inhibited the enhanced rise of intracellular free Ca2+ level ([Ca2+]i) evoked by the P2Y12 agonist 2-methylthio-adenosine-5'-diphosphate (2-MeSADP) in SGCs of SCGs after oxygen-glucose deprivation (OGD) treatment. These data demonstrated that uc.48+ shRNA could counteract the P2Y12 upregulation and improve P2Y12-implicated cardiac dysfunction due to MI.
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Affiliation(s)
- Lifang Zou
- Neuropharmacology Laboratory of Physiology Department, Medical School of Nanchang University, Nanchang, 330006, PR China; Department of Hematology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, PR China
| | - Shuangmei Liu
- Neuropharmacology Laboratory of Physiology Department, Medical School of Nanchang University, Nanchang, 330006, PR China; Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang, Jiangxi, 330006, PR China
| | - Lin Li
- Neuropharmacology Laboratory of Physiology Department, Medical School of Nanchang University, Nanchang, 330006, PR China; Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang, Jiangxi, 330006, PR China
| | - Runan Yang
- Neuropharmacology Laboratory of Physiology Department, Medical School of Nanchang University, Nanchang, 330006, PR China; Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang, Jiangxi, 330006, PR China
| | - Xiumei Xu
- Neuropharmacology Laboratory of Physiology Department, Medical School of Nanchang University, Nanchang, 330006, PR China; Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang, Jiangxi, 330006, PR China
| | - Guilin Li
- Neuropharmacology Laboratory of Physiology Department, Medical School of Nanchang University, Nanchang, 330006, PR China; Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang, Jiangxi, 330006, PR China
| | - Chunping Zhang
- Department of Cell Biology, Medical School of Nanchang University, Nanchang, 330006, PR China; Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang, Jiangxi, 330006, PR China
| | - Guodong Li
- Neuropharmacology Laboratory of Physiology Department, Medical School of Nanchang University, Nanchang, 330006, PR China; Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang, Jiangxi, 330006, PR China
| | - Shangdong Liang
- Neuropharmacology Laboratory of Physiology Department, Medical School of Nanchang University, Nanchang, 330006, PR China; Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang, Jiangxi, 330006, PR China.
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13
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Tang G, Pi L, Guo H, Hu Z, Zhou C, Hu Q, Peng H, Xiao Z, Zhang Z, Wang M, Peng T, Huang J, Liang S, Li G. Naringin Relieves Diabetic Cardiac Autonomic Neuropathy Mediated by P2Y14 Receptor in Superior Cervical Ganglion. Front Pharmacol 2022; 13:873090. [PMID: 35529431 PMCID: PMC9068893 DOI: 10.3389/fphar.2022.873090] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 03/23/2022] [Indexed: 12/30/2022] Open
Abstract
Diabetes mellitus (DM), an emerging chronic epidemic, contributes to mortality and morbidity around the world. Diabetic cardiac autonomic neuropathy (DCAN) is one of the most common complications associated with DM. Previous studies have shown that satellite glial cells (SGCs) in the superior cervical ganglia (SCG) play an indispensable role in DCAN progression. In addition, it has been shown that purinergic neurotransmitters, as well as metabotropic GPCRs, are involved in the pathophysiological process of DCAN. Furthermore, one traditional Chinese medicine, naringin may potently alleviate the effects of DCAN. Ferroptosis may be involved in DCAN progression. However, the role of naringin in DCAN as well as its detailed mechanism requires further investigation. In this research, we attempted to identify the effect and relevant mechanism of naringin in DCAN mitigation. We observed that compared with those of normal subjects, there were significantly elevated expression levels of P2Y14 and IL-1β in diabetic rats, both of which were remarkably diminished by treatment with either P2Y14 shRNA or naringin. In addition, abnormalities in blood pressure (BP), heart rate (HR), heart rate variability (HRV), sympathetic nerve discharge (SND), and cardiac structure in the diabetic model can also be partially returned to normal through the use of those treatments. Furthermore, a reduced expression of NRF2 and GPX4, as well as an elevated level of ROS, were detected in diabetic cases, which can also be improved with those treatments. Our results showed that naringin can effectively relieve DCAN mediated by the P2Y14 receptor of SGCs in the SCG. Moreover, the NRF2/GPX4 pathway involved in ferroptosis may become one of the principal mechanisms participating in DCAN progression, which can be modulated by P2Y14-targeted naringin and thus relieve DCAN. Hopefully, our research can supply one novel therapeutic target and provide a brilliant perspective for the treatment of DCAN.
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Affiliation(s)
- Gan Tang
- Queen Mary School, Medical School of Nanchang University, Nanchang, China
| | - Lingzhi Pi
- School of Basic Medicine, Medical School of Nanchang University, Nanchang, China
| | - Hongmin Guo
- Department of Physiology, Medical School of Nanchang University, Nanchang, China
| | - Zihui Hu
- Department of Physiology, Medical School of Nanchang University, Nanchang, China
| | - Congfa Zhou
- Department of Anatomy, Medical School of Nanchang University, Nanchang, China
| | - Qixing Hu
- Department of Physiology, Medical School of Nanchang University, Nanchang, China
| | - Hao Peng
- School of Basic Medicine, Medical School of Nanchang University, Nanchang, China
| | - Zehao Xiao
- Queen Mary School, Medical School of Nanchang University, Nanchang, China
| | - Zhihua Zhang
- Queen Mary School, Medical School of Nanchang University, Nanchang, China
| | - Miaomiao Wang
- Queen Mary School, Medical School of Nanchang University, Nanchang, China
| | - Taotao Peng
- School of Basic Medicine, Medical School of Nanchang University, Nanchang, China
| | - Jiaqi Huang
- Queen Mary School, Medical School of Nanchang University, Nanchang, China
| | - Shangdong Liang
- Department of Physiology, Medical School of Nanchang University, Nanchang, China
| | - Guilin Li
- Department of Physiology, Medical School of Nanchang University, Nanchang, China
- *Correspondence: Guilin Li,
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14
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Lei X, Zeng J, Yan Y, Liu X. Blockage of HCN Channels Inhibits the Function of P2X Receptors in Rat Dorsal Root Ganglion Neurons. Neurochem Res 2022; 47:1083-1096. [PMID: 35064517 DOI: 10.1007/s11064-021-03509-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 12/06/2021] [Accepted: 12/14/2021] [Indexed: 12/12/2022]
Abstract
Hyperpolarization-activated cyclic nucleotide-gated channels and purinergic P2X receptors play critical roles in the nerve injury-induced pain hypersensitivity. Both HCN channels and P2XR are expressed in dorsal root ganglia sensory neurons. However, it is not clear whether the expression and function of P2X2 and P2X3 receptors can be modulated by HCN channel activity. For this reason, in rats with chronic constriction injury of sciatic nerve, we evaluated the effect of intrathecal administration of HCN channel blocker ZD7288 on nociceptive behavior and the expression of P2X2 and P2X3 in rat DRG. The mechanical withdrawal threshold was measured to evaluate pain behavior in rats. The protein expression of P2X2 and P2X3 receptor in rat DRG was observed by using Western Blot. The level of cAMP in rat DRG was measured by ELISA. As a result, decreased MWT was observed in CCI rats on 1 d after surgery, and the allodynia was sustained throughout the experimental period. In addition, CCI rats presented increased expression of P2X2 and P2X3 receptor in the ipsilateral DRG at 7 d and 14 d after CCI operation. Intrathecal injection of ZD7288 significantly reversed CCI-induced mechanical hyperalgesia, and attenuated the increased expression of P2X2 and P2X3 receptor in rat DRG, which open up the possibility that the expression of P2X2 and P2X3 receptor in DRG is down-regulated by HCN channel blocker ZD7288 in CCI rats. Furthermore, the level of cAMP in rat DRG significantly increased after nerve injury. Intrathecal administration of ZD7288 attenuated the increase of cAMP in DRG caused by nerve injury. Subsequently, effects of HCN channel activity on ATP-induced current (IATP) in rat DRG neurons were explored by using whole-cell patch-clamp techniques. ATP (100 μM) elicited three types of currents (fast, slow and mixed IATP) in cultured DRG neurons. Pretreatment with ZD7288 concentration-dependently inhibited three types of ATP-activated currents. On the other hand, pretreatment with 8-Br-cAMP (a cell-permeable cAMP analog, also known as an activator of PKA) significantly increased the amplitude of fast, slow and mixed IATP in DRG neurons. The enhanced effect of 8-Br-cAMP on ATP-activated currents could be reversed by ZD7288. In a summary, our observations suggest that the opening of HCN channels could enhance the expression and function of P2X2 and P2X3 receptor via the cAMP-PKA signaling pathway. This may be important for pathophysiological events occurring within the DRG, for where it is implicated in nerve injury-induced pain hypersensitivity.
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Affiliation(s)
- Xiaolu Lei
- Key Laboratory of Brain Science, Zunyi Medical University, Zunyi, 563000, China
| | - Junwei Zeng
- Department of Physiology, Zunyi Medical University, No. 6, Xuefu west road, Zunyi, 563000, Guizhou province, China
| | - Yan Yan
- Key Laboratory of Brain Science, Zunyi Medical University, Zunyi, 563000, China
| | - Xiaohong Liu
- Department of Physiology, Zunyi Medical University, No. 6, Xuefu west road, Zunyi, 563000, Guizhou province, China.
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15
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Magalhães HIR, Castelucci P. Enteric nervous system and inflammatory bowel diseases: Correlated impacts and therapeutic approaches through the P2X7 receptor. World J Gastroenterol 2021; 27:7909-7924. [PMID: 35046620 PMCID: PMC8678817 DOI: 10.3748/wjg.v27.i46.7909] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Revised: 08/19/2021] [Accepted: 11/25/2021] [Indexed: 02/06/2023] Open
Abstract
The enteric nervous system (ENS) consists of thousands of small ganglia arranged in the submucosal and myenteric plexuses, which can be negatively affected by Crohn's disease and ulcerative colitis - inflammatory bowel diseases (IBDs). IBDs are complex and multifactorial disorders characterized by chronic and recurrent inflammation of the intestine, and the symptoms of IBDs may include abdominal pain, diarrhea, rectal bleeding, and weight loss. The P2X7 receptor has become a promising therapeutic target for IBDs, especially owing to its wide expression and, in the case of other purinergic receptors, in both human and model animal enteric cells. However, little is known about the actual involvement between the activation of the P2X7 receptor and the cascade of subsequent events and how all these activities associated with chemical signals interfere with the functionality of the affected or treated intestine. In this review, an integrated view is provided, correlating the structural organization of the ENS and the effects of IBDs, focusing on cellular constituents and how therapeutic approaches through the P2X7 receptor can assist in both protection from damage and tissue preservation.
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Affiliation(s)
| | - Patricia Castelucci
- Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo, São Paulo 08000-000, Brazil
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16
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Su L, Bai X, Niu T, Zhuang X, Dong B, Wang G, Yu Y. P2Y1 purinergic receptor inhibition attenuated remifentanil-induced postoperative hyperalgesia via decreasing NMDA receptor phosphorylation in dorsal root ganglion. Brain Res Bull 2021; 177:352-362. [PMID: 34653560 DOI: 10.1016/j.brainresbull.2021.10.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 10/06/2021] [Accepted: 10/08/2021] [Indexed: 12/22/2022]
Abstract
BACKGROUND Remifentanil-induced postoperative hyperalgesia is an intractable side effect of the clinical use of remifentanil, the mechanism of which remains obscure, especially in the peripheral nervous system. N-methyl-D-aspartate receptor (NMDAR) phosphorylation in dorsal root ganglion (DRG) plays a pronociceptive role in neuropathic pain. The contribution of the P2Y1 purinergic receptor (P2Y1R) in DRG to pain hypersensitivity derived from various origins and P2Y1R upregulation-induced NMDAR activation in neurons have also been uncovered. This study aimed to investigate whether P2Y1R participates in nociceptive processing in the DRG and spinal cord in remifentanil-induced postoperative hyperalgesia. METHODS Rats with remifentanil-induced postoperative hyperalgesia were intrathecally injected with NMDAR antagonist MK801 or P2Y1R antagonist MRS2179 at 10 min prior to remifentanil infusion. Mechanical allodynia, heat hyperalgesia, and cold hyperalgesia were measured at -24 h, 2 h, 6 h, 24 h, and 48 h following remifentanil infusion. The P2Y1R expression and NMDAR expression and phosphorylation in DRG ipsilateral to the incision were detected by Western blot and immunofluorescence. RESULTS Incision and remifentanil induced mechanical allodynia, heat hyperalgesia, and cold hyperalgesia accompanied by upregulated P2Y1R expression, increased NMDAR subunit NR1 expression and phosphorylation at Ser896, and NR2B expression and phosphorylation at Tyr1472 in DRG. Inhibition of NMDAR phosphorylation by MK801 effectively attenuated remifentanil-induced postoperative hyperalgesia. Furthermore, P2Y1R blockade by MRS2179 not only lessened remifentanil-evoked postoperative hypersensitivity to mechanical, heat, and cold stimuli, but also suppressed the increases in NR1 and NR2B expression and phosphorylation in DRG induced by incision and remifentanil. CONCLUSION The process by which P2Y1R mediates NMDAR expression and phosphorylation represents a mechanism of remifentanil-induced postoperative hyperalgesia in the DRG and/or spinal cord.
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Affiliation(s)
- Lin Su
- Department of Anesthesiology, Tianjin Medical University General Hospital, No. 154 Anshan Road, Heping District, Tianjin 300052, PR China; Tianjin Research Institute of Anesthesiology, No. 154 Anshan Road, Heping District, Tianjin 300052, PR China
| | - Xiaoqing Bai
- Department of Science and Education, Tianjin Beichen Hospital, No. 7 Beiyi Road, Beichen District, Tianjin 300400, PR China
| | - Tongxiang Niu
- Tianjin Research Institute of Anesthesiology, No. 154 Anshan Road, Heping District, Tianjin 300052, PR China; Department of Anesthesiology, Tianjin Jinnan Hospital, No. 120 Jingu Road, Jinnan District, Tianjin 300350, PR China
| | - Xinqi Zhuang
- Tianjin Research Institute of Anesthesiology, No. 154 Anshan Road, Heping District, Tianjin 300052, PR China; Department of Anesthesiology, Tianjin Medical University Second Hospital, No. 23 Pingjiang Road, Hexi District, Tianjin 300211, PR China
| | - Beibei Dong
- Department of Anesthesiology, Tianjin Medical University General Hospital, No. 154 Anshan Road, Heping District, Tianjin 300052, PR China; Tianjin Research Institute of Anesthesiology, No. 154 Anshan Road, Heping District, Tianjin 300052, PR China
| | - Guolin Wang
- Department of Anesthesiology, Tianjin Medical University General Hospital, No. 154 Anshan Road, Heping District, Tianjin 300052, PR China; Tianjin Research Institute of Anesthesiology, No. 154 Anshan Road, Heping District, Tianjin 300052, PR China
| | - Yonghao Yu
- Department of Anesthesiology, Tianjin Medical University General Hospital, No. 154 Anshan Road, Heping District, Tianjin 300052, PR China; Tianjin Research Institute of Anesthesiology, No. 154 Anshan Road, Heping District, Tianjin 300052, PR China.
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17
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Cutaneous innervation in impaired diabetic wound healing. Transl Res 2021; 236:87-108. [PMID: 34029747 PMCID: PMC8380642 DOI: 10.1016/j.trsl.2021.05.003] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 05/09/2021] [Accepted: 05/11/2021] [Indexed: 12/11/2022]
Abstract
Type 2 diabetes is associated with several potential comorbidities, among them impaired wound healing, chronic ulcerations, and the requirement for lower extremity amputation. Disease-associated abnormal cellular responses, infection, immunological and microvascular dysfunction, and peripheral neuropathy are implicated in the pathogenesis of the wound healing impairment and the diabetic foot ulcer. The skin houses a dense network of sensory nerve afferents and nerve-derived modulators, which communicate with epidermal keratinocytes and dermal fibroblasts bidirectionally to effect normal wound healing after trauma. However, the mechanisms through which cutaneous innervation modulates wound healing are poorly understood, especially in humans. Better understanding of these mechanisms may provide the basis for targeted treatments for chronic diabetic wounds. This review provides an overview of wound healing pathophysiology with a focus on neural involvement in normal and diabetic wound healing, as well as future therapeutic perspectives to address the unmet needs of diabetic patients with chronic wounds.
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18
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Boakye PA, Tang SJ, Smith PA. Mediators of Neuropathic Pain; Focus on Spinal Microglia, CSF-1, BDNF, CCL21, TNF-α, Wnt Ligands, and Interleukin 1β. FRONTIERS IN PAIN RESEARCH 2021; 2:698157. [PMID: 35295524 PMCID: PMC8915739 DOI: 10.3389/fpain.2021.698157] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 07/14/2021] [Indexed: 01/04/2023] Open
Abstract
Intractable neuropathic pain is a frequent consequence of nerve injury or disease. When peripheral nerves are injured, damaged axons undergo Wallerian degeneration. Schwann cells, mast cells, fibroblasts, keratinocytes and epithelial cells are activated leading to the generation of an "inflammatory soup" containing cytokines, chemokines and growth factors. These primary mediators sensitize sensory nerve endings, attract macrophages, neutrophils and lymphocytes, alter gene expression, promote post-translational modification of proteins, and alter ion channel function in primary afferent neurons. This leads to increased excitability and spontaneous activity and the generation of secondary mediators including colony stimulating factor 1 (CSF-1), chemokine C-C motif ligand 21 (CCL-21), Wnt3a, and Wnt5a. Release of these mediators from primary afferent neurons alters the properties of spinal microglial cells causing them to release tertiary mediators, in many situations via ATP-dependent mechanisms. Tertiary mediators such as BDNF, tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), and other Wnt ligands facilitate the generation and transmission of nociceptive information by increasing excitatory glutamatergic transmission and attenuating inhibitory GABA and glycinergic transmission in the spinal dorsal horn. This review focusses on activation of microglia by secondary mediators, release of tertiary mediators from microglia and a description of their actions in the spinal dorsal horn. Attention is drawn to the substantial differences in the precise roles of various mediators in males compared to females. At least 25 different mediators have been identified but the similarity of their actions at sensory nerve endings, in the dorsal root ganglia and in the spinal cord means there is considerable redundancy in the available mechanisms. Despite this, behavioral studies show that interruption of the actions of any single mediator can relieve signs of pain in experimental animals. We draw attention this paradox. It is difficult to explain how inactivation of one mediator can relieve pain when so many parallel pathways are available.
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Affiliation(s)
- Paul A. Boakye
- Department of Anesthesiology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, United States
| | - Shao-Jun Tang
- Department of Anesthesiology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, United States
| | - Peter A. Smith
- Neuroscience and Mental Health Institute and Department of Pharmacology, University of Alberta, Edmonton, AB, Canada
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Fan X, Wang C, Han J, Ding X, Tang S, Ning L. Role of TRPV4-P2X7 Pathway in Neuropathic Pain in Rats with Chronic Compression of the Dorsal Root Ganglion. Neurochem Res 2021; 46:2143-2153. [PMID: 34014488 DOI: 10.1007/s11064-021-03352-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 04/16/2021] [Accepted: 05/12/2021] [Indexed: 10/21/2022]
Abstract
Transient receptor potential vanilloid 4 (TRPV4) is a Ca2+-permeable non-selective cation channel that is involved in the development of neuropathic pain. P2X7 receptor (P2X7) belongs to a class of ATP-gated nonselective cation channels that plays an important role in neuropathic pain. Nevertheless, little is known about the interaction between them for neuropathic pain. In this paper, we investigated role of TRPV4-P2X7 pathway in neuropathic pain. We evaluated the effect of TRPV4-P2X7 pathway on neuropathic pain in a chronic compression of the dorsal root ganglion (DRG) (hereafter termed CCD) model. We analyzed the effect of P2X7 on mechanical and thermal hyperalgesia mediated by TRPV4 in CCD. Furthermore, we assessed the effect of TRPV4 on the expression of P2X7 and the release of IL-1β and IL-6 in DRG after CCD. We found that intraperitoneal injection of TRPV4 agonist GSK-1016790A led to a significant increase of mechanical and thermal hyperalgesia in CCD, which was partially suppressed by P2X7 blockade with antagonist Brilliant Blue G (BBG). Then, we further noticed that GSK-1016790A injection increased the P2X7 expression of CCD, which was decreased by TRPV4 blockade with antagonist RN-1734 and HC-067047. Furthermore, we also discovered that the expressions of IL-1β and IL-6 were upregulated by GSK-1016790A injection but reduced by RN-1734 and HC-067047. Our results provide evidence that P2X7 contributes to development of neuropathic pain mediated by TRPV4 in the CCD model, which may be the basis for treatment of neuropathic pain relief.
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Affiliation(s)
- Xiaohua Fan
- Department of Rehabilitation Medicine, Shandong Provincial Hospital, 324 Jing Wu Wei Qi Road, Jinan, 250012, China
- Department of Rehabilitation Medicine, Shandong First Medical University, Taian, 250012, China
| | - Chuanwei Wang
- Department of Neurosurgery, Qilu Hospital Affiliated To Shandong University, 44 West Wenhua Road, Jinan, 250012, China
| | - Junting Han
- Department of Rehabilitation Medicine, Shandong First Medical University, Taian, 250012, China
| | - Xinli Ding
- Department of Rehabilitation Medicine, Shandong Provincial Hospital, 324 Jing Wu Wei Qi Road, Jinan, 250012, China
- Department of Rehabilitation Medicine, Shandong First Medical University, Taian, 250012, China
| | - Shaocan Tang
- Department of Rehabilitation Medicine, Shandong Provincial Hospital, 324 Jing Wu Wei Qi Road, Jinan, 250012, China
- Department of Rehabilitation Medicine, Shandong First Medical University, Taian, 250012, China
| | - Liping Ning
- Department of Rehabilitation Medicine, Shandong Provincial Hospital, 324 Jing Wu Wei Qi Road, Jinan, 250012, China.
- Department of Rehabilitation Medicine, Shandong First Medical University, Taian, 250012, China.
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20
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Peng L, Wu B, Shi L, Zou L, Li L, Yang R, Xu X, Li G, Liu S, Zhang C, Liang S. Long Non-coding RNA Uc.48+ Small Interfering RNA Alleviates Neuroinflammatory Hyperalgesia in Gp120-Treated Rats via the P2Y12 Receptor. Front Neurosci 2021; 15:663962. [PMID: 34326715 PMCID: PMC8315484 DOI: 10.3389/fnins.2021.663962] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Accepted: 04/29/2021] [Indexed: 01/22/2023] Open
Abstract
Human immunodeficiency virus envelope glycoprotein 120 (gp120) leads to hyperalgesia. Long non-coding RNAs are characterized by the lack of a protein-coding sequence and may contribute to the development and maintenance of inflammatory and neuroinflammatory pain. Rats with neuroinflammatory pain were established by gp120 treatment, which is featured by intensified pain behaviors. Long non-coding RNA uc.48+ was increased in the dorsal root ganglia of gp120-treated rats, and small interfering RNA that targets uc.48+ markedly alleviated hyperalgesia in gp120-treated rats. Notably, uc.48+ overexpression increased P2Y12 expression in control rats dorsal root ganglia and induced hyperalgesia. Uc.48+ small interfering RNA inhibited P2Y12 expression in gp120-treated rats. Uc.48+ potentiated P2Y12 receptor functions in the neurons and heterologous cells. Therefore, uc.48+ siRNA treatment reduced the upregulation of P2Y12 expression and function in DRG neurons, and, hence, alleviated hyperalgesia in gp120-treated rats.
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Affiliation(s)
- Lichao Peng
- School of Life Sciences, Xiamen University, Xiamen, China
| | - Bing Wu
- Neuropharmacology Laboratory of Physiology Department, Medical School of Nanchang University, Nanchang, China.,Department of Cell Biology, Medical School of Nanchang University, Nanchang, China
| | - Liran Shi
- Neuropharmacology Laboratory of Physiology Department, Medical School of Nanchang University, Nanchang, China.,Department of Cell Biology, Medical School of Nanchang University, Nanchang, China
| | - Lifang Zou
- Neuropharmacology Laboratory of Physiology Department, Medical School of Nanchang University, Nanchang, China.,Department of Cell Biology, Medical School of Nanchang University, Nanchang, China
| | - Lin Li
- Neuropharmacology Laboratory of Physiology Department, Medical School of Nanchang University, Nanchang, China.,Department of Cell Biology, Medical School of Nanchang University, Nanchang, China
| | - Runan Yang
- Neuropharmacology Laboratory of Physiology Department, Medical School of Nanchang University, Nanchang, China.,Department of Cell Biology, Medical School of Nanchang University, Nanchang, China
| | - Xiumei Xu
- Neuropharmacology Laboratory of Physiology Department, Medical School of Nanchang University, Nanchang, China.,Department of Cell Biology, Medical School of Nanchang University, Nanchang, China
| | - Guilin Li
- Neuropharmacology Laboratory of Physiology Department, Medical School of Nanchang University, Nanchang, China.,Department of Cell Biology, Medical School of Nanchang University, Nanchang, China
| | - Shuangmei Liu
- Neuropharmacology Laboratory of Physiology Department, Medical School of Nanchang University, Nanchang, China.,Department of Cell Biology, Medical School of Nanchang University, Nanchang, China
| | - Chunping Zhang
- Department of Cell Biology, Medical School of Nanchang University, Nanchang, China.,Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang, China
| | - Shangdong Liang
- Neuropharmacology Laboratory of Physiology Department, Medical School of Nanchang University, Nanchang, China.,Department of Cell Biology, Medical School of Nanchang University, Nanchang, China
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21
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Wang A, Shi X, Yu R, Qiao B, Yang R, Xu C. The P2X 7 Receptor Is Involved in Diabetic Neuropathic Pain Hypersensitivity Mediated by TRPV1 in the Rat Dorsal Root Ganglion. Front Mol Neurosci 2021; 14:663649. [PMID: 34163328 PMCID: PMC8215290 DOI: 10.3389/fnmol.2021.663649] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Accepted: 05/05/2021] [Indexed: 12/30/2022] Open
Abstract
The purinergic 2X7 (P2X7) receptor expressed in satellite glial cells (SGCs) is involved in the inflammatory response, and transient receptor potential vanilloid 1 (TRPV1) participates in the process of neurogenic inflammation, such as that in diabetic neuropathic pain (DNP) and peripheral neuralgia. The main purpose of this study was to explore the role of the P2X7 receptor in DNP hypersensitivity mediated by TRPV1 in the rat and its possible mechanism. A rat model of type 2 diabetes mellitus-related neuropathic pain (NPP) named the DNP rat model was established in this study. The mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) of DNP rats were increased after intrathecal injection of the P2X7 receptor antagonist A438079, and the mRNA and protein levels of TRPV1 in the dorsal root ganglion (DRG) were decreased in DNP rats treated with A438079 compared to untreated DNP rats; in addition, A438079 also decreased the phosphorylation of p38 and extracellular signal-regulated kinase 1/2 (ERK1/2) in the DNP group. Based on these results, the P2X7 receptor might be involved in DNP mediated by TRPV1.
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Affiliation(s)
- Anhui Wang
- Department of Physiology, Basic Medical College of Nanchang University, Nanchang, China
| | - Xiangchao Shi
- Medical Department, Queen Mary School, Nanchang University, Nanchang, China
| | - Ruoyang Yu
- Medical Department, Queen Mary School, Nanchang University, Nanchang, China
| | - Bao Qiao
- Medical Department, Queen Mary School, Nanchang University, Nanchang, China
| | - Runan Yang
- Department of Physiology, Basic Medical College of Nanchang University, Nanchang, China
| | - Changshui Xu
- Department of Physiology, Basic Medical College of Nanchang University, Nanchang, China.,Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang, China
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22
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Abstract
The evolution of therapeutics for and management of human immunodeficiency virus-1 (HIV-1) infection has shifted it from predominately manifesting as a severe, acute disease with high mortality to a chronic, controlled infection with a near typical life expectancy. However, despite extensive use of highly active antiretroviral therapy, the prevalence of chronic widespread pain in people with HIV remains high even in those with a low viral load and high CD4 count. Chronic widespread pain is a common comorbidity of HIV infection and is associated with decreased quality of life and a high rate of disability. Chronic pain in people with HIV is multifactorial and influenced by HIV-induced peripheral neuropathy, drug-induced peripheral neuropathy, and chronic inflammation. The specific mechanisms underlying these three broad categories that contribute to chronic widespread pain are not well understood, hindering the development and application of pharmacological and nonpharmacological approaches to mitigate chronic widespread pain. The consequent insufficiencies in clinical approaches to alleviation of chronic pain in people with HIV contribute to an overreliance on opioids and alarming rise in active addiction and overdose. This article reviews the current understanding of the pathogenesis of chronic widespread pain in people with HIV and identifies potential biomarkers and therapeutic targets to mitigate it.
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Affiliation(s)
- Dylan R Addis
- Department of Anesthesiology and Perioperative Medicine, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.,Division of Molecular and Translational Biomedicine, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Jennifer J DeBerry
- Department of Anesthesiology and Perioperative Medicine, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.,Division of Molecular and Translational Biomedicine, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Saurabh Aggarwal
- Department of Anesthesiology and Perioperative Medicine, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.,Division of Molecular and Translational Biomedicine, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.,Pulmonary Injury and Repair Center, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
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23
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Effects of Curcumin and Its Different Formulations in Preclinical and Clinical Studies of Peripheral Neuropathic and Postoperative Pain: A Comprehensive Review. Int J Mol Sci 2021; 22:ijms22094666. [PMID: 33925121 PMCID: PMC8125634 DOI: 10.3390/ijms22094666] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 04/22/2021] [Accepted: 04/26/2021] [Indexed: 12/11/2022] Open
Abstract
Lesion or disease of the somatosensory system leads to the development of neuropathic pain. Peripheral neuropathic pain encompasses damage or injury of the peripheral nervous system. On the other hand, 10–15% of individuals suffer from acute postoperative pain followed by persistent pain after undergoing surgeries. Antidepressants, anticonvulsants, baclofen, and clonidine are used to treat peripheral neuropathy, whereas opioids are used to treat postoperative pain. The negative effects associated with these drugs emphasize the search for alternative therapeutics with better efficacy and fewer side effects. Curcumin, a polyphenol isolated from the roots of Curcuma longa, possesses antibacterial, antioxidant, and anti-inflammatory properties. Furthermore, the low bioavailability and fast metabolism of curcumin have led to the advent of various curcumin formulations. The present review provides a comprehensive analysis on the effects of curcumin and its formulations in preclinical and clinical studies of neuropathic and postoperative pain. Based on the positive outcomes from both preclinical and clinical studies, curcumin holds the promise of mitigating or preventing neuropathic and postoperative pain conditions. However, more clinical studies with improved curcumin formulations are required to involve its use as adjuvant to neuropathic and postoperative drugs.
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24
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Ding S, Yu Q, Wang J, Zhu L, Li T, Guo X, Zhang X. Activation of ATF3/AP-1 signaling pathway is required for P2X3-induced endometriosis pain. Hum Reprod 2021; 35:1130-1144. [PMID: 32303740 DOI: 10.1093/humrep/deaa061] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Revised: 02/26/2020] [Indexed: 12/22/2022] Open
Abstract
STUDY QUESTION Does P2X ligand-gated ion channel 3 (P2X3) play a role in endometriosis pain? SUMMARY ANSWER Upregulation of P2X3 in dorsal root ganglia (DRG) tissues via the activating transcription factor 3 (ATF3)/activator protein (AP)-1 pathway contributed to endometriosis-associated hyperalgesia, which could be attenuated by the chitosan oligosaccharide stearic acid (CSOSA)/liposomes (LPs)/SP600125 delivery system. WHAT IS KNOWN ALREADY Infiltrating nerve fibers and elevated nociceptors in endometriotic lesions are associated with endometriosis pain. P2X3 has been demonstrated to play an important role in neuropathic pain. STUDY DESIGN, SIZE, DURATION A rat model of endometriosis was used to investigate the signaling pathways involved in P2X3-induced pain. PARTICIPANTS/MATERIALS, SETTING, METHODS Degrees of hyperalgesia, endogenous adenosine 5'-triphosphate (ATP) contents and P2X3 expression levels in endometriotic lesions and DRG tissues were detected in a rat model of endometriosis. The expression levels of ATF3 and P2X3 were measured using qRT-PCR, western blot analysis and immunofluorescence analysis after adenosine 5'-diphosphate (ADP) exposure in DRG cells. Plasmids encoding ATF3 and its siRNA were used to investigate the role of ATF3 on ADP-induced P2X3 upregulation. The activity of ATF binding to the P2X3 promoter was evaluated by using chromatin immunoprecipitation (CHIP) and luciferase assays. SP600125, an inhibitor of c-JUN N-terminal kinase, was wrapped in CSOSA/LPs delivery system and its inhibitory effects on ADP-induced upregulation of P2X3 in DRG cells and endometriosis-induced hyperalgesia in rats were tested. MAIN RESULTS AND THE ROLE OF CHANCE The concentrations of endogenous ATP and expression levels of P2X3 were significantly increased in both endometriotic lesions and DRG tissues in endometriosis rat models and were found to be positively correlated with the severity of hyperalgesia. In DRG cells, P2X3 expression levels were elevated by ADP stimulation, but dramatically inhibited by blocking ATF3 with its siRNA and SP600125. CHIP and luciferase assay showed that ADP increased the binding of ATF3 to the P2X3 promoter, resulting in an increase in P2X3 expression levels. In the CSOSA/LPs/SP600125 delivery system, the drug could be effectively concentrated in endometriotic lesions, and it could alleviate endometriosis-induced hyperalgesia, reduce the size of endometriotic lesions and attenuate upregulated P2X3 expression levels in endometriosis rat models. LARGE SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION Changes in the sensitivity and function of P2X3 caused by endometriosis need to be further investigated. WIDER IMPLICATIONS OF THE FINDINGS This study indicates that ATP and the P2X3 receptor are involved in endometriosis pain, thus providing a novel therapeutic approach for the treatment of endometriosis pain by targeting the P2X3 receptor. STUDY FUNDING/COMPETING INTEREST(S) This work was funded by National Key R&D Program of China (Grant No. 2017YFC1001202) and National Natural Science Foundation of China (Grant Nos. 81974225, 81671429 and 81471433). There are no competing interests.
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Affiliation(s)
- Shaojie Ding
- Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, Zhejiang, P.R. China
| | - Qin Yu
- Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, Zhejiang, P.R. China
| | - Jianzhang Wang
- Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, Zhejiang, P.R. China
| | - Libo Zhu
- Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, Zhejiang, P.R. China
| | - Tiantian Li
- Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, Zhejiang, P.R. China
| | - Xinyue Guo
- Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, Zhejiang, P.R. China
| | - Xinmei Zhang
- Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, Zhejiang, P.R. China
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25
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Zeng Y, Luo H, Gao Z, Zhu X, Shen Y, Li Y, Hu J, Yang J. Reduction of prefrontal purinergic signaling is necessary for the analgesic effect of morphine. iScience 2021; 24:102213. [PMID: 33733073 PMCID: PMC7940985 DOI: 10.1016/j.isci.2021.102213] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 01/26/2021] [Accepted: 02/17/2021] [Indexed: 01/14/2023] Open
Abstract
Morphine is commonly used to relieve moderate to severe pain, but repeated doses cause opioid tolerance. Here, we used ATP sensor and fiber photometry to detect prefrontal ATP level. It showed that prefrontal ATP level decreased after morphine injection and the event amplitude tended to decrease with continuous morphine exposure. Morphine had little effect on prefrontal ATP due to its tolerance. Therefore, we hypothesized that the analgesic effect of morphine might be related to ATP in the medial prefrontal cortex (mPFC). Moreover, local infusion of ATP partially antagonized morphine analgesia. Then we found that inhibiting P2X7R in the mPFC mimicked morphine analgesia. In morphine-tolerant mice, pretreatment with P2X4R or P2X7R antagonists in the mPFC enhanced analgesic effect. Our findings suggest that reduction of prefrontal purinergic signaling is necessary for the morphine analgesia, which help elucidate the mechanism of morphine analgesia and may lead to the development of new clinical treatments for neuropathic pain.
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Affiliation(s)
- Yeting Zeng
- Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Huoqing Luo
- School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
| | - Zilong Gao
- Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China
- Chinese Institute for Brain Research, Beijing (CIBR), Beijing 102206, China
| | - Xiaona Zhu
- School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
| | - Yinbo Shen
- Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Yulong Li
- Chinese Institute for Brain Research, Beijing (CIBR), Beijing 102206, China
- State Key Laboratory of Membrane Biology, Peking University School of Life Sciences, Beijing 100871, China
- PKU-IDG/McGovern Institute for Brain Research, Beijing 100871, China
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China
| | - Ji Hu
- School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, 200030, China
- Co-innovation Center of Neuroregeneration, Nantong University, Nantong 226019, China
- gCAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai 200030, China
| | - Jiajun Yang
- Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
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26
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Wang M, Cai X, Wang Y, Li S, Wang N, Sun R, Xing J, Liang S, Liu S. Astragalin Alleviates Neuropathic Pain by Suppressing P2X4-Mediated Signaling in the Dorsal Root Ganglia of Rats. Front Neurosci 2021; 14:570831. [PMID: 33505232 PMCID: PMC7829479 DOI: 10.3389/fnins.2020.570831] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 11/18/2020] [Indexed: 01/03/2023] Open
Abstract
Neurologic damage often leads to neuropathic pain, for which there are no effective treatments owing to its complex pathogenesis. The purinergic receptor P2X4 is closely associated with neuropathic pain. Astragalin (AST), a compound that is used in traditional Chinese medicine, has protective effects against allergic dermatitis and neuronal injury, but its mechanism of action is not well understood. The present study investigated whether AST can alleviate neuropathic pain in a rat model established by chronic constriction injury (CCI) to the sciatic nerve. The model rats exhibited pain behavior and showed increased expression of P2X4 and the activated satellite glial cell (SGC) marker glial fibrillary acidic protein in dorsal root ganglia (DRG). AST treatment partly abrogated the upregulation of P2X4, inhibited SGC activation, and alleviated pain behavior in CCI rats; it also suppressed ATP-activated currents in HEK293 cells overexpressing P2X4. These data demonstrate that AST relieves neuropathic pain by inhibiting P2X4 and SGC activation in DRG, highlighting its therapeutic potential for clinical pain management.
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Affiliation(s)
- Mengke Wang
- Department of Physiology, Medical School of Nanchang University, Nanchang, China
| | - Xia Cai
- Department of Endocrinology, Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yueying Wang
- Department of Physiology, Medical School of Nanchang University, Nanchang, China
| | - Shizhen Li
- Undergraduate Student of the Second Clinical Department, Medical School of Nanchang University, Nanchang, China
| | - Na Wang
- Undergraduate Student of the Second Clinical Department, Medical School of Nanchang University, Nanchang, China
| | - Rui Sun
- Undergraduate Student of the Anesthesiology Department, Medical School of Nanchang University, Nanchang, China
| | - Jingming Xing
- Undergraduate Student of the Basic Medical Science Department, Medical School of Nanchang University, Nanchang, China
| | - Shangdong Liang
- Department of Physiology, Medical School of Nanchang University, Nanchang, China
| | - Shuangmei Liu
- Department of Physiology, Medical School of Nanchang University, Nanchang, China
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27
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Sakamoto I, Himi N, Hayashi N, Okabe N, Nakamura-Maruyama E, Tsukamoto I, Hasegawa T, Miyamoto O. The protective effect and mechanism of COA-Cl in acute phase after spinal cord injury. Neurosci Res 2020; 170:114-121. [PMID: 33316301 DOI: 10.1016/j.neures.2020.10.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 09/16/2020] [Accepted: 10/16/2020] [Indexed: 11/28/2022]
Abstract
Spinal cord injury (SCI) induces severe motor and sensory dysfunction. We previously showed the neuroprotective effects of COA-Cl, a novel synthesized adenosine analog, in a rat stroke model. In this study, we evaluated the neuroprotective effects of COA-Cl in acute phase of SCI. SCI was induced in rats at the T9 vertebra by using a drop device. Rats were divided into acute and subacute groups. A 5-day dose of 6 mg/kg COA-Cl in saline was given to the acute group immediately after SCI and the subacute group 4 days after SCI. Motor function assessed by Basso-Beattie-Bresnahan scoring and inclined plane test improved significantly in the acute group while the subacute group did not. Histological evaluation and TUNEL staining revealed that both the cavity volume and apoptosis were significantly decreased in the acute group compared with the subacute group. In addition, pERK/ERK was increased in the acute group 7 days after SCI. These results suggest that COA-Cl exerts neuroprotective effects via the ERK pathway when administered in the acute phase after SCI, resulting in the recovery of motor function. COA-Cl could be a novel therapeutic agent for the acute phase of SCI.
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Affiliation(s)
- Issei Sakamoto
- Department of Physiology 2, Kawasaki Medical School, Matsushima, Kurashiki, Okayama, Japan; Department of Orthopedic Surgery, Kawasaki Medical School, Matsushima, Kurashiki, Okayama, Japan
| | - Naoyuki Himi
- Department of Physiology 2, Kawasaki Medical School, Matsushima, Kurashiki, Okayama, Japan.
| | - Norito Hayashi
- Department of Physiology 2, Kawasaki Medical School, Matsushima, Kurashiki, Okayama, Japan; Department of Orthopedic Surgery, Kawasaki Medical School, Matsushima, Kurashiki, Okayama, Japan
| | - Naohiko Okabe
- Department of Physiology 2, Kawasaki Medical School, Matsushima, Kurashiki, Okayama, Japan
| | - Emi Nakamura-Maruyama
- Department of Physiology 2, Kawasaki Medical School, Matsushima, Kurashiki, Okayama, Japan
| | - Ikuko Tsukamoto
- Department of Pharmaco-bio-informatics, Kagawa University Faculty of Medicine, Miki, Kagawa, Japan
| | - Toru Hasegawa
- Department of Orthopedic Surgery, Kawasaki Medical School, Matsushima, Kurashiki, Okayama, Japan
| | - Osamu Miyamoto
- Department of Physiology 2, Kawasaki Medical School, Matsushima, Kurashiki, Okayama, Japan
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Effect of PKC/NF- κB on the Regulation of P2X 3 Receptor in Dorsal Root Ganglion in Rats with Sciatic Nerve Injury. Pain Res Manag 2020; 2020:7104392. [PMID: 33014214 PMCID: PMC7519985 DOI: 10.1155/2020/7104392] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Accepted: 09/01/2020] [Indexed: 11/17/2022]
Abstract
Background Protein kinase C (PKC), nuclear factor-kappa B p65 (NF-κB p65), and P2X3 receptor (P2X3R) play significant roles in the sensitization and transduction of nociceptive signals, which are considered as potential targets for the treatment of neuropathic pain. However, the mechanisms and relationships among them have not been clearly clarified. Methods 80 rats were randomized and divided into 10 groups (n = 8). Sciatic chronic constriction injury (CCI) rats were intrathecally administered with bisindolylmaleimide I (GF109203X), a PKC-selective antagonist once a day, or pyrrolidine dithiocarbamate (PDTC), an NF-κB inhibitor twice a day. Sham-operated rats were intrathecally administered with saline. Thermal withdrawal latency (TWL) and mechanical withdrawal threshold (MWT) were evaluated in all the groups before CCI operation (baseline) and on the 1st, 3rd, 7th, 10th, and 14th day after CCI operation. Protein levels of p-PKCα, p-NF-κB p65, and P2X3R were analyzed in the CCI ipsilateral L4-6 dorsal root ganglions (DRGs). Results Intrathecal injection of GF109203X or PDTC alleviated the TWL and MWT in the following 2 weeks after CCI surgery. The protein levels of p-PKCα, p-NF-κB p65, and P2X3R in the ipsilateral DRGs significantly increased after CCI operation, which could be partly reversed by intrathecal administration of GF109203X or PDTC. Conclusion The upregulation of p-PKCα, p-NF-κB p65, and P2X3R expression in the DRGs of CCI rats was involved in the occurrence and development of neuropathic pain. Phosphorylated PKCα and phosphorylated NF-κB p65 regulated with each other. Phosphorylated NF-κB p65 and PKCα have a mutual regulation relationship with P2X3R, respectively, while the specific regulatory mechanism needs further research.
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Implication of Neuronal Versus Microglial P2X4 Receptors in Central Nervous System Disorders. Neurosci Bull 2020; 36:1327-1343. [PMID: 32889635 DOI: 10.1007/s12264-020-00570-y] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 05/06/2020] [Indexed: 02/08/2023] Open
Abstract
The P2X4 receptor (P2X4) is an ATP-gated cation channel that is highly permeable to Ca2+ and widely expressed in neuronal and glial cell types throughout the central nervous system (CNS). A growing body of evidence indicates that P2X4 plays key roles in numerous central disorders. P2X4 trafficking is highly regulated and consequently in normal situations, P2X4 is present on the plasma membrane at low density and found mostly within intracellular endosomal/lysosomal compartments. An increase in the de novo expression and/or surface density of P2X4 has been observed in microglia and/or neurons during pathological states. This review aims to summarize knowledge on P2X4 functions in CNS disorders and provide some insights into the relative contributions of neuronal and glial P2X4 in pathological contexts. However, determination of the cell-specific functions of P2X4 along with its intracellular and cell surface roles remain to be elucidated before its potential as a therapeutic target in multiple disorders can be defined.
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Retrograde Labeling of Different Distribution Features of DRG P2X2 and P2X3 Receptors in a Neuropathic Pain Rat Model. BIOMED RESEARCH INTERNATIONAL 2020; 2020:9861459. [PMID: 32775458 PMCID: PMC7396081 DOI: 10.1155/2020/9861459] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 07/03/2020] [Accepted: 07/08/2020] [Indexed: 12/25/2022]
Abstract
The distributions of P2X subtypes during peripheral neuropathic pain conditions and their differential roles are not fully understood. To explore these characteristics, the lumbosacral dorsal root ganglion (DRG) in the chronic constriction injury (CCI) sciatic nerve rat model was studied. Retrograde trace labeling combined with immunofluorescence technology was applied to analyze the distribution of neuropathic nociceptive P2X1-6 receptors. Our results suggest that Fluoro-Gold (FG) retrograde trace labeling is an efficient method for studying lumbosacral DRG neurons in the CCI rat model, especially when the DRG neurons are divided into small, medium, and large subgroups. We found that neuropathic nociceptive lumbosacral DRG neurons (i.e., FG-positive cells) were significantly increased in medium DRG neurons, while they declined in the large DRG neurons in the CCI group. P2X3 receptors were markedly upregulated in medium while P2X2 receptors were significantly decreased in small FG-positive DRG neurons. There were no significant changes in other P2X receptors (including P2X1, P2X4, P2X5, and P2X6). We anticipate that P2X receptors modulate nociceptive sensitivity primarily through P2X3 subtypes that are upregulated in medium neuropathic nociceptive DRG neurons and/or via the downregulation of P2X2 cells in neuropathic nociceptive small DRG neurons.
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Neves AF, Farias FH, de Magalhães SF, Araldi D, Pagliusi M, Tambeli CH, Sartori CR, Lotufo CMDC, Parada CA. Peripheral Inflammatory Hyperalgesia Depends on P2X7 Receptors in Satellite Glial Cells. Front Physiol 2020; 11:473. [PMID: 32523543 PMCID: PMC7261868 DOI: 10.3389/fphys.2020.00473] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Accepted: 04/17/2020] [Indexed: 12/23/2022] Open
Abstract
Peripheral inflammatory hyperalgesia depends on the sensitization of primary nociceptive neurons. Inflammation drives molecular alterations not only locally but also in the dorsal root ganglion (DRG) where interleukin-1 beta (IL-1β) and purinoceptors are upregulated. Activation of the P2X7 purinoceptors by ATP is essential for IL-1β maturation and release. At the DRG, P2X7R are expressed by satellite glial cells (SGCs) surrounding sensory neurons soma. Although SGCs have no projections outside the sensory ganglia these cells affect pain signaling through intercellular communication. Therefore, here we investigated whether activation of P2X7R by ATP and the subsequent release of IL-1β in DRG participate in peripheral inflammatory hyperalgesia. Immunofluorescent images confirmed the expression of P2X7R and IL-1β in SGCs of the DRG. The function of P2X7R was then verified using a selective antagonist, A-740003, or antisense for P2X7R administered in the L5-DRG. Inflammation was induced by CFA, carrageenan, IL-1β, or PGE2 administered in rat's hind paw. Blockage of P2X7R at the DRG reduced the mechanical hyperalgesia induced by CFA, and prevented the mechanical hyperalgesia induced by carrageenan or IL-1β, but not PGE2. It was also found an increase in P2X7 mRNA expression at the DRG after peripheral inflammation. IL-1β production was also increased by inflammatory stimuli in vivo and in vitro, using SGC-enriched cultures stimulated with LPS. In LPS-stimulated cultures, activation of P2X7R by BzATP induced the release of IL-1β, which was blocked by A-740003. In summary, our data suggest that peripheral inflammation leads to the activation of P2X7R expressed by SGCs at the DRG. Then, ATP-induced activation of P2X7R mediates the release of IL-1β from SGC. This evidence places the SGC as an active player in the establishment of peripheral inflammatory hyperalgesia and highlights the importance of the events in DRG for the treatment of inflammatory diseases.
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Affiliation(s)
- Amanda Ferreira Neves
- Department of Structural and Functional Biology, Institute of Biology, University of Campinas, Campinas, Brazil
| | - Felipe Hertzing Farias
- Department of Structural and Functional Biology, Institute of Biology, University of Campinas, Campinas, Brazil
| | | | - Dionéia Araldi
- Department of Structural and Functional Biology, Institute of Biology, University of Campinas, Campinas, Brazil
| | - Marco Pagliusi
- Department of Structural and Functional Biology, Institute of Biology, University of Campinas, Campinas, Brazil
| | - Claudia Herrera Tambeli
- Department of Structural and Functional Biology, Institute of Biology, University of Campinas, Campinas, Brazil
| | - Cesar Renato Sartori
- Department of Structural and Functional Biology, Institute of Biology, University of Campinas, Campinas, Brazil
| | | | - Carlos Amílcar Parada
- Department of Structural and Functional Biology, Institute of Biology, University of Campinas, Campinas, Brazil
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32
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Zhang WJ, Zhu ZM, Liu ZX. The role and pharmacological properties of the P2X7 receptor in neuropathic pain. Brain Res Bull 2020; 155:19-28. [PMID: 31778766 DOI: 10.1016/j.brainresbull.2019.11.006] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Revised: 11/03/2019] [Accepted: 11/11/2019] [Indexed: 02/07/2023]
Abstract
Neuropathic Pain (NPP) is caused by direct or indirect damage to the nervous system and is a common symptom of many diseases. Clinically, drugs are usually used to suppress pain, such as (lidocaine, morphine, etc.), but the effect is short-lived, poor analgesia, and there are certain dependence and side effects. Therefore, the investigation of the treatment of NPP has become an urgent problem in medical, attracting a lot of research attention. P2X7 is dependent on Adenosine triphosphate (ATP) ion channel receptors and has dual functions for the development of nerve damage and pain. In this review, we explored the link between the P2X7 receptor (P2X7R) and NPP, providing insight into the P2X7R and NPP, discussing the pathological mechanism of P2 X7R in NPP and the biological characteristics of P2X7R antagonist inhibiting its over-expression for the targeted therapy of NPP.
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Affiliation(s)
- Wen-Jun Zhang
- The Second Affiliate Hospital. Nanchang University, Nanchang City. Jiangxi Province, China; Basic Medical School, Nanchang University, Nanchang City, Jiangxi Province, China
| | - Zheng-Ming Zhu
- The Second Affiliate Hospital. Nanchang University, Nanchang City. Jiangxi Province, China.
| | - Zeng-Xu Liu
- Basic Medical School, Nanchang University, Nanchang City, Jiangxi Province, China
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33
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Zhao S, Zhou Y, Fan Y, Gong Y, Yang J, Yang R, Li L, Zou L, Xu X, Li G, Liu S, Zhang C, Li G, Liang S. Involvement of purinergic 2X 4 receptor in glycoprotein 120-induced pyroptosis in dorsal root ganglia. J Neurochem 2019; 151:584-594. [PMID: 31418825 DOI: 10.1111/jnc.14850] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Revised: 08/22/2019] [Accepted: 08/08/2019] [Indexed: 12/11/2022]
Abstract
Pyroptosis is a type of programmed cell death, displaying caspase-1-dependent and pro-inflammatory features. Purinergic 2X4 (P2X4 ) receptor activation in response to high-adenosine triphosphate release can induce inflammation. Envelope glycoprotein 120 (gp120) of human immunodeficiency virus type 1 is considered one of the primary pathogens leading to neuronal injury. In this study, we investigated the possible role of P2X4 receptor activation in gp120-triggered pyroptosis in cultured satellite glial cells (SGCs) of rat dorsal root ganglia (DRG). MTS assay, TdT-mediated dUTP Nick-end labeling assay, real-time RT-PCR, and western blotting et al. methods were used. The results indicated that the expression of P2X4 receptor in SGCs of DRG was up-regulated upon cultured with gp120 for 24 h. The highest decrease in viability of SGCs due to gp120 treatment was accompanied by marked increases of positive pyroptosis cells and cellular lactate dehydrogenase release, elevated levels of interleukin-1β, interleukin-18, active caspase-1 and NOD-like receptor family, pyrin domain containing 1, and enhanced phosphorylation of p38MAPK. These abnormal changes because of gp120 were significantly inhibited and cell viability was markedly improved when SGCs of DRG were treated with short hairpin RNAs targeting P2X4 receptor. Our data suggest that silencing of P2X4 receptor may act effectively against gp120-induced pyroptosis mediated by the activation of NOD-like receptor family, pyrin domain containing 1 inflammasome and caspase-1 signaling in SGCs of DRG.
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Affiliation(s)
- Shanhong Zhao
- Neuropharmacology Laboratory of Physiology Department, Basic Medical College of Nanchang University, Nanchang, Jiangxi, P.R. China.,Jiangxi Provincial Key Laboratory of autonomic nervous function and disease, Nanchang, Jiangxi, P.R. China
| | - Yanhong Zhou
- Undergraduate student of Medical College of Nanchang University, Nanchang, Jiangxi, P.R. China
| | - Yang Fan
- Undergraduate student of Medical College of Nanchang University, Nanchang, Jiangxi, P.R. China
| | - Yingxin Gong
- Undergraduate student of Medical College of Nanchang University, Nanchang, Jiangxi, P.R. China
| | - Jingjian Yang
- Undergraduate student of Medical College of Nanchang University, Nanchang, Jiangxi, P.R. China
| | - Runan Yang
- Neuropharmacology Laboratory of Physiology Department, Basic Medical College of Nanchang University, Nanchang, Jiangxi, P.R. China.,Jiangxi Provincial Key Laboratory of autonomic nervous function and disease, Nanchang, Jiangxi, P.R. China
| | - Lin Li
- Neuropharmacology Laboratory of Physiology Department, Basic Medical College of Nanchang University, Nanchang, Jiangxi, P.R. China.,Jiangxi Provincial Key Laboratory of autonomic nervous function and disease, Nanchang, Jiangxi, P.R. China
| | - Lifang Zou
- Neuropharmacology Laboratory of Physiology Department, Basic Medical College of Nanchang University, Nanchang, Jiangxi, P.R. China.,Jiangxi Provincial Key Laboratory of autonomic nervous function and disease, Nanchang, Jiangxi, P.R. China
| | - Xiumei Xu
- Neuropharmacology Laboratory of Physiology Department, Basic Medical College of Nanchang University, Nanchang, Jiangxi, P.R. China.,Jiangxi Provincial Key Laboratory of autonomic nervous function and disease, Nanchang, Jiangxi, P.R. China
| | - Guilin Li
- Neuropharmacology Laboratory of Physiology Department, Basic Medical College of Nanchang University, Nanchang, Jiangxi, P.R. China.,Jiangxi Provincial Key Laboratory of autonomic nervous function and disease, Nanchang, Jiangxi, P.R. China
| | - Shuangmei Liu
- Neuropharmacology Laboratory of Physiology Department, Basic Medical College of Nanchang University, Nanchang, Jiangxi, P.R. China.,Jiangxi Provincial Key Laboratory of autonomic nervous function and disease, Nanchang, Jiangxi, P.R. China
| | - Chunping Zhang
- Neuropharmacology Laboratory of Physiology Department, Basic Medical College of Nanchang University, Nanchang, Jiangxi, P.R. China.,Department of Cell Biology, Medical School of Nanchang University, Nanchang, Jiangxi, P.R. China
| | - Guodong Li
- Neuropharmacology Laboratory of Physiology Department, Basic Medical College of Nanchang University, Nanchang, Jiangxi, P.R. China.,Jiangxi Provincial Key Laboratory of autonomic nervous function and disease, Nanchang, Jiangxi, P.R. China
| | - Shangdong Liang
- Neuropharmacology Laboratory of Physiology Department, Basic Medical College of Nanchang University, Nanchang, Jiangxi, P.R. China.,Jiangxi Provincial Key Laboratory of autonomic nervous function and disease, Nanchang, Jiangxi, P.R. China
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Gong Y, Zhou Y, Yang J, Li S, Wang Z, Rao J, Li L, Yuan H, Shi L, Yang R, Xu X, Liu S, Liang S, Zou L. Abnormal sympathetic activity after myocardial ischemia involving P2X4 in dorsal root ganglia. Brain Res Bull 2019; 149:216-221. [PMID: 31051227 DOI: 10.1016/j.brainresbull.2019.04.024] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Revised: 04/19/2019] [Accepted: 04/24/2019] [Indexed: 12/30/2022]
Abstract
The satellite glial cells (SGCs) of the dorsal root ganglia (DRG) expressed P2X4 receptor. In this study, we investigated the abnormal sympathetic activity after myocardial ischemia (MI) involving P2X4 receptor in the cervical DRG SGC. The results showed that MI injury upregulated the P2X4 receptor mRNA and protein in DRG, and the upregulated P2X4 receptor was co-localized with glial fibrillary acidic protein (GFAP) in DRG SGCs. P2X4 short hairpin RNA (shRNA) treatment decreased the expression of P2X4 receptor, counteracted the upregulation of GFAP and IL-1β and inhibited P38MAPK phosphorylation in DRG of MI rats. These results indicate that application of P2X4 shRNA may reduce P2X4-mediated nociceptive signal via inhibiting DRG afferents to alleviate the abnormal sympathetic activity induced by MI.
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Affiliation(s)
- Yingxin Gong
- Undergraduate student of Medical School of Nanchang University, Nanchang, Jiangxi, 330006, People's Republic of China
| | - Yanhong Zhou
- Undergraduate student of Medical School of Nanchang University, Nanchang, Jiangxi, 330006, People's Republic of China
| | - Jingjian Yang
- Undergraduate student of Medical School of Nanchang University, Nanchang, Jiangxi, 330006, People's Republic of China
| | - Shunhua Li
- Undergraduate student of Medical School of Nanchang University, Nanchang, Jiangxi, 330006, People's Republic of China
| | - Zilin Wang
- Undergraduate student of Medical School of Nanchang University, Nanchang, Jiangxi, 330006, People's Republic of China
| | - Jingan Rao
- Undergraduate student of Medical School of Nanchang University, Nanchang, Jiangxi, 330006, People's Republic of China
| | - Lin Li
- Neuropharmacology Laboratory of Physiology Department, Medical School of Nanchang University, Nanchang, Jiangxi, 330006, People's Republic of China; Jiangxi Provincial Key Laboratory of autonomic nervous function and disease, Nanchang, Jiangxi, 330006, People's Republic of China
| | - Huilong Yuan
- Neuropharmacology Laboratory of Physiology Department, Medical School of Nanchang University, Nanchang, Jiangxi, 330006, People's Republic of China; Jiangxi Provincial Key Laboratory of autonomic nervous function and disease, Nanchang, Jiangxi, 330006, People's Republic of China
| | - Liran Shi
- Neuropharmacology Laboratory of Physiology Department, Medical School of Nanchang University, Nanchang, Jiangxi, 330006, People's Republic of China; Jiangxi Provincial Key Laboratory of autonomic nervous function and disease, Nanchang, Jiangxi, 330006, People's Republic of China
| | - Runan Yang
- Neuropharmacology Laboratory of Physiology Department, Medical School of Nanchang University, Nanchang, Jiangxi, 330006, People's Republic of China; Jiangxi Provincial Key Laboratory of autonomic nervous function and disease, Nanchang, Jiangxi, 330006, People's Republic of China
| | - Xiumei Xu
- Neuropharmacology Laboratory of Physiology Department, Medical School of Nanchang University, Nanchang, Jiangxi, 330006, People's Republic of China; Jiangxi Provincial Key Laboratory of autonomic nervous function and disease, Nanchang, Jiangxi, 330006, People's Republic of China
| | - Shuangmei Liu
- Neuropharmacology Laboratory of Physiology Department, Medical School of Nanchang University, Nanchang, Jiangxi, 330006, People's Republic of China; Jiangxi Provincial Key Laboratory of autonomic nervous function and disease, Nanchang, Jiangxi, 330006, People's Republic of China
| | - Shangdong Liang
- Neuropharmacology Laboratory of Physiology Department, Medical School of Nanchang University, Nanchang, Jiangxi, 330006, People's Republic of China; Jiangxi Provincial Key Laboratory of autonomic nervous function and disease, Nanchang, Jiangxi, 330006, People's Republic of China.
| | - Lifang Zou
- Neuropharmacology Laboratory of Physiology Department, Medical School of Nanchang University, Nanchang, Jiangxi, 330006, People's Republic of China; Jiangxi Provincial Key Laboratory of autonomic nervous function and disease, Nanchang, Jiangxi, 330006, People's Republic of China.
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Zou L, Yu K, Fan Y, Cao S, Liu S, Shi L, Li L, Yuan H, Yang R, Yi Z, Gao Y, Li G, Greffrath W, Treede RD, Li M, Xu H, Zhang C, Liang S. The Inhibition by Guanfu Base A of Neuropathic Pain Mediated by P2Y 12 Receptor in Dorsal Root Ganglia. ACS Chem Neurosci 2019; 10:1318-1325. [PMID: 30475578 DOI: 10.1021/acschemneuro.8b00399] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Activation of satellite glial cells (SGCs) in the dorsal root ganglia (DRG) is involved in mechanical and thermal hyperalgesia. The upregulated P2Y12 receptor expressed in SGCs of the DRG participates in the nociceptive transmission of neuropathic pain. Guanfu base A (GFA) has been reported to exhibit antiarrhythmic and anti-inflammatory effects. In this study, we explored the effects of GFA on P2Y12 receptor-mediated mechanical and thermal hyperalgesia in chronic constriction injury (CCI) rats. Sprague-Dawley rats were randomly divided into sham operation group (Sham), CCI operation group (CCI), CCI rats treated with guanfu base A group (CCI + GFA) and control rats treated with GFA group (Ctrl + GFA). Mechanical withdrawal threshold and thermal withdrawal latency were measured. P2Y12 expression in L4-L6 dorsal root ganglion (DRG) was detected by quantitative real-time PCR and Western blot. After CCI treatment, mechanical and thermal hyperalgesia and the expression values of P2Y12 receptor mRNA and protein in DRG were increased. Dual-labeling immunofluorescence showed that the coexpression of P2Y12 receptor and glial fibrillary acidic protein (GFAP) in the DRG of CCI rats was increased compared to sham rats. GFA relieved mechanical and thermal hyperalgesia in the CCI rats, decreased the expression of P2Y12 mRNA and protein and phosphorylation of p38 MAPK in the DRG, and increased the ADP-downregulated cAMP concentrations in HEK293 cells transfected with P2Y12 plasmid. After CCI rats were treated with GFA, the coexpression of P2Y12 receptor and GFAP in the DRG was significantly decreased compared to the untreated CCI group. Thus, downregulating the P2Y12 receptor relieved mechanical and thermal hyperalgesia in the CCI rats.
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Affiliation(s)
- Lifang Zou
- Neuropharmacology Laboratory of Physiology Department, Medical School of Nanchang University, Nanchang, Jiangxi 330006, PR China
| | - Kehua Yu
- Medical Laboratory Center of Nanchang University, Nanchang, Jiangxi 330006, People’s Republic of China
| | - Yang Fan
- Undergraduate student of Clinic Medicine Department, Medical School of Nanchang University, Nanchang, Jiangxi 330006, PR China
| | - Suixia Cao
- Undergraduate student of Clinic Medicine Department, Medical School of Nanchang University, Nanchang, Jiangxi 330006, PR China
| | - Shuangmei Liu
- Neuropharmacology Laboratory of Physiology Department, Medical School of Nanchang University, Nanchang, Jiangxi 330006, PR China
| | - Liran Shi
- Neuropharmacology Laboratory of Physiology Department, Medical School of Nanchang University, Nanchang, Jiangxi 330006, PR China
| | - Lin Li
- Neuropharmacology Laboratory of Physiology Department, Medical School of Nanchang University, Nanchang, Jiangxi 330006, PR China
| | - Huilong Yuan
- Neuropharmacology Laboratory of Physiology Department, Medical School of Nanchang University, Nanchang, Jiangxi 330006, PR China
| | - Runan Yang
- Neuropharmacology Laboratory of Physiology Department, Medical School of Nanchang University, Nanchang, Jiangxi 330006, PR China
| | - Zhihua Yi
- Neuropharmacology Laboratory of Physiology Department, Medical School of Nanchang University, Nanchang, Jiangxi 330006, PR China
| | - Yun Gao
- Neuropharmacology Laboratory of Physiology Department, Medical School of Nanchang University, Nanchang, Jiangxi 330006, PR China
| | - Guilin Li
- Neuropharmacology Laboratory of Physiology Department, Medical School of Nanchang University, Nanchang, Jiangxi 330006, PR China
| | - Wolfgang Greffrath
- Department of Neurophysiology, Centre for Biomedicine and Medical Technology Mannheim, Heidelberg University, Mannheim 68167, Germany
| | - Rolf-Detlef Treede
- Department of Neurophysiology, Centre for Biomedicine and Medical Technology Mannheim, Heidelberg University, Mannheim 68167, Germany
| | - Man Li
- Department of Neurobiology, Tongji Medical College of Huazhong University of Science and Technology, Wuhan 430030, China
| | - Hong Xu
- Neuropharmacology Laboratory of Physiology Department, Medical School of Nanchang University, Nanchang, Jiangxi 330006, PR China
| | - Chunping Zhang
- Department of Cell Biology, Medical School of Nanchang University, Nanchang, Jiangxi 330006, PR China
| | - Shangdong Liang
- Neuropharmacology Laboratory of Physiology Department, Medical School of Nanchang University, Nanchang, Jiangxi 330006, PR China
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Yang R, Li L, Yuan H, Liu H, Gong Y, Zou L, Li S, Wang Z, Shi L, Jia T, Zhao S, Wu B, Yi Z, Gao Y, Li G, Xu H, Liu S, Zhang C, Li G, Liang S. Quercetin relieved diabetic neuropathic pain by inhibiting upregulated P2X 4 receptor in dorsal root ganglia. J Cell Physiol 2019; 234:2756-2764. [DOI: 10.1002/jcp.27091] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Accepted: 06/29/2018] [Indexed: 08/30/2023]
Abstract
The upregulation of nociceptive ion channels expressed in dorsal root ganglia (DRG) contributes to the development and retaining of diabetic pain symptoms. The flavonoid quercetin (3,3′,4′,5,7‐pentahydroxyflavone) is a component extracted from various fruits and vegetables and exerts anti‐inflammatory, analgesic, anticarcinogenic, antiulcer, and antihypertensive effects. However, the exact mechanism underlying quercetin's analgesic action remains poorly understood. The aim of this study was to investigate the effects of quercetin on diabetic neuropathic pain related to the P2X4 receptor in the DRG of type 2 diabetic rat model. Our data showed that both mechanical withdrawal threshold and thermal withdrawal latency in diabetic rats treated with quercetin were higher compared with those in untreated diabetic rats. The expression levels of P2X4 messenger RNA and protein in the DRG of diabetic rats were increased compared with the control rats, while quercetin treatment significantly inhibited such enhanced P2X4 expression in diabetic rats. The satellite glial cells (SGCs) enwrap the neuronal soma in the DRG. Quercetin treatment also lowered the elevated coexpression of P2X4 and glial fibrillary acidic protein (a marker of SGCs) and decreased the upregulation of phosphorylated p38 mitogen‐activated protein kinase (p38MAPK) in the DRG of diabetic rats. Quercetin significantly reduced the P2X4 agonist adenosine triphosphate‐activated currents in HEK293 cells transfected with P2X4 receptors. Thus, our data demonstrate that quercetin may decrease the upregulation of the P2X4 receptor in DRG SGCs, and consequently inhibit P2X4 receptor‐mediated p38MAPK activation to relieve the mechanical and thermal hyperalgesia in diabetic rats.
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Affiliation(s)
- Runan Yang
- Department of Physiology Medical School of Nanchang University Nanchang China
- Jiangxi Provincial Key Laboratory Autonomic Nervous Function and Disease Nanchang China
| | - Lin Li
- Department of Physiology Medical School of Nanchang University Nanchang China
- Jiangxi Provincial Key Laboratory Autonomic Nervous Function and Disease Nanchang China
| | - Huilong Yuan
- Department of Physiology Medical School of Nanchang University Nanchang China
- Jiangxi Provincial Key Laboratory Autonomic Nervous Function and Disease Nanchang China
| | - Hui Liu
- Department of Physiology Medical School of Nanchang University Nanchang China
- Jiangxi Provincial Key Laboratory Autonomic Nervous Function and Disease Nanchang China
| | - Yingxin Gong
- Clinical Department Medical School of Nanchang University Nanchang China
| | - Lifang Zou
- Department of Physiology Medical School of Nanchang University Nanchang China
- Jiangxi Provincial Key Laboratory Autonomic Nervous Function and Disease Nanchang China
| | - Shunhua Li
- Clinical Department Medical School of Nanchang University Nanchang China
| | - Zilin Wang
- Clinical Department Medical School of Nanchang University Nanchang China
| | - Liran Shi
- Department of Physiology Medical School of Nanchang University Nanchang China
- Jiangxi Provincial Key Laboratory Autonomic Nervous Function and Disease Nanchang China
| | - Tianyu Jia
- Department of Physiology Medical School of Nanchang University Nanchang China
- Jiangxi Provincial Key Laboratory Autonomic Nervous Function and Disease Nanchang China
| | - Shanhong Zhao
- Department of Physiology Medical School of Nanchang University Nanchang China
- Jiangxi Provincial Key Laboratory Autonomic Nervous Function and Disease Nanchang China
| | - Bing Wu
- Department of Physiology Medical School of Nanchang University Nanchang China
- Jiangxi Provincial Key Laboratory Autonomic Nervous Function and Disease Nanchang China
| | - Zhihua Yi
- Department of Physiology Medical School of Nanchang University Nanchang China
- Jiangxi Provincial Key Laboratory Autonomic Nervous Function and Disease Nanchang China
| | - Yun Gao
- Department of Physiology Medical School of Nanchang University Nanchang China
- Jiangxi Provincial Key Laboratory Autonomic Nervous Function and Disease Nanchang China
| | - Guilin Li
- Department of Physiology Medical School of Nanchang University Nanchang China
- Jiangxi Provincial Key Laboratory Autonomic Nervous Function and Disease Nanchang China
| | - Hong Xu
- Department of Physiology Medical School of Nanchang University Nanchang China
- Jiangxi Provincial Key Laboratory Autonomic Nervous Function and Disease Nanchang China
| | - Shuangmei Liu
- Department of Physiology Medical School of Nanchang University Nanchang China
- Jiangxi Provincial Key Laboratory Autonomic Nervous Function and Disease Nanchang China
| | - Chunping Zhang
- Jiangxi Provincial Key Laboratory Autonomic Nervous Function and Disease Nanchang China
- Department of Cell Biology Medical School of Nanchang University Nanchang China
| | - Guodong Li
- Department of Physiology Medical School of Nanchang University Nanchang China
- Jiangxi Provincial Key Laboratory Autonomic Nervous Function and Disease Nanchang China
| | - Shangdong Liang
- Department of Physiology Medical School of Nanchang University Nanchang China
- Jiangxi Provincial Key Laboratory Autonomic Nervous Function and Disease Nanchang China
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Mitchell R, Campbell G, Mikolajczak M, McGill K, Mahad D, Fleetwood-Walker SM. A Targeted Mutation Disrupting Mitochondrial Complex IV Function in Primary Afferent Neurons Leads to Pain Hypersensitivity Through P2Y 1 Receptor Activation. Mol Neurobiol 2019; 56:5917-5933. [PMID: 30689196 DOI: 10.1007/s12035-018-1455-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Accepted: 12/14/2018] [Indexed: 01/20/2023]
Abstract
As mitochondrial dysfunction is evident in neurodegenerative disorders that are accompanied by pain, we generated inducible mutant mice with disruption of mitochondrial respiratory chain complex IV, by COX10 deletion limited to sensory afferent neurons through the use of an Advillin Cre-reporter. COX10 deletion results in a selective energy-deficiency phenotype with minimal production of reactive oxygen species. Mutant mice showed reduced activity of mitochondrial respiratory chain complex IV in many sensory neurons, increased ADP/ATP ratios in dorsal root ganglia and dorsal spinal cord synaptoneurosomes, as well as impaired mitochondrial membrane potential, in these synaptoneurosome preparations. These changes were accompanied by marked pain hypersensitivity in mechanical and thermal (hot and cold) tests without altered motor function. To address the underlying basis, we measured Ca2+ fluorescence responses of dorsal spinal cord synaptoneurosomes to activation of the GluK1 (kainate) receptor, which we showed to be widely expressed in small but not large nociceptive afferents, and is minimally expressed elsewhere in the spinal cord. Synaptoneurosomes from mutant mice showed greatly increased responses to GluK1 agonist. To explore whether altered nucleotide levels may play a part in this hypersensitivity, we pharmacologically interrogated potential roles of AMP-kinase and ADP-sensitive purinergic receptors. The ADP-sensitive P2Y1 receptor was clearly implicated. Its expression in small nociceptive afferents was increased in mutants, whose in vivo pain hypersensitivity, in mechanical, thermal and cold tests, was reversed by a selective P2Y1 antagonist. Energy depletion and ADP elevation in sensory afferents, due to mitochondrial respiratory chain complex IV deficiency, appear sufficient to induce pain hypersensitivity, by ADP activation of P2Y1 receptors.
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MESH Headings
- Adenosine Diphosphate/metabolism
- Adenosine Monophosphate/metabolism
- Alkyl and Aryl Transferases/metabolism
- Animals
- Behavior, Animal
- Calcium/metabolism
- Cells, Cultured
- Electron Transport Complex IV/genetics
- Electron Transport Complex IV/metabolism
- Fluorescence
- Ganglia, Spinal/drug effects
- Ganglia, Spinal/metabolism
- Hypersensitivity/complications
- Hypersensitivity/pathology
- Membrane Proteins/metabolism
- Mice, Inbred C57BL
- Mice, Transgenic
- Mitochondria/drug effects
- Mitochondria/metabolism
- Mutation/genetics
- Neurons, Afferent/drug effects
- Neurons, Afferent/metabolism
- Neurons, Afferent/pathology
- Nociception/drug effects
- Pain/complications
- Pain/pathology
- Phenotype
- Purinergic P2Y Receptor Antagonists/pharmacology
- Receptors, Kainic Acid/metabolism
- Receptors, Purinergic P2Y1/metabolism
- Spinal Cord/pathology
- Synapses/drug effects
- Synapses/metabolism
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Affiliation(s)
- Rory Mitchell
- Centre for Discovery Brain Sciences, Edinburgh Medical School: Biomedical Sciences, College of Medicine and Veterinary Medicine, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK
| | - Graham Campbell
- Centre for Clinical Brain Sciences, Edinburgh Medical School, College of Medicine and Veterinary Medicine, University of Edinburgh, Chancellor's Building, Little France, Edinburgh, Edinburgh, EH16 4SB, UK
| | - Marta Mikolajczak
- Centre for Discovery Brain Sciences, Edinburgh Medical School: Biomedical Sciences, College of Medicine and Veterinary Medicine, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK
| | - Katie McGill
- Centre for Clinical Brain Sciences, Edinburgh Medical School, College of Medicine and Veterinary Medicine, University of Edinburgh, Chancellor's Building, Little France, Edinburgh, Edinburgh, EH16 4SB, UK
| | - Don Mahad
- Centre for Clinical Brain Sciences, Edinburgh Medical School, College of Medicine and Veterinary Medicine, University of Edinburgh, Chancellor's Building, Little France, Edinburgh, Edinburgh, EH16 4SB, UK
| | - Sue M Fleetwood-Walker
- Centre for Discovery Brain Sciences, Edinburgh Medical School: Biomedical Sciences, College of Medicine and Veterinary Medicine, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK.
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Wang S, Wang Z, Li L, Zou L, Gong Y, Jia T, Zhao S, Yuan H, Shi L, Liu S, Wu B, Yi Z, Liu H, Gao Y, Li G, Deussing JM, Li M, Zhang C, Liang S. P2Y12 shRNA treatment decreases SGC activation to relieve diabetic neuropathic pain in type 2 diabetes mellitus rats. J Cell Physiol 2018; 233:9620-9628. [DOI: 10.1002/jcp.26867] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Accepted: 05/23/2018] [Indexed: 08/30/2023]
Abstract
Diabetic neuropathic pain is a common complication of type 2 diabetes mellitus (DM). Activation of satellite glial cells (SGCs) in the dorsal root ganglia (DRG) plays a crucial role in neuropathic pain through the release of proinflammatory cytokines. The P2Y12 receptor is expressed in SGCs of the DRG. In this study, our aim was to investigate the role of the P2Y12 receptor on the pathological changes in diabetic neuropathic pain. The present study showed that diabetic neuropathic pain increased mechanical and thermal hyperalgesia in type 2 DM model rats. The results showed that the expression levels of P2Y12 messenger RNA (mRNA) and protein in DRG SGCs were increased in DM model rats compared with control rats. Glial fibrillary acidic protein (GFAP) and interleukin‐1β (IL‐1β) expression levels in the DRG were increased in DM rats. Upregulation of GFAP is a marker of SGC activation. Targeting the P2Y12 receptor by short hairpin RNA (shRNA) decreased the upregulated expression of P2Y12 mRNA and protein, coexpression of P2Y12 and GFAP, the expression of GFAP, IL‐1β, and tumor necrosis factor‐receptor 1 in the DRG of DM rats, and relieved mechanical and thermal hyperalgesia in DM rats. After treatment with the P2Y12 receptor shRNA, the enhancing integrated OPTICAL density (IOD) ratios of p‐P38 MAPK to P38 mitogen activated protein kinase (MAPK) in the DM rats treated with P2Y12 shRNA were significantly lower than that in the untreated DM rats. Therefore, P2Y12 shRNA treatment decreased SGC activation to relieve mechanical and thermal hyperalgesia in DM rats.
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Affiliation(s)
- Shouyu Wang
- Department of Physiology Medical School of Nanchang University Nanchang Jiangxi China
- Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease Nanchang University Nanchang Jiangxi China
| | - Zilin Wang
- Queen Mary School Medical School of Nanchang University Nanchang Jiangxi China
| | - Lin Li
- Department of Physiology Medical School of Nanchang University Nanchang Jiangxi China
- Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease Nanchang University Nanchang Jiangxi China
| | - Lifang Zou
- Department of Physiology Medical School of Nanchang University Nanchang Jiangxi China
- Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease Nanchang University Nanchang Jiangxi China
| | - Yingxin Gong
- The Clinical Department Medical School of Nanchang University Nanchang Jiangxi China
| | - Tianyu Jia
- Department of Physiology Medical School of Nanchang University Nanchang Jiangxi China
- Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease Nanchang University Nanchang Jiangxi China
| | - Shanhong Zhao
- Department of Physiology Medical School of Nanchang University Nanchang Jiangxi China
- Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease Nanchang University Nanchang Jiangxi China
| | - Huilong Yuan
- Department of Physiology Medical School of Nanchang University Nanchang Jiangxi China
- Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease Nanchang University Nanchang Jiangxi China
| | - Liran Shi
- Department of Physiology Medical School of Nanchang University Nanchang Jiangxi China
- Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease Nanchang University Nanchang Jiangxi China
| | - Shuangmei Liu
- Department of Physiology Medical School of Nanchang University Nanchang Jiangxi China
- Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease Nanchang University Nanchang Jiangxi China
| | - Bing Wu
- Department of Physiology Medical School of Nanchang University Nanchang Jiangxi China
- Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease Nanchang University Nanchang Jiangxi China
| | - Zhihua Yi
- Department of Physiology Medical School of Nanchang University Nanchang Jiangxi China
- Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease Nanchang University Nanchang Jiangxi China
| | - Hui Liu
- Department of Physiology Medical School of Nanchang University Nanchang Jiangxi China
- Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease Nanchang University Nanchang Jiangxi China
| | - Yun Gao
- Department of Physiology Medical School of Nanchang University Nanchang Jiangxi China
- Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease Nanchang University Nanchang Jiangxi China
| | - Guilin Li
- Department of Physiology Medical School of Nanchang University Nanchang Jiangxi China
- Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease Nanchang University Nanchang Jiangxi China
| | | | - Man Li
- Department of Neurobiology Tongji Medical College of Huazhong University of Science and Technology Wuhan China
| | - Chunping Zhang
- Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease Nanchang University Nanchang Jiangxi China
- Department of Cell Biology Medical School of Nanchang University Nanchang Jiangxi China
| | - Shangdong Liang
- Department of Physiology Medical School of Nanchang University Nanchang Jiangxi China
- Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease Nanchang University Nanchang Jiangxi China
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39
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Su WF, Wu F, Jin ZH, Gu Y, Chen YT, Fei Y, Chen H, Wang YX, Xing LY, Zhao YY, Yuan Y, Tang X, Chen G. Overexpression of P2X4 receptor in Schwann cells promotes motor and sensory functional recovery and remyelination via BDNF secretion after nerve injury. Glia 2018; 67:78-90. [DOI: 10.1002/glia.23527] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Revised: 08/10/2018] [Accepted: 08/10/2018] [Indexed: 02/01/2023]
Affiliation(s)
- Wen-Feng Su
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration; Nantong University; Nantong China
| | - Fan Wu
- Medical School of Nantong University; Nantong China
| | - Zi-Han Jin
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration; Nantong University; Nantong China
| | - Yun Gu
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration; Nantong University; Nantong China
| | - Ying-Ting Chen
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration; Nantong University; Nantong China
| | - Ying Fei
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration; Nantong University; Nantong China
| | - Hui Chen
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration; Nantong University; Nantong China
| | - Ya-Xian Wang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration; Nantong University; Nantong China
| | - Ling-Yan Xing
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration; Nantong University; Nantong China
| | - Ya-Yu Zhao
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration; Nantong University; Nantong China
| | - Ying Yuan
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration; Nantong University; Nantong China
- Affiliated Hospital of Nantong University; Nantong China
| | - Xin Tang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration; Nantong University; Nantong China
| | - Gang Chen
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration; Nantong University; Nantong China
- Department of Anesthesiology; Affiliated Hospital of Nantong University; Nantong China
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40
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Parsamanesh N, Moossavi M, Bahrami A, Butler AE, Sahebkar A. Therapeutic potential of curcumin in diabetic complications. Pharmacol Res 2018; 136:181-193. [DOI: 10.1016/j.phrs.2018.09.012] [Citation(s) in RCA: 150] [Impact Index Per Article: 21.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Revised: 08/19/2018] [Indexed: 12/22/2022]
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41
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Yuan H, Ouyang S, Yang R, Li S, Gong Y, Zou L, Jia T, Zhao S, Wu B, Yi Z, Liu H, Shi L, Li L, Gao Y, Li G, Xu H, Liu S, Zhang C, Liang S. Osthole alleviated diabetic neuropathic pain mediated by the P2X4 receptor in dorsal root ganglia. Brain Res Bull 2018; 142:289-296. [DOI: 10.1016/j.brainresbull.2018.08.008] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Revised: 08/10/2018] [Accepted: 08/11/2018] [Indexed: 12/14/2022]
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42
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Guo J, Sheng X, Dan Y, Xu Y, Zhang Y, Ji H, Wang J, Xu Z, Che H, Li G, Liang S, Li G. Involvement of P2Y 12 receptor of stellate ganglion in diabetic cardiovascular autonomic neuropathy. Purinergic Signal 2018; 14:345-357. [PMID: 30084083 DOI: 10.1007/s11302-018-9616-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2017] [Accepted: 06/26/2018] [Indexed: 12/22/2022] Open
Abstract
Diabetes as a chronic epidemic disease with obvious symptom of hyperglycemia is seriously affecting human health globally due to the diverse diabetic complications. Diabetic cardiovascular autonomic neuropathy (DCAN) is a common complication of both type 1 and type 2 diabetes and incurs high morbidity and mortality. However, the underlying mechanism for DCAN is unclear. It is well known that purinergic signaling is involved in the regulation of cardiovascular function. In this study, we examined whether the P2Y12 receptor could mediate DCAN-induced sympathetic reflexes. Our results revealed that the abnormal changes of blood pressure, heart rate, heart rate variability, and sympathetic nerve discharge were improved in diabetic rats treated with P2Y12 short hairpin RNA (shRNA). Meanwhile, the expression of P2Y12 receptor, interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and connexin 43 (Cx43) in stellate ganglia (SG) was decreased in P2Y12 shRNA-treated diabetic rats. In addition, knocking down the P2Y12 receptor also inhibited the activation of p38 MARK in the SG of diabetic rats. Taken together, these findings demonstrated that P2Y12 receptor in the SG may participate in developing diabetic autonomic neuropathy, suggesting that the P2Y12 receptor could be a potential therapeutic target for the treatment of DCAN.
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Affiliation(s)
- Jingjing Guo
- Department of Physiology, Medical College of Nanchang University, Nanchang, 330006, China
| | - Xuan Sheng
- Department of Physiology, Medical College of Nanchang University, Nanchang, 330006, China
| | - Yu Dan
- Department of Physiology, Medical College of Nanchang University, Nanchang, 330006, China
| | - Yurong Xu
- Department of Physiology, Medical College of Nanchang University, Nanchang, 330006, China
| | - Yuanruohan Zhang
- Queen Mary School, Medical College of Nanchang University, Nanchang, 330006, China
| | - Huihong Ji
- Department of the First Clinical, Medical College of Nanchang University, Nanchang, 330006, China
| | - Jiayue Wang
- Department of the First Clinical, Medical College of Nanchang University, Nanchang, 330006, China
| | - Zixi Xu
- Department of the First Clinical, Medical College of Nanchang University, Nanchang, 330006, China
| | - Hongyu Che
- Queen Mary School, Medical College of Nanchang University, Nanchang, 330006, China
| | - Guodong Li
- Department of Physiology, Medical College of Nanchang University, Nanchang, 330006, China.,Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Shangdong Liang
- Department of Physiology, Medical College of Nanchang University, Nanchang, 330006, China
| | - Guilin Li
- Department of Physiology, Medical College of Nanchang University, Nanchang, 330006, China.
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43
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Zou L, Han X, Liu S, Gong Y, Wu B, Yi Z, Liu H, Zhao S, Jia T, Li L, Yuan H, Shi L, Zhang C, Gao Y, Li G, Xu H, Liang S. Baicalin Depresses the Sympathoexcitatory Reflex Induced by Myocardial Ischemia via the Dorsal Root Ganglia. Front Physiol 2018; 9:928. [PMID: 30065662 PMCID: PMC6056627 DOI: 10.3389/fphys.2018.00928] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Accepted: 06/25/2018] [Indexed: 12/11/2022] Open
Abstract
Myocardial ischemia (MI) is one of the major causes of death in cardiac diseases. Purinergic signaling is involved in bidirectional neuronal-glial communication in the primary sensory ganglia. The sensory neuritis of cardiac afferent neurons in cervical dorsal root ganglion (cDRG) interacts with cardiac sympathetic efferent postganglionic neurons, forming feedback loops. The P2Y12 receptor is expressed in satellite glial cells (SGCs) of DRG. Baicalin is a major active ingredient extracted from natural herbal medicines, which has anti-inflammatory and strong anti-oxidation properties. In this study we investigated the effect of baicalin on P2Y12 receptor in the cervical DRG SGC-mediated sympathoexcitatory reflex, which is increased during MI. The results showed that the expression of P2Y12 receptor mRNA and protein in DRG, and the co-localization values of P2Y12 receptor and glial fibrillary acidic protein (GFAP) in cDRG SGCs were increased after MI. The activated SGCs increased IL-1β protein expression and elevated Akt phosphorylation in cDRG. Baicalin treatment inhibited the upregulation of the P2Y12 receptor, GFAP protein and Akt phosphorylation in cDRG neurons/SGCs. The stellate ganglia (SG) affect cardiac sympathetic activity. Baicalin treatment also decreased the upregulation of the P2Y12 receptor, GFAP protein in the SG. The P2Y12 agonist, 2Me-SADP, increased [Ca2+]i in HEK293 cells transfected with the P2Y12 receptor plasmid and SGCs in cDRG. These results indicate that application of baicalin alleviates pathologic sympathetic activity induced by MI via inhibition of afferents in the cDRG.
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Affiliation(s)
- Lifang Zou
- Department of Physiology, Medical School of Nanchang University, Nanchang, China.,Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang, China
| | - Xinyao Han
- First Clinical Department, Medical School of Nanchang University, Nanchang, China
| | - Shuangmei Liu
- Department of Physiology, Medical School of Nanchang University, Nanchang, China.,Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang, China
| | - Yingxin Gong
- First Clinical Department, Medical School of Nanchang University, Nanchang, China
| | - Bing Wu
- Department of Physiology, Medical School of Nanchang University, Nanchang, China.,Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang, China
| | - Zhihua Yi
- Department of Physiology, Medical School of Nanchang University, Nanchang, China.,Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang, China
| | - Hui Liu
- Department of Physiology, Medical School of Nanchang University, Nanchang, China.,Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang, China
| | - Shanhong Zhao
- Department of Physiology, Medical School of Nanchang University, Nanchang, China.,Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang, China
| | - Tianyu Jia
- Department of Physiology, Medical School of Nanchang University, Nanchang, China.,Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang, China
| | - Lin Li
- Department of Physiology, Medical School of Nanchang University, Nanchang, China.,Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang, China
| | - Huilong Yuan
- Department of Physiology, Medical School of Nanchang University, Nanchang, China.,Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang, China
| | - Liran Shi
- Department of Physiology, Medical School of Nanchang University, Nanchang, China.,Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang, China
| | - Chunping Zhang
- Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang, China.,Department of Cell Biology, Medical School of Nanchang University, Nanchang, China
| | - Yun Gao
- Department of Physiology, Medical School of Nanchang University, Nanchang, China.,Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang, China
| | - Guilin Li
- Department of Physiology, Medical School of Nanchang University, Nanchang, China.,Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang, China
| | - Hong Xu
- Department of Physiology, Medical School of Nanchang University, Nanchang, China.,Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang, China
| | - Shangdong Liang
- Department of Physiology, Medical School of Nanchang University, Nanchang, China.,Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang, China
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Boehmerle W, Huehnchen P, Lee SLL, Harms C, Endres M. TRPV4 inhibition prevents paclitaxel-induced neurotoxicity in preclinical models. Exp Neurol 2018; 306:64-75. [DOI: 10.1016/j.expneurol.2018.04.014] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2017] [Revised: 04/17/2018] [Accepted: 04/27/2018] [Indexed: 12/15/2022]
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45
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Liu CL, Deng ZY, Du ER, Xu CS. Long non‑coding RNA BC168687 small interfering RNA reduces high glucose and high free fatty acid‑induced expression of P2X7 receptors in satellite glial cells. Mol Med Rep 2018; 17:5851-5859. [PMID: 29436679 PMCID: PMC5866030 DOI: 10.3892/mmr.2018.8601] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Accepted: 12/12/2017] [Indexed: 12/19/2022] Open
Abstract
Purinergic signaling contributes to inflammatory and immune responses. The activation of the P2X purinoceptor 7 (P2X7) in satellite glial cells (SGCs) may be an essential component in the promotion of inflammation and neuropathic pain. Long non-coding RNAs (lncRNAs) are involved in multiple physiological and pathological processes. The aim of the present study was to investigate the effects of a small interfering RNA for the lncRNA BC168687 on SGC P2X7 expression in a high glucose and high free fatty acids (HGHF) environment. It was demonstrated that BC168687 small interfering (si)RNA downregulated the co-expression of the P2X7 and glial fibrillary acidic protein and P2X7 mRNA expression. Additionally, HGHF may activate the mitogen-activated protein kinase signaling pathway by increasing the release of nitric oxide and reactive oxygen species in SGCs. Taken together, these results indicate that silencing BC168687 expression may downregulate the increased expression of P2X7 receptors in SGCs induced by a HGHF environment.
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Affiliation(s)
- Cheng-Long Liu
- Department of Physiology, Basic Medical College of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Ze-Yu Deng
- Department of Physiology, Basic Medical College of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Er-Rong Du
- Department of Physiology, Basic Medical College of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Chang-Shui Xu
- Department of Physiology, Basic Medical College of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
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46
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Jia T, Rao J, Zou L, Zhao S, Yi Z, Wu B, Li L, Yuan H, Shi L, Zhang C, Gao Y, Liu S, Xu H, Liu H, Liang S, Li G. Nanoparticle-Encapsulated Curcumin Inhibits Diabetic Neuropathic Pain Involving the P2Y12 Receptor in the Dorsal Root Ganglia. Front Neurosci 2018; 11:755. [PMID: 29422835 PMCID: PMC5788895 DOI: 10.3389/fnins.2017.00755] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Accepted: 12/29/2017] [Indexed: 12/28/2022] Open
Abstract
Diabetic peripheral neuropathy results in diabetic neuropathic pain (DNP). Satellite glial cells (SGCs) enwrap the neuronal soma in the dorsal root ganglia (DRG). The purinergic 2 (P2) Y12 receptor is expressed on SGCs in the DRG. SGC activation plays an important role in the pathogenesis of DNP. Curcumin has anti-inflammatory and antioxidant properties. Because curcumin has poor metabolic stability in vivo and low bioavailability, nanoparticle-encapsulated curcumin was used to improve its targeting and bioavailability. In the present study, our aim was to investigate the effects of nanoparticle-encapsulated curcumin on DNP mediated by the P2Y12 receptor on SGCs in the rat DRG. Diabetic peripheral neuropathy increased the expression levels of the P2Y12 receptor on SGCs in the DRG and enhanced mechanical and thermal hyperalgesia in rats with diabetes mellitus (DM). Up-regulation of the P2Y12 receptor in SGCs in the DRG increased the production of pro-inflammatory cytokines. Up-regulation of interleukin-1β (IL-1β) and connexin43 (Cx43) resulted in mechanical and thermal hyperalgesia in rats with DM. The nanoparticle-encapsulated curcumin decreased up-regulated IL-1β and Cx43 expression and reduced levels of phosphorylated-Akt (p-Akt) in the DRG of rats with DM. The up-regulation of P2Y12 on SGCs and the up-regulation of the IL-1β and Cx43 in the DRG indicated the activation of SGCs in the DRG. The nano-curcumin treatment inhibited the activation of SGCs accompanied by its anti-inflammatory effect to decrease the up-regulated CGRP expression in the DRG neurons. Therefore, the nanoparticle-encapsulated curcumin treatment decreased the up-regulation of the P2Y12 receptor on SGCs in the DRG and decreased mechanical and thermal hyperalgesia in rats with DM.
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Affiliation(s)
- Tianyu Jia
- Department of Physiology, Medical School, Nanchang University, Nanchang, China.,Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang, China
| | - Jingan Rao
- Second Clinical Department, Medical School, Nanchang University, Nanchang, China
| | - Lifang Zou
- Department of Physiology, Medical School, Nanchang University, Nanchang, China.,Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang, China
| | - Shanhong Zhao
- Department of Physiology, Medical School, Nanchang University, Nanchang, China.,Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang, China
| | - Zhihua Yi
- Department of Physiology, Medical School, Nanchang University, Nanchang, China.,Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang, China
| | - Bing Wu
- Department of Physiology, Medical School, Nanchang University, Nanchang, China.,Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang, China
| | - Lin Li
- Department of Physiology, Medical School, Nanchang University, Nanchang, China.,Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang, China
| | - Huilong Yuan
- Department of Physiology, Medical School, Nanchang University, Nanchang, China.,Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang, China
| | - Liran Shi
- Department of Physiology, Medical School, Nanchang University, Nanchang, China.,Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang, China
| | - Chunping Zhang
- Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang, China.,Department of Cell Biology, Medical School, Nanchang University, Nanchang, China
| | - Yun Gao
- Department of Physiology, Medical School, Nanchang University, Nanchang, China.,Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang, China
| | - Shuangmei Liu
- Department of Physiology, Medical School, Nanchang University, Nanchang, China.,Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang, China
| | - Hong Xu
- Department of Physiology, Medical School, Nanchang University, Nanchang, China.,Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang, China
| | - Hui Liu
- Department of Physiology, Medical School, Nanchang University, Nanchang, China.,Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang, China
| | - Shangdong Liang
- Department of Physiology, Medical School, Nanchang University, Nanchang, China.,Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang, China
| | - Guilin Li
- Department of Physiology, Medical School, Nanchang University, Nanchang, China.,Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang, China
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Moehring F, Cowie AM, Menzel AD, Weyer AD, Grzybowski M, Arzua T, Geurts AM, Palygin O, Stucky CL. Keratinocytes mediate innocuous and noxious touch via ATP-P2X4 signaling. eLife 2018; 7:31684. [PMID: 29336303 PMCID: PMC5777822 DOI: 10.7554/elife.31684] [Citation(s) in RCA: 131] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2017] [Accepted: 12/29/2017] [Indexed: 12/22/2022] Open
Abstract
The first point of our body’s contact with tactile stimuli (innocuous and noxious) is the epidermis, the outermost layer of skin that is largely composed of keratinocytes. Here, we sought to define the role that keratinocytes play in touch sensation in vivo and ex vivo. We show that optogenetic inhibition of keratinocytes decreases behavioral and cellular mechanosensitivity. These processes are inherently mediated by ATP signaling, as demonstrated by complementary cutaneous ATP release and degradation experiments. Specific deletion of P2X4 receptors in sensory neurons markedly decreases behavioral and primary afferent mechanical sensitivity, thus positioning keratinocyte-released ATP to sensory neuron P2X4 signaling as a critical component of baseline mammalian tactile sensation. These experiments lay a vital foundation for subsequent studies into the dysfunctional signaling that occurs in cutaneous pain and itch disorders, and ultimately, the development of novel topical therapeutics for these conditions. The skin is the largest sensory organ of the body, and the first point of contact with the outside world. Whether it is being pinched or caressed, the skin’s sense of touch informs organisms about their surroundings and allows them to react appropriately. Nerve cells present in the skin capture information about touch and transmit it to the brain where it is decoded. However, there are many other types of cells in the skin besides nerve cells. The role that these other skin cells play in perceiving non-painful and painful touch is still unclear. Moehring et al. now report how the skin cells that form 95% of the most outer layer of the skin are involved in detecting touch. In mutant mice whose cells can be ‘switched off’ by a certain light, artificially deactivating these cells makes the animals less able to respond to tactile stimuli. Further experiments show that when pressure is applied onto the skin, the surface skin cells release a chemical messenger, which then binds specifically to the nerve cells. When the messaging molecule is experimentally destroyed or prevented from attaching to the nerve cell, the mice react less to non-painful and painful touch. This means the cells at the surface of the skin detect tactile signals from the environment and then communicate this information to the nerve cells, where it is taken to the brain. Disrupted communication between the cells in the outer layer of the skin and the nerve cells is found in painful and itchy skin conditions such as eczema and psoriasis. Knowing how these two types of cells normally work together may help with finding new pain and itch treatments for these skin disorders.
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Affiliation(s)
- Francie Moehring
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, United States
| | - Ashley M Cowie
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, United States
| | - Anthony D Menzel
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, United States
| | - Andy D Weyer
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, United States
| | - Michael Grzybowski
- Department of Physiology, Medical College of Wisconsin, Milwaukee, United States
| | - Thiago Arzua
- Department of Physiology, Medical College of Wisconsin, Milwaukee, United States
| | - Aron M Geurts
- Department of Physiology, Medical College of Wisconsin, Milwaukee, United States
| | - Oleg Palygin
- Department of Physiology, Medical College of Wisconsin, Milwaukee, United States
| | - Cheryl L Stucky
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, United States
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48
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Yi Z, Ouyang S, Zhou C, Xie L, Fang Z, Yuan H, Yang J, Zou L, Jia T, Zhao S, Li L, Shi L, Gao Y, Li G, Liu S, Xu H, Xu C, Zhang C, Liang S. Andrographolide Inhibits Mechanical and Thermal Hyperalgesia in a Rat Model of HIV-Induced Neuropathic Pain. Front Pharmacol 2018; 9:593. [PMID: 29950989 PMCID: PMC6008568 DOI: 10.3389/fphar.2018.00593] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2017] [Accepted: 05/17/2018] [Indexed: 12/17/2022] Open
Abstract
Aim: In this study, we investigated whether andrographolide (Andro) can alleviate neuropathic pain induced by HIV gp120 plus ddC treatment and the mechanism of its action. Methods: The paw withdrawal threshold and the paw withdrawal latency were observed to assess pain behaviors in all groups of the rats, including control group, control combined with Andro treatment group, sham group, gp120 combined with ddC treatment group, gp120 plus ddC combined with A438079 treatment group, and gp120 plus ddC combined with Andro treatment by intrathecally injecting at a dose of 25 μg/20 μl group. The protein expression levels of the P2X7 receptor, tumor necrosis factor-α-receptor (TNFα-R), interleukin-1β (IL-1β), IL-10, phospho-extracellular regulated protein kinases (ERK) (p-ERK) in the L4-L6 dorsal root ganglia (DRG) were measured by western blotting. Real-time quantitative polymerase chain reaction was used to test the mRNA expression level of the P2X7 receptor. Double-labeling immunofluorescence was used to identify the co-localization of the P2X7 receptor with glial fibrillary acidic protein (GFAP) in DRG. Molecular docking was performed to identify whether the Andro interacted perfectly with the rat P2X7 (rP2X7) receptor. Results: Andro attenuated the mechanical and thermal hyperalgesia in gp120+ddC-treated rats and down-regulated the P2X7 receptor mRNA and protein expression in the L4-L6 DRGs of gp120+ddC-treated rats. Additionally, Andro simultaneously decreased the expression of TNFα-R and IL-1β protein, increased the expression of IL-10 protein in L4-L6 DRGs, and inhibited the activation of ERK signaling pathways. Moreover, Andro decreased the co-expression of GFAP and the P2X7 receptor in the SGCs of L4-L6 DRG on 14th day after surgery. Conclusion: Andro decreased the hyperalgesia induced by gp120 plus ddC.
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Affiliation(s)
- Zhihua Yi
- Department of Physiology, Medical College of Nanchang University, Nanchang, China
- Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang, China
- Nursing College, Medical College of Nanchang University, Nanchang, China
- School of Life Sciences, Nanchang University, Nanchang, China
| | - Shuai Ouyang
- Undergraduate Student of the Clinical Department, Medical College of Nanchang University, Nanchang, China
| | - Congfa Zhou
- Department of Anatomy, Medical College of Nanchang University, Nanchang, China
| | - Lihui Xie
- Undergraduate Student of the Clinical Department, Medical College of Nanchang University, Nanchang, China
| | - Zhi Fang
- Undergraduate Student of the Clinical Department, Medical College of Nanchang University, Nanchang, China
| | - Huilong Yuan
- Department of Physiology, Medical College of Nanchang University, Nanchang, China
- Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang, China
| | - Jinpu Yang
- Undergraduate Student of the Queen Mary School, Medical College of Nanchang University, Nanchang, China
| | - Lifang Zou
- Department of Physiology, Medical College of Nanchang University, Nanchang, China
- Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang, China
| | - Tianyu Jia
- Department of Physiology, Medical College of Nanchang University, Nanchang, China
- Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang, China
| | - Shanhong Zhao
- Department of Physiology, Medical College of Nanchang University, Nanchang, China
- Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang, China
| | - Lin Li
- Department of Physiology, Medical College of Nanchang University, Nanchang, China
- Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang, China
| | - Liran Shi
- Department of Physiology, Medical College of Nanchang University, Nanchang, China
- Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang, China
| | - Yun Gao
- Department of Physiology, Medical College of Nanchang University, Nanchang, China
- Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang, China
| | - Guilin Li
- Department of Physiology, Medical College of Nanchang University, Nanchang, China
- Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang, China
| | - Shuangmei Liu
- Department of Physiology, Medical College of Nanchang University, Nanchang, China
- Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang, China
| | - Hong Xu
- Department of Physiology, Medical College of Nanchang University, Nanchang, China
- Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang, China
| | - Changshui Xu
- Department of Physiology, Medical College of Nanchang University, Nanchang, China
- Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang, China
| | - Chunping Zhang
- Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang, China
- Department of Cell Biology, Medical College of Nanchang University, Nanchang, China
| | - Shangdong Liang
- Department of Physiology, Medical College of Nanchang University, Nanchang, China
- Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang, China
- School of Life Sciences, Nanchang University, Nanchang, China
- *Correspondence: Shangdong Liang,
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49
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Shi L, Wu B, Yi Z, Zhao S, Zou L, Li L, Yuan H, Jia T, Liu S, Liu H, Gao Y, Li G, Xu H, Zhang C, Liang S. P2Y 12 shRNA treatment relieved HIV gp120-induced neuropathic pain in rats. Neurochem Int 2018; 112:259-266. [DOI: 10.1016/j.neuint.2017.08.006] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2017] [Revised: 08/02/2017] [Accepted: 08/11/2017] [Indexed: 11/26/2022]
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50
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Yi Z, Xie L, Zhou C, Yuan H, Ouyang S, Fang Z, Zhao S, Jia T, Zou L, Wang S, Xue Y, Wu B, Gao Y, Li G, Liu S, Xu H, Xu C, Zhang C, Liang S. P2Y 12 receptor upregulation in satellite glial cells is involved in neuropathic pain induced by HIV glycoprotein 120 and 2',3'-dideoxycytidine. Purinergic Signal 2017; 14:47-58. [PMID: 29159762 DOI: 10.1007/s11302-017-9594-z] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2017] [Accepted: 11/02/2017] [Indexed: 02/06/2023] Open
Abstract
The direct neurotoxicity of HIV and neurotoxicity of combination antiretroviral therapy medications both contribute to the development of neuropathic pain. Activation of satellite glial cells (SGCs) in the dorsal root ganglia (DRG) plays a crucial role in mechanical and thermal hyperalgesia. The P2Y12 receptor expressed in SGCs of the DRG is involved in pain transmission. In this study, we explored the role of the P2Y12 receptor in neuropathic pain induced by HIV envelope glycoprotein 120 (gp120) combined with ddC (2',3'-dideoxycytidine). A rat model of gp120+ddC-induced neuropathic pain was used. Peripheral nerve exposure to HIV-gp120+ddC increased mechanical and thermal hyperalgesia in gp120+ddC-treated model rats. The gp120+ddC treatment increased expression of P2Y12 receptor mRNA and protein in DRG SGCs. In primary cultured DRG SGCs treated with gp120+ddC, the levels of [Ca2+]i activated by the P2Y12 receptor agonist 2-(Methylthio) adenosine 5'-diphosphate trisodium salt (2-MeSADP) were significantly increased. P2Y12 receptor shRNA treatment inhibited 2-MeSADP-induced [Ca2+]i in primary cultured DRG SGCs treated with gp120+ddC. Intrathecal treatment with a shRNA against P2Y12 receptor in DRG SGCs reduced the release of pro-inflammatory cytokines, decreased phosphorylation of p38 MAPK in the DRG of gp120+ddC-treated rats. Thus, downregulating the P2Y12 receptor relieved mechanical and thermal hyperalgesia in gp120+ddC-treated rats.
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Affiliation(s)
- Zhihua Yi
- School of life Sciences of Nanchang University, Nanchang, Jiangxi, 330006, People's Republic of China
- Department of Physiology, Basic Medical School of Nanchang University, Nanchang, Jiangxi, 330006, People's Republic of China
- Nursing College, Medical School of Nanchang University, Nanchang, Jiangxi, 330006, People's Republic of China
| | - Lihui Xie
- Undergraduate student of Clinic Medicine School of Nanchang University, Nanchang, Jiangxi, 330006, People's Republic of China
| | - Congfa Zhou
- Department of Physiology, Basic Medical School of Nanchang University, Nanchang, Jiangxi, 330006, People's Republic of China
| | - Huilong Yuan
- Department of Physiology, Basic Medical School of Nanchang University, Nanchang, Jiangxi, 330006, People's Republic of China
| | - Shuai Ouyang
- Undergraduate student of Clinic Medicine School of Nanchang University, Nanchang, Jiangxi, 330006, People's Republic of China
| | - Zhi Fang
- Undergraduate student of Clinic Medicine School of Nanchang University, Nanchang, Jiangxi, 330006, People's Republic of China
| | - Shanhong Zhao
- Department of Physiology, Basic Medical School of Nanchang University, Nanchang, Jiangxi, 330006, People's Republic of China
| | - Tianyu Jia
- Department of Physiology, Basic Medical School of Nanchang University, Nanchang, Jiangxi, 330006, People's Republic of China
| | - Lifang Zou
- Department of Physiology, Basic Medical School of Nanchang University, Nanchang, Jiangxi, 330006, People's Republic of China
| | - Shouyu Wang
- Department of Physiology, Basic Medical School of Nanchang University, Nanchang, Jiangxi, 330006, People's Republic of China
| | - Yun Xue
- Department of Physiology, Basic Medical School of Nanchang University, Nanchang, Jiangxi, 330006, People's Republic of China
| | - Bing Wu
- Department of Physiology, Basic Medical School of Nanchang University, Nanchang, Jiangxi, 330006, People's Republic of China
| | - Yun Gao
- Department of Physiology, Basic Medical School of Nanchang University, Nanchang, Jiangxi, 330006, People's Republic of China
| | - Guilin Li
- Department of Physiology, Basic Medical School of Nanchang University, Nanchang, Jiangxi, 330006, People's Republic of China
| | - Shuangmei Liu
- Department of Physiology, Basic Medical School of Nanchang University, Nanchang, Jiangxi, 330006, People's Republic of China
| | - Hong Xu
- Department of Physiology, Basic Medical School of Nanchang University, Nanchang, Jiangxi, 330006, People's Republic of China
| | - Changshui Xu
- Department of Physiology, Basic Medical School of Nanchang University, Nanchang, Jiangxi, 330006, People's Republic of China
| | - Chunping Zhang
- Department of Physiology, Basic Medical School of Nanchang University, Nanchang, Jiangxi, 330006, People's Republic of China
| | - Shangdong Liang
- School of life Sciences of Nanchang University, Nanchang, Jiangxi, 330006, People's Republic of China.
- Department of Physiology, Basic Medical School of Nanchang University, Nanchang, Jiangxi, 330006, People's Republic of China.
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