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Li R, Zhang W, Bai X, Wang F, Yao M, Zhao C, Wang J. Duhuo Jisheng Mixture attenuates neuropathic pain by inhibiting S1PR1/P2Y 1R pathway after Chronic Constriction Injury in mice. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 138:156413. [PMID: 39862793 DOI: 10.1016/j.phymed.2025.156413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 12/29/2024] [Accepted: 01/19/2025] [Indexed: 01/27/2025]
Abstract
BACKGROUND The pathogenesis of neuropathic pain is complex and lacks effective clinical treatment strategies. Medical plants and herbal extracts from traditional Chinese medicine with multi-target comprehensive effects have attracted great attention from scientists. PURPOSE To investigate the pharmacological active components and mechanism underlying the anti-neuralgia effect of classic analgesic formulas Duhuo Jisheng Mixture (DJM). STUDY DESIGN AND METHODS Chronic Constriction Injury (CCI) surgery was used to assess the efficiency of DJM in treating neuropathic pain. Forty-two C57BL/6 mice were evenly divided into seven groups: sham-operated, sham treatment with DJM (20 ml/kg), CCI treatment with DJM (0, 10, 20, or 40 ml/kg) and CCI treatment with Morphine (3 mg/kg). DJM irrigation stomach was implemented from post-operative day (POD) 0 to POD 21. Paw withdrawal threshold and Thermal latency were conducted on POD 0, 1, 3, 5, 7, 14 and 21. On POD 14, eEPSP in spinal dorsal horn neurons was recorded by patch-clamp. mRNA transcription in spinal cord was also monitored to screen molecular targets and signaling pathways on POD 14. To further validate the influence of DJM on the S1PR1 signaling pathway, 1 mg/kg W146 was infused into mice intrathecally and delivered to the cerebral spinal fluid through one 30 G needle with a whole 20 μl intervertebral between the L5 and L6. Furthermore, the active ingredients of DJM were identified through LC/MS equipment and predicted through Molecular Docking. RESULTS We demonstrated that DJM treatment reversed CCI-induced pain sensitivity and the excitability of neurons, decreased up-regulation of astrocyte S1PR1, inhibited astrocyte activation, and further inhibited the expression of Purinergic P2Y1R and its downstream molecule p-JNK in mouse spinal cord, as well as the release of inflammatory factors. Interestingly, due to the regulatory role of astrocytes on neurons, the effects of DJM on astrocytes ultimately manifest in pain-effector neurons, resulting in decreased p-ERK, p-CREB, and pain-marking protein c-fos in neurons. S1PR1 Antagonist W146 possessed an equivalent analgesic effect as DJM and inhibited S1PR1 and c-fos expression. According to LC/MS analysis results, a total of 33 active ingredients were screened, of which 20 active ingredients had good binding activity with S1PR1 and were considered to be the main active ingredients for analgesia. CONCLUSION This study is the first to clarify the effect and molecular mechanism of DJM for anti-neuralgia in particular, which confirms the clinical value of DJM in relieving neuropathic pain. Furthermore, this study innovatively identifies the potential pharmacological components of DJM through LC/MS and Bioinformatics technology, which forms a framework for people's understanding of DJM treatment for neuropathic pain and provides a sufficient theoretical basis of DJM for clinical application.
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Affiliation(s)
- Ruili Li
- Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Changle West Street 15, Xi'an, Shaanxi, 710032, China
| | - Wei Zhang
- Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Changle West Street 15, Xi'an, Shaanxi, 710032, China
| | - Xiaodan Bai
- Department of Pharmacy, Tangdu Hospital, Fourth Military Medical University, Xinsi Street 1, Xi'an, Shaanxi, 710038, China
| | - Fan Wang
- Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Changle West Street 15, Xi'an, Shaanxi, 710032, China
| | - Minna Yao
- Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Changle West Street 15, Xi'an, Shaanxi, 710032, China
| | - Chao Zhao
- Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Changle West Street 15, Xi'an, Shaanxi, 710032, China.
| | - Jingwen Wang
- Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Changle West Street 15, Xi'an, Shaanxi, 710032, China.
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Alami K, Fathollahi Y, Hashemizadeh S, Mosleh M, Semnanian S, Mousavi SY, Azizi H. Microglia-dependent peripheral neuropathic pain in adulthood following adolescent exposure to morphine in male rats. Neuropharmacology 2025; 263:110211. [PMID: 39521039 DOI: 10.1016/j.neuropharm.2024.110211] [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: 08/07/2024] [Revised: 11/04/2024] [Accepted: 11/06/2024] [Indexed: 11/16/2024]
Abstract
Persistent effects of adolescent morphine exposure on neurobiological processes and behaviors in adulthood have been partially identified. Hypersensitivity following adolescent exposure to morphine is a complex and multifaceted phenomenon whose underlying mechanisms remain largely unknown. This study aimed to investigate the involvement of microglia in neuropathic pain sensitivity following adolescent morphine exposure, focused on hippocampal genes expression and plasticity. To achieve this, adolescent male Wistar rats received morphine, along with minocycline, to inhibit microglial activity. The allodynia and hyperalgesia of adult rats were evaluated using von-Frey filaments and the Hargreaves plantar test in both baseline and neuropathic pain conditions. Hippocampal genes expression was analyzed following the behavioral tests. The plasticity of the Schaffer-CA1 hippocampal synapses was also assessed using field potential recording following neuropathy. Results showed that adolescent morphine exposure exacerbated the allodynia and hyperalgesia in both baseline and neuropathic pain states in adult rats, which was significantly reduced by the co-administration of minocycline during adolescence. Neuropathy in adult rats was found to increase hippocampal expression of inflammatory mediators, but adolescent morphine prevented this effect. Additionally, we observed a reduction in the baseline synaptic transmission and long-term potentiation (LTP) at the Schaffer-CA1 hippocampal synapses after neuropathy in adult rats following adolescent exposure to morphine. The reduction of synaptic activity was not altered by the co-administration of minocycline with morphine during adolescence. It is concluded that microglia play an important role in mediating hypersensitivity induced by adolescent morphine exposure, although hippocampal microglia may not be directly involved in this process.
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Affiliation(s)
- Kawsar Alami
- Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Yaghoub Fathollahi
- Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Shiva Hashemizadeh
- School of Cognitive Sciences, Institute for Research in Fundamental Sciences, IPM, Tehran, Iran; Institute for Brain and Cognition, Tarbiat Modares University, Tehran, Iran
| | - Masoumeh Mosleh
- Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Saeed Semnanian
- Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran; School of Cognitive Sciences, Institute for Research in Fundamental Sciences, IPM, Tehran, Iran
| | - Sayed Yousof Mousavi
- Department of Cognitive Neuroscience, Neuroscience Research Center, Kavosh Nonprofit Educational Research Institute, Kabul, Afghanistan
| | - Hossein Azizi
- Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran; Institute for Brain and Cognition, Tarbiat Modares University, Tehran, Iran.
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Feng HN, Zhong LQY, Xu CX, Wang TT, Wu H, Wang L, Traub RJ, Chen X, Cao DY. Up-regulation of IL-1β and sPLA2-III in the medial prefrontal cortex contributes to orofacial and somatic hyperalgesia induced by malocclusion via glial-neuron crosstalk. Eur J Pharmacol 2024; 982:176933. [PMID: 39182540 DOI: 10.1016/j.ejphar.2024.176933] [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: 05/24/2024] [Revised: 08/21/2024] [Accepted: 08/22/2024] [Indexed: 08/27/2024]
Abstract
The medial prefrontal cortex (mPFC) has been identified as a key brain region involved in the modulation of chronic pain. Our recent study demonstrated that unilateral anterior crossbite (UAC) developed the comorbidity model of temporomandibular disorders (TMD) and fibromyalgia syndrome (FMS), which was characterized by both orofacial and somatic hyperalgesia. In the present study, UAC rats exhibited significant changes in gene expression in the mPFC. Enrichment analysis revealed that the significantly involved pathways were cytokines-cytokine receptor interaction and immune response. The expression of group III secretory phospholipase A2 (sPLA2-III) was significantly increased in the mPFC of UAC rats. Silencing sPLA2-III expression in the mPFC blocked the orofacial and somatic hyperalgesia. Immunofluorescence showed that sPLA2-III was mainly localized in neurons. The expression of interleukin-1β (IL-1β) in the mPFC significantly increased after UAC. Injection of IL-1β antibody into the mPFC blocked orofacial and somatic hyperalgesia. IL-1β was mainly localized in microglia cells. Furthermore, injection of IL-1β antibody significantly reduced the expression of sPLA2-III. These results indicate that neuroinflammatory cascade responses induced by glial-neuron crosstalk in the mPFC may contribute to the development of TMD and FMS comorbidity, and IL-1β and sPLA2-III are identified as novel potential therapeutic targets for the treatment of chronic pain in the comorbidity of TMD and FMS.
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Affiliation(s)
- Hai-Nan Feng
- Department of Stomatology, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an, Shaanxi, 710061, China; Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, Testing Center of Stomatology, Xi'an Jiaotong University College of Stomatology, 98 West 5th Road, Xi'an, Shaanxi, 710004, China
| | - Liang-Qiu-Yue Zhong
- Department of Stomatology, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an, Shaanxi, 710061, China
| | - Chen-Xi Xu
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, Testing Center of Stomatology, Xi'an Jiaotong University College of Stomatology, 98 West 5th Road, Xi'an, Shaanxi, 710004, China
| | - Ting-Ting Wang
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, Testing Center of Stomatology, Xi'an Jiaotong University College of Stomatology, 98 West 5th Road, Xi'an, Shaanxi, 710004, China
| | - Hao Wu
- Department of Stomatology, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an, Shaanxi, 710061, China
| | - Lu Wang
- Department of Stomatology, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an, Shaanxi, 710061, China
| | - Richard J Traub
- Department of Neural and Pain Sciences, School of Dentistry, the UM Center to Advance Chronic Pain Research, University of Maryland Baltimore, Baltimore, MD, 21201, USA
| | - Xi Chen
- Department of Stomatology, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an, Shaanxi, 710061, China.
| | - Dong-Yuan Cao
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, Testing Center of Stomatology, Xi'an Jiaotong University College of Stomatology, 98 West 5th Road, Xi'an, Shaanxi, 710004, China; Department of Neural and Pain Sciences, School of Dentistry, the UM Center to Advance Chronic Pain Research, University of Maryland Baltimore, Baltimore, MD, 21201, USA.
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Han S, Wang J, Zhang W, Tian X. Chronic Pain-Related Cognitive Deficits: Preclinical Insights into Molecular, Cellular, and Circuit Mechanisms. Mol Neurobiol 2024; 61:8123-8143. [PMID: 38470516 DOI: 10.1007/s12035-024-04073-z] [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: 10/13/2023] [Accepted: 02/23/2024] [Indexed: 03/14/2024]
Abstract
Cognitive impairment is a common comorbidity of chronic pain, significantly disrupting patients' quality of life. Despite this comorbidity being clinically recognized, the underlying neuropathological mechanisms remain unclear. Recent preclinical studies have focused on the fundamental mechanisms underlying the coexistence of chronic pain and cognitive decline. Pain chronification is accompanied by structural and functional changes in the neural substrate of cognition. Based on the developments in electrophysiology and optogenetics/chemogenetics, we summarized the relevant neural circuits involved in pain-induced cognitive impairment, as well as changes in connectivity and function in brain regions. We then present the cellular and molecular alternations related to pain-induced cognitive impairment in preclinical studies, mainly including modifications in neuronal excitability and structure, synaptic plasticity, glial cells and cytokines, neurotransmitters and other neurochemicals, and the gut-brain axis. Finally, we also discussed the potential treatment strategies and future research directions.
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Affiliation(s)
- Siyi Han
- Department of Anesthesiology, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jiefang Avenue, Wuhan, Hubei, China
| | - Jie Wang
- Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan, Hubei, China
| | - Wen Zhang
- Department of Anesthesiology, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jiefang Avenue, Wuhan, Hubei, China.
| | - Xuebi Tian
- Department of Anesthesiology, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jiefang Avenue, Wuhan, Hubei, China.
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Yang XL, Gao W, Dong WY, Zheng C, Wang S, Wei HR, Luo Y, Zhang Z, Chen Y, Jin Y. A neural circuit for alcohol withdrawal-induced hyperalgesia in a nondependent state. SCIENCE ADVANCES 2024; 10:eadp8636. [PMID: 39331713 PMCID: PMC11430459 DOI: 10.1126/sciadv.adp8636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Accepted: 08/23/2024] [Indexed: 09/29/2024]
Abstract
Alcohol use disorder is highly prevalent worldwide, with characteristically severe pain sensitivity during withdrawal. Here, we established a mouse model of hyperalgesia during ethanol withdrawal (EW) before addiction to investigate the window for onset and underlying mechanisms. Viral tracing with in vivo microendoscopic and two-photon calcium imaging identified a circuit pathway from dorsal hippocampal CA1 glutamatergic neurons (dCA1Glu) to anterior cingulate cortex glutamatergic neurons (ACCGlu) activated in EW mice with hyperalgesia. Chemogenetic inhibition of this pathway can alleviate hyperalgesia in EW mice, whereas artificial activation recapitulates EW-induced hyperalgesia in naïve mice. These findings demonstrate that the dCA1Glu → ACCGlu neuronal pathway participates in driving EW-induced hyperalgesia before ethanol dependence in mice.
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Affiliation(s)
- Xin-Lu Yang
- Department of Anesthesiology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China
- Department of Anesthesiology, First Affiliated Hospital of Wannan Medical College, Wuhu 241002, China
| | - Wei Gao
- Department of Anesthesiology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China
| | - Wan-Ying Dong
- Department of Anesthesiology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China
| | - Changjian Zheng
- Department of Anesthesiology, First Affiliated Hospital of Wannan Medical College, Wuhu 241002, China
| | - Sheng Wang
- Department of Anesthesiology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China
| | - Hong-Rui Wei
- Department of Anesthesiology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China
| | - Yanli Luo
- Department of Psychological Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Zhi Zhang
- Department of Anesthesiology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China
- Department of Biophysics and Neurobiology, CAS Key laboratory of Brain Function and Disease, University of Science and Technology of China, Hefei 230026, China
| | - Yongquan Chen
- Department of Anesthesiology, First Affiliated Hospital of Wannan Medical College, Wuhu 241002, China
| | - Yan Jin
- Department of Biophysics and Neurobiology, CAS Key laboratory of Brain Function and Disease, University of Science and Technology of China, Hefei 230026, China
- Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China
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Denizci E, Altun G, Kaplan S. Morphological evidence for the potential protective effects of curcumin and Garcinia kola against diabetes in the rat hippocampus. Brain Res 2024; 1839:149020. [PMID: 38788929 DOI: 10.1016/j.brainres.2024.149020] [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: 04/11/2024] [Revised: 05/16/2024] [Accepted: 05/22/2024] [Indexed: 05/26/2024]
Abstract
This research investigated the effects of sciatic nerve transection and diabetes on the hippocampus, and the protective effects of Garcinia kola and curcumin. Thirty-five adults male Wistar albino rats were divided into five groups: a control group (Cont), a transected group (Sham group), a transected + diabetes mellitus group (DM), a transected + diabetes mellitus + Garcinia kola group (DM + GK), and a transected + DM + curcumin group (DM + Cur), each containing seven animals. The experimental diabetes model was created with the intraperitoneal injection of a single dose of streptozotocin. No procedure was applied to the Cont group, while sciatic nerve transection was performed on the other groups. Garcinia kola was administered to the rats in DM + GK, and curcumin to those in DM + Cur. Cardiac perfusion was performed at the end of the experimental period. Brain tissues were dissected for stereological, histopathological, and immunohistochemical evaluations. The volume ratios of hippocampal layers to the entire hippocampus volume were compared between the groups. Anti-S100, anti-caspase 3, and anti-SOX 2 antibodies were used for immunohistochemical analysis. No statistically significant difference was observed in the volume ratios of the four hippocampal layers. However, the volume ratio of the stratum lucidum was higher in the Sham, DM, and DM + Cur groups compared to the Cont group. While curcumin exhibited a protective effect on hippocampal tissue following diabetes induction, Garcinia kola had only a weak protective effect. Increased cell density and nuclear deterioration due to diabetes and nerve transection can be partially ameliorated by treatment with Garcinia kola and curcumin.
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Affiliation(s)
- Eda Denizci
- Department of Histology and Embryology, Ondokuz Mayıs University, Samsun 55139, Turkey
| | - Gamze Altun
- Department of Histology and Embryology, Ondokuz Mayıs University, Samsun 55139, Turkey
| | - Süleyman Kaplan
- Department of Histology and Embryology, Ondokuz Mayıs University, Samsun 55139, Turkey; Nelson Mandela African Institution of Science and Technology, Arusha, Tanzania.
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Wang W, Zheng WQ, Du X, Chen SC, Chen YH, Ma QY, Wang H, Gao S, Tan R, Zhang HT, Zhou YM, Zhang FF. Chronic pain exacerbates memory impairment and pathology of Aβ and tau by upregulating IL-1β and p-65 signaling in a mouse model of Alzheimer's disease. Brain Res 2024; 1832:148843. [PMID: 38430996 DOI: 10.1016/j.brainres.2024.148843] [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: 12/14/2023] [Revised: 02/15/2024] [Accepted: 02/28/2024] [Indexed: 03/05/2024]
Abstract
BACKGROUND Chronic pain is linked to cognitive impairment; however, the underlying mechanisms remain unclear. In the present study, we examined these mechanisms in a well-established mouse model of Alzheimer's disease (AD). METHODS Neuropathic pain was modeled in 5-month-old transgenic APPswe/PS1dE9 (APP/PS1) mice by partial ligation of the sciatic nerve on the left side, and chronic inflammatory pain was modeled in another group of APP/PS1 mice by injecting them with complete Freund's adjuvant on the plantar surface of the left hind paw. Six weeks after molding, the animals were tested to assess pain threshold (von Frey filament), learning, memory (novel object recognition, Morris water maze, Y-maze, and passive avoidance), and depression-like symptoms (sucrose preference, tail suspension, and forced swimming). After behavioral testing, mice were sacrificed and the levels of p65, amyloid-β (residues 1-42) and phospho-tau in the hippocampus and cerebral cortex were assayed using western blotting, while interleukin (IL)-1β levels were measured by enzyme-linked immunosorbent assay. RESULTS Animals subjected to either type of chronic pain showed lower pain thresholds, more severe deficits in learning and memory, and stronger depression-like symptoms than the corresponding control animals. Either type of chronic pain was associated with upregulation of p65, amyloid-β (1-42), and IL-1β in the hippocampus and cerebral cortex, as well as higher levels of phosphorylated tau. CONCLUSIONS Chronic pain may exacerbate cognitive deficits and depression-like symptoms in APP/PS1 mice by worsening pathology related to amyloid-β and tau and by upregulating signaling involving IL-1β and p65.
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Affiliation(s)
- Wei Wang
- Institute of Pharmacology, Pharmacy College, Shandong First Medical University & Shandong Academy of Medical Sciences, Ji'nan, China
| | - Wen-Qing Zheng
- Institute of Pharmacology, Pharmacy College, Shandong First Medical University & Shandong Academy of Medical Sciences, Ji'nan, China; Department of Pharmacy, the Second Affiliated Hospital of Shandong First Medical University, Tai'an, China
| | - Xian Du
- Tai'an Municipal Hospital, Tai'an, China
| | - Shi-Cai Chen
- Institute of Pharmacology, Pharmacy College, Shandong First Medical University & Shandong Academy of Medical Sciences, Ji'nan, China
| | - Yan-Han Chen
- Institute of Pharmacology, Pharmacy College, Shandong First Medical University & Shandong Academy of Medical Sciences, Ji'nan, China
| | - Qing-Yang Ma
- Institute of Pharmacology, Pharmacy College, Shandong First Medical University & Shandong Academy of Medical Sciences, Ji'nan, China
| | - Hao Wang
- Institute of Pharmacology, Pharmacy College, Shandong First Medical University & Shandong Academy of Medical Sciences, Ji'nan, China
| | - Shan Gao
- Institute of Pharmacology, Pharmacy College, Shandong First Medical University & Shandong Academy of Medical Sciences, Ji'nan, China
| | - Rui Tan
- Institute of Pharmacology, Pharmacy College, Shandong First Medical University & Shandong Academy of Medical Sciences, Ji'nan, China
| | - Han-Ting Zhang
- Institute of Pharmacology, Pharmacy College, Shandong First Medical University & Shandong Academy of Medical Sciences, Ji'nan, China
| | - Yan-Meng Zhou
- Institute of Pharmacology, Pharmacy College, Shandong First Medical University & Shandong Academy of Medical Sciences, Ji'nan, China.
| | - Fang-Fang Zhang
- Institute of Pharmacology, Pharmacy College, Shandong First Medical University & Shandong Academy of Medical Sciences, Ji'nan, China.
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Yao R, Man Y, Lu Y, Su Y, Zhou M, Wang S, Gu X, Wang R, Wu Y, Wang L. Infliximab alleviates memory impairment in rats with chronic pain by suppressing neuroinflammation and restoring hippocampal neurogenesis. Neuropharmacology 2024; 245:109813. [PMID: 38110173 DOI: 10.1016/j.neuropharm.2023.109813] [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: 10/20/2023] [Revised: 11/30/2023] [Accepted: 12/06/2023] [Indexed: 12/20/2023]
Abstract
Patients with chronic pain commonly report impaired memory. Increasing evidence has demonstrated that inhibition of neurogenesis by neuroinflammation plays a crucial role in chronic pain-associated memory impairments. There is currently a lack of treatment strategies for this condition. An increasing number of clinical trials have reported the therapeutic potential of anti-inflammatory therapies targeting tumour necrosis factor-α (TNF-α) for inflammatory diseases. The present study investigated whether infliximab alleviates chronic pain-associated memory impairments in rats with chronic constriction injury (CCI). We demonstrated that infliximab alleviated spatial memory impairment and hyperalgesia induced by CCI. Furthermore, infliximab inhibited the activation of hippocampal astrocytes and microglia and decreased the release of proinflammatory cytokines in CCI rats. Furthermore, infliximab reversed the decrease in the numbers of newborn neurons and mature neurons in the dentate gyrus (DG) caused by chronic pain. Our data provide evidence that infliximab alleviates chronic pain-associated memory impairments, suppresses neuroinflammation and restores hippocampal neurogenesis in a CCI model. These facts indicate that infliximab may be a potential therapeutic agent for the treatment of chronic pain and associated memory impairments.
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Affiliation(s)
- Rui Yao
- Department of Anesthesiology, Xuzhou First People's Hospital, Xuzhou, 22100, China
| | - Yuanyuan Man
- Department of Respiratory Medicine, Xuzhou Central Hospital, Xuzhou, 22100, China
| | - Yao Lu
- Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, 22100, China
| | - Yang Su
- Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, 22100, China
| | - Meiyan Zhou
- Department of Anesthesiology, Xuzhou Central Hospital, Xuzhou, 22100, China
| | - Shuang Wang
- Department of Anesthesiology, Xuzhou Central Hospital, Xuzhou, 22100, China
| | - Xiaoping Gu
- Department of Anesthesiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, China
| | - Rongguo Wang
- Department of Anesthesiology, Xuzhou Central Hospital, Xuzhou, 22100, China.
| | - Yuqing Wu
- Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, 22100, China.
| | - Liwei Wang
- Department of Anesthesiology, Xuzhou Central Hospital, Xuzhou, 22100, China.
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Han S, Yuan X, Zhao F, Manyande A, Gao F, Wang J, Zhang W, Tian X. Activation of LXRs alleviates neuropathic pain-induced cognitive dysfunction by modulation of microglia polarization and synaptic plasticity via PI3K/AKT pathway. Inflamm Res 2024; 73:157-174. [PMID: 38183431 DOI: 10.1007/s00011-023-01826-9] [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: 08/06/2023] [Revised: 10/20/2023] [Accepted: 11/22/2023] [Indexed: 01/08/2024] Open
Abstract
OBJECTIVE Cognitive dysfunction is a common comorbidity in patients with chronic pain. Activation of Liver X receptors (LXRs) plays a potential role in improving cognitive disorders in central nervous diseases. In this study, we investigated the role of LXRs in cognitive deficits induced by neuropathic pain. METHODS We established the spared nerve injury (SNI) model to investigate pain-induced memory dysfunction. Pharmacological activation of LXRs with T0901317 or inhibition with GSK2033 was applied. PI3K inhibitor LY294002 was administered to explore the underlying mechanism of LXRs. Changes in neuroinflammation, microglia polarization, and synaptic plasticity were assessed using biochemical technologies. RESULTS We found that SNI-induced cognitive impairment was associated with reduced LXRβ expression, increased M1-phenotype microglia, decreased synaptic proteins, and inhibition of PI3K/AKT signaling pathway in the hippocampus. Activation of LXRs using T0901317 effectively alleviated SNI-induced cognitive impairment. Additionally, T0901317 promoted the polarization of microglia from M1 to M2, reduced pro-inflammatory cytokines, and upregulated synaptic proteins in the hippocampus. However, administration of GSK2033 or LY294002 abolished these protective effects of T0901317 in SNI mice. CONCLUSIONS LXRs activation alleviates neuropathic pain-induced cognitive impairment by modulating microglia polarization, neuroinflammation, and synaptic plasticity, at least partly via activation of PI3K/AKT signaling in the hippocampus. LXRs may be promising targets for addressing pain-related cognitive deficits.
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Affiliation(s)
- Siyi Han
- Department of Anesthesiology, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan, Hubei Province, China
| | - Xiaoman Yuan
- Department of Anesthesiology, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan, Hubei Province, China
| | - Fengtian Zhao
- Department of Anesthesiology, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan, Hubei Province, China
| | - Anne Manyande
- School of Human and Social Sciences, University of West London, London, UK
| | - Feng Gao
- Department of Anesthesiology, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan, Hubei Province, China
| | - Jie Wang
- Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan, Hubei Province, China
| | - Wen Zhang
- Department of Anesthesiology, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan, Hubei Province, China.
| | - Xuebi Tian
- Department of Anesthesiology, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan, Hubei Province, China.
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10
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Kunioku Y, Kimura M, Ouchi T, Fukuda K, Shibukawa Y. Intracellular cAMP Signaling Pathway via G s Protein-Coupled Receptor Activation in Rat Primary Cultured Trigeminal Ganglion Cells. Biomedicines 2023; 11:2347. [PMID: 37760789 PMCID: PMC10525138 DOI: 10.3390/biomedicines11092347] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 08/13/2023] [Accepted: 08/17/2023] [Indexed: 09/29/2023] Open
Abstract
G protein-coupled receptors in trigeminal ganglion (TG) neurons are often associated with sensory mechanisms, including nociception. We have previously reported the expression of P2Y12 receptors, which are Gi protein-coupled receptors, in TG cells. Activating P2Y12 receptors decreased the intracellular free Ca2+ concentration ([Ca2+]i). This indicated that intracellular adenosine 3',5'-cyclic monophosphate (cAMP) levels can mediate Ca2+ signaling in TG cells. Here, we report more extensive-expression patterns of Gs protein-coupled receptors in primary cultured TG neurons isolated from 7-day-old newborn Wistar rats and further examine the roles of these receptors in cAMP signaling using the BacMam sensor in these neurons. To identify TG neurons, we also measured [Ca2+]i using fura-2 in TG cells and measured intracellular cAMP levels. TG neurons were positive for Gαs protein-coupled receptors, beta-2 adrenergic (β2), calcitonin gene-related peptide (CGRP), adenosine A2A (A2A), dopamine 1 (D1), prostaglandin I2 (IP), and 5-hydroxytriptamine 4 (5-HT4) receptor. Application of forskolin (FSK), an activator of adenylyl cyclase, transiently increased intracellular cAMP levels in TG neurons. The application of a phosphodiesterase inhibitor augmented the FSK-elicited intracellular cAMP level increase. These increases were significantly suppressed by the application of SQ22536, an adenylyl cyclase inhibitor, in TG neurons. Application of agonists for β2, CGRP, A2A, D1-like, IP, and 5-HT4 receptors increased intracellular cAMP levels. These increases were SQ22536-sensitive. These results suggested that TG neurons express β2, CGRP, A2A, D1, IP, and 5-HT4 receptors, and the activations of these Gαs protein-coupled receptors increase intracellular cAMP levels by activating adenylyl cyclase.
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Affiliation(s)
- Yuki Kunioku
- Department of Physiology, Tokyo Dental College, 2-9-18, Kanda-Misaki-cho, Chiyoda-ku, Tokyo 101-0061, Japan; (Y.K.); (T.O.); (Y.S.)
- Division of Special Needs Dentistry and Orofacial Pain, Department of Oral Health and Clinical Science, Tokyo Dental College, 2-9-18, Kanda-Misaki-cho, Chiyoda-ku, Tokyo 101-0061, Japan;
| | - Maki Kimura
- Department of Physiology, Tokyo Dental College, 2-9-18, Kanda-Misaki-cho, Chiyoda-ku, Tokyo 101-0061, Japan; (Y.K.); (T.O.); (Y.S.)
| | - Takehito Ouchi
- Department of Physiology, Tokyo Dental College, 2-9-18, Kanda-Misaki-cho, Chiyoda-ku, Tokyo 101-0061, Japan; (Y.K.); (T.O.); (Y.S.)
| | - Kenichi Fukuda
- Division of Special Needs Dentistry and Orofacial Pain, Department of Oral Health and Clinical Science, Tokyo Dental College, 2-9-18, Kanda-Misaki-cho, Chiyoda-ku, Tokyo 101-0061, Japan;
| | - Yoshiyuki Shibukawa
- Department of Physiology, Tokyo Dental College, 2-9-18, Kanda-Misaki-cho, Chiyoda-ku, Tokyo 101-0061, Japan; (Y.K.); (T.O.); (Y.S.)
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11
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Gonçalves S, Hathway GJ, Woodhams SG, Chapman V, Bast T. No Evidence for Cognitive Impairment in an Experimental Rat Model of Knee Osteoarthritis and Associated Chronic Pain. THE JOURNAL OF PAIN 2023; 24:1478-1492. [PMID: 37044295 DOI: 10.1016/j.jpain.2023.04.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 03/08/2023] [Accepted: 04/04/2023] [Indexed: 04/14/2023]
Abstract
Although chronic pain states have been associated with impaired cognitive functions, including memory and cognitive flexibility, the cognitive effects of osteoarthritis (OA) pain remain to be clarified. The aim of this study was to measure cognitive function in the mono-iodoacetate (MIA) rat model of chronic OA-like knee pain. We used young adult male Lister hooded rats, which are well-suited for cognitive testing. Rats received either a unilateral knee injection of MIA (3 mg/50 µL) or saline as control. Joint pain at rest was assessed for up to 12 weeks, using weight-bearing asymmetry, and referred pain at a distal site, using determination of hindpaw withdrawal thresholds. The watermaze delayed-matching-to-place test of rapid place learning, novel object recognition memory assay, and an operant response-shift and -reversal task were used to measure memory and behavioral flexibility. Open-field locomotor activity, startle response, and prepulse inhibition were also measured for comparison. MIA-injected rats showed markedly reduced weight-bearing on the injured limb, as well as pronounced cartilage damage and synovitis, but interestingly no changes in paw withdrawal threshold. Rearing was reduced, but otherwise, locomotor activity was normal and no changes in startle and prepulse inhibition were detected. MIA-injected rats had intact watermaze delayed-matching-to-place performance, suggesting no substantial change in hippocampal function, and there were no changes in novel object recognition memory or performance on the operant task of behavioral flexibility. Our finding that OA-like pain does not alter hippocampal function, unlike other chronic pain conditions, is consistent with human neuroimaging findings. PERSPECTIVE: Young adult rats with OA-like knee pain showed no impairments in hippocampal memory function and behavioral flexibility, suggesting that OA pain impacts cognitive functions less than other chronic pain conditions. In patients, OA pain may interact with other factors (e.g., age, socio-economic factors, and medication) to impair cognition.
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Affiliation(s)
- Sara Gonçalves
- Pain Centre Versus Arthritis, University of Nottingham, Medical School, Queen's Medical Centre, Nottingham, United Kingdom; School of Life Sciences, Medical School, Queen's Medical Centre, Nottingham, United Kingdom
| | - Gareth J Hathway
- Pain Centre Versus Arthritis, University of Nottingham, Medical School, Queen's Medical Centre, Nottingham, United Kingdom; School of Life Sciences, Medical School, Queen's Medical Centre, Nottingham, United Kingdom
| | - Stephen G Woodhams
- Pain Centre Versus Arthritis, University of Nottingham, Medical School, Queen's Medical Centre, Nottingham, United Kingdom; School of Life Sciences, Medical School, Queen's Medical Centre, Nottingham, United Kingdom
| | - Victoria Chapman
- Pain Centre Versus Arthritis, University of Nottingham, Medical School, Queen's Medical Centre, Nottingham, United Kingdom; School of Life Sciences, Medical School, Queen's Medical Centre, Nottingham, United Kingdom; NIHR Nottingham Biomedical Research Centre, University of Nottingham, Nottingham, United Kingdom
| | - Tobias Bast
- Pain Centre Versus Arthritis, University of Nottingham, Medical School, Queen's Medical Centre, Nottingham, United Kingdom; NIHR Nottingham Biomedical Research Centre, University of Nottingham, Nottingham, United Kingdom; School of Psychology and Neuroscience at Nottingham, University of Nottingham, Nottingham, United Kingdom
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12
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Ma L, Zhao W, Huang S, Xu F, Wang Y, Deng D, Zhang T, Shu S, Chen X. IGF/IGF-1R signal pathway in pain: a promising therapeutic target. Int J Biol Sci 2023; 19:3472-3482. [PMID: 37497005 PMCID: PMC10367553 DOI: 10.7150/ijbs.84353] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Accepted: 06/20/2023] [Indexed: 07/28/2023] Open
Abstract
Pain, one of the most important problems in the field of medicine and public health, has great research significance. Opioids are still the main drugs to relieve pain now. However, its application is limited due to its obvious side effects. Therefore, it is urgent to develop new drugs to relieve pain. Multiple studies have found that IGF/IGF-1R pathway plays an important role in the occurrence and development of pain. The regulation of IGF/IGF-1R pathway has obvious effect on pain. This review summarized and discussed the therapeutic potential of IGF/IGF-1R signal pathway for pain. It also summarized that IGF/IGF-1R regulates pain by acting on neuronal excitability, neuroinflammation, glial cells, apoptosis, etc. However, its mechanisms of occurrence and development in pain still need further study in the future. In conclusion, although more deep researches are needed, these studies indicate that IGF/IGF-1R signal pathway is a promising therapeutic target for pain.
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Affiliation(s)
- Lulin Ma
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, China
| | - Wenjing Zhao
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, China
| | - Shiqian Huang
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, China
| | - Feng Xu
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, China
| | - Yafeng Wang
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, China
| | - Daling Deng
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, China
| | - Tianhao Zhang
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, China
| | - Shaofang Shu
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, China
| | - Xiangdong Chen
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, China
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13
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Minami K, Kami K, Nishimura Y, Kawanishi M, Imashiro K, Kami T, Habata S, Senba E, Umemoto Y, Tajima F. Voluntary running-induced activation of ventral hippocampal GABAergic interneurons contributes to exercise-induced hypoalgesia in neuropathic pain model mice. Sci Rep 2023; 13:2645. [PMID: 36788313 PMCID: PMC9929335 DOI: 10.1038/s41598-023-29849-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 02/11/2023] [Indexed: 02/16/2023] Open
Abstract
The exact mechanism of exercise-induced hypoalgesia (EIH) in exercise therapy to improve chronic pain has not been fully clarified. Recent studies have suggested the importance of the ventral hippocampus (vHPC) in inducing chronic pain. We investigated the effects of voluntary running (VR) on FosB+ cells and GABAergic interneurons (parvalbumin-positive [PV+] and somatostatin-positive [SOM+]) in the vHPC-CA1 in neuropathic pain (NPP) model mice. VR significantly improved thermal hyperalgesia in the NPP model. The number of the FosB+ cells was significantly higher in partial sciatic nerve ligation-sedentary mice than in Sham and Naive mice, whereas VR significantly suppressed the FosB+ cells in the vHPC-CA1. Furthermore, VR significantly increased the proportion of activated PV+ and SOM+ interneurons in the vHPC-CA1, and tracer experiments indicated that approximately 24% of neurons projecting from the vHPC-CA1 to the basolateral nucleus of amygdala were activated in NPP mice. These results indicate that feedforward suppression of the activated neurons via VR-induced activation of GABAergic interneurons in the vHPC-CA1 may be a mechanism to produce EIH effects, and suggested that disappearance of negative emotions such as fear and anxiety by VR may play a critical role in improving chronic pain.
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Affiliation(s)
- Kohei Minami
- Department of Rehabilitation Medicine, Wakayama Medical University, Wakayama, Japan
| | - Katsuya Kami
- Department of Rehabilitation Medicine, Wakayama Medical University, Wakayama, Japan.
- Department of Rehabilitation, Faculty of Wakayama Health Care Sciences, Takarazuka University of Medical and Health Care, Wakayama, Japan.
| | - Yukihide Nishimura
- Department of Rehabilitation Medicine, Iwate Medical University, Morioka, Japan
| | - Makoto Kawanishi
- Department of Rehabilitation Medicine, Wakayama Medical University, Wakayama, Japan
| | - Kyosuke Imashiro
- Department of Rehabilitation Medicine, Wakayama Medical University, Wakayama, Japan
| | - Takuma Kami
- Department of Rehabilitation Medicine, Wakayama Medical University, Wakayama, Japan
| | - Shogo Habata
- Department of Rehabilitation Medicine, Wakayama Medical University, Wakayama, Japan
| | - Emiko Senba
- Department of Rehabilitation Medicine, Wakayama Medical University, Wakayama, Japan
- Department of Physical Therapy, Osaka Yukioka College of Health Science, Ibaraki, Japan
| | - Yasunori Umemoto
- Department of Rehabilitation Medicine, Wakayama Medical University, Wakayama, Japan
| | - Fumihiro Tajima
- Department of Rehabilitation Medicine, Wakayama Medical University, Wakayama, Japan
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14
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Xiao D. Temporal lobe epilepsy manifests refractory recurrent abdominal visceral pain in a 7-year-old children. JOURNAL OF PEDIATRIC SURGERY CASE REPORTS 2022. [DOI: 10.1016/j.epsc.2022.102477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
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15
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Cardoso-Cruz H, Laranjeira I, Monteiro C, Galhardo V. Altered prefrontal-striatal theta-band oscillatory dynamics underlie working memory deficits in neuropathic pain rats. Eur J Pain 2022; 26:1546-1568. [PMID: 35603472 DOI: 10.1002/ejp.1982] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 04/21/2022] [Accepted: 05/16/2022] [Indexed: 11/09/2022]
Abstract
BACKGROUND Prelimbic medial prefrontal cortex (PL-mPFC) and nucleus accumbens core region (NAcc) play an important role in supporting several executive cognitive mechanisms, such as spatial working-memory (WM). Recently, this circuit has been also associated with both sensory and affective components of pain. However, it is still unclear whether this circuit is endogenously engaged in neuropathic pain-related cognitive dysfunctions. METHODS To answer this question, we induced the expression of halorhodopsin in local PL-mPFC neurons projecting to NAcc, and then selectively inhibited the terminals of these neurons in the NAcc while recording neural activity during the performance of a delayed non-match to sample (DNMS) spatial WM task. Within-subject behavioral performance and PL-mPFC to NAcc circuit neural activity was assessed after the onset of a persistent rodent neuropathic pain model - spared nerve injury (SNI). RESULTS Our results revealed that the induction of the neuropathy reduced WM performance, and altered the interplay between PL-mPFC and NAcc neurons namely in increasing the functional connectivity from NAcc to PL-mPFC, particularly in the theta-band spontaneous oscillations; in addition, these behavioral and functional perturbations were partially reversed by selective optogenetic inhibition of PL-mPFC neuron terminals into the NAcc during the DNMS task delay-period, without significant antinociceptive effects. CONCLUSIONS Altogether, these results strongly suggest that the PL-mPFC excitatory output into the NAcc plays an important role in the deregulation of WM under pain conditions. SIGNIFICANCE Selective optogenetic inhibition of prefrontal-striatal microcircuit reverses pain-related working memory deficits, but has no significant impact on pain responses. Neuropathic pain underlies an increase of functional connectivity between the nucleus accumbens core area and the prelimbic medial prefrontal cortex mediated by theta-band activity.
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Affiliation(s)
- Helder Cardoso-Cruz
- Instituto de Investigação e Inovação em Saúde (i3S), Pain Neurobiology Group; Universidade do Porto, 4200-135, Porto, Portugal.,Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, 4200-135, Porto, Portugal.,Faculdade de Medicina (FMUP), Departamento de Biomedicina - Unidade de Biologia Experimental; Universidade do Porto, 4200-319, Porto, Portugal
| | - Inês Laranjeira
- Instituto de Investigação e Inovação em Saúde (i3S), Pain Neurobiology Group; Universidade do Porto, 4200-135, Porto, Portugal.,Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, 4200-135, Porto, Portugal.,Faculdade de Medicina (FMUP), Departamento de Biomedicina - Unidade de Biologia Experimental; Universidade do Porto, 4200-319, Porto, Portugal.,Mestrado em Neurobiologia da Faculdade de Medicina da Universidade do Porto. 4200-319, Porto, Portugal
| | - Clara Monteiro
- Instituto de Investigação e Inovação em Saúde (i3S), Pain Neurobiology Group; Universidade do Porto, 4200-135, Porto, Portugal.,Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, 4200-135, Porto, Portugal.,Faculdade de Medicina (FMUP), Departamento de Biomedicina - Unidade de Biologia Experimental; Universidade do Porto, 4200-319, Porto, Portugal
| | - Vasco Galhardo
- Instituto de Investigação e Inovação em Saúde (i3S), Pain Neurobiology Group; Universidade do Porto, 4200-135, Porto, Portugal.,Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, 4200-135, Porto, Portugal.,Faculdade de Medicina (FMUP), Departamento de Biomedicina - Unidade de Biologia Experimental; Universidade do Porto, 4200-319, Porto, Portugal
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16
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Wei X, Centeno MV, Ren W, Borruto AM, Procissi D, Xu T, Jabakhanji R, Mao Z, Kim H, Li Y, Yang Y, Gutruf P, Rogers JA, Surmeier DJ, Radulovic J, Liu X, Martina M, Apkarian AV. Activation of the dorsal, but not the ventral, hippocampus relieves neuropathic pain in rodents. Pain 2021; 162:2865-2880. [PMID: 34160168 PMCID: PMC8464622 DOI: 10.1097/j.pain.0000000000002279] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 02/23/2021] [Accepted: 02/25/2021] [Indexed: 11/26/2022]
Abstract
ABSTRACT Accumulating evidence suggests hippocampal impairment under the chronic pain phenotype. However, it is unknown whether neuropathic behaviors are related to dysfunction of the hippocampal circuitry. Here, we enhanced hippocampal activity by pharmacological, optogenetic, and chemogenetic techniques to determine hippocampal influence on neuropathic pain behaviors. We found that excitation of the dorsal (DH), but not the ventral (VH) hippocampus induces analgesia in 2 rodent models of neuropathic pain (SNI and SNL) and in rats and mice. Optogenetic and pharmacological manipulations of DH neurons demonstrated that DH-induced analgesia was mediated by N-Methyl-D-aspartate and μ-opioid receptors. In addition to analgesia, optogenetic stimulation of the DH in SNI mice also resulted in enhanced real-time conditioned place preference for the chamber where the DH was activated, a finding consistent with pain relief. Similar manipulations in the VH were ineffective. Using chemo-functional magnetic resonance imaging (fMRI), where awake resting-state fMRI was combined with viral vector-mediated chemogenetic activation (PSAM/PSEM89s) of DH neurons, we demonstrated changes of functional connectivity between the DH and thalamus and somatosensory regions that tracked the extent of relief from tactile allodynia. Moreover, we examined hippocampal functional connectivity in humans and observe differential reorganization of its anterior and posterior subdivisions between subacute and chronic back pain. Altogether, these results imply that downregulation of the DH circuitry during chronic neuropathic pain aggravates pain-related behaviors. Conversely, activation of the DH reverses pain-related behaviors through local excitatory and opioidergic mechanisms affecting DH functional connectivity. Thus, this study exhibits a novel causal role for the DH but not the VH in controlling neuropathic pain-related behaviors.
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Affiliation(s)
- Xuhong Wei
- Pain Research Center and Department of Physiology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
- Departments of Physiology and
| | | | | | | | - Daniele Procissi
- Radiology, Albert Einstein College of Medicine, The Bronx, NY, United States
| | - Ting Xu
- Pain Research Center and Department of Physiology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
| | | | | | | | - Yajing Li
- Departments of Materials Science and Engineering and
- Biomedical Engineering, Northwestern University, Evanston, IL, United States
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Yiyuan Yang
- Departments of Materials Science and Engineering and
- Biomedical Engineering, Northwestern University, Evanston, IL, United States
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Philipp Gutruf
- Departments of Materials Science and Engineering and
- Biomedical Engineering, Northwestern University, Evanston, IL, United States
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - John A. Rogers
- Departments of Materials Science and Engineering and
- Biomedical Engineering, Northwestern University, Evanston, IL, United States
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | | | - Jelena Radulovic
- Department of Neuroscience and Department of Psychiatry and Behavioral Science, Albert Einstein College of Medicine, The Bronx, NY, United States
| | - Xianguo Liu
- Pain Research Center and Department of Physiology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
| | - Marco Martina
- Departments of Physiology and
- Department of Neuroscience and Department of Psychiatry and Behavioral Science, Albert Einstein College of Medicine, The Bronx, NY, United States
| | - Apkar Vania Apkarian
- Departments of Physiology and
- Department of Physical Medicine and Rehabilitation, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
- Department of Anesthesia, at Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
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17
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Barroso J, Branco P, Apkarian AV. Brain mechanisms of chronic pain: critical role of translational approach. Transl Res 2021; 238:76-89. [PMID: 34182187 PMCID: PMC8572168 DOI: 10.1016/j.trsl.2021.06.004] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 06/16/2021] [Accepted: 06/19/2021] [Indexed: 01/15/2023]
Abstract
Chronic pain is a leading cause of disability worldwide and its prevalence is likely to increase over the next decades. Treatment for chronic pain remains insufficient and therapeutical advances have not made comparable progress with that for many chronic disorders, thus amplifying the concern on the future burden of the disease. At the same time, and even after decades of intense research, the underlying pathophysiology of chronic pain remains minimally understood. We believe advancing our current understanding of chronic pain requires mechanistically explicit, hypothesis-driven, and clinically focused models. In this review we highlight some of the main findings over the last decades that have contributed to the present knowledge of brain mechanisms of chronic pain, and how such advances were possible due to a reverse translational research approach. We argue that this approach is essential in the chronic pain field, in order to generate new scientific hypotheses, probe physiological mechanisms, develop therapeutic strategies and translate findings back into promising human clinical trials.
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Affiliation(s)
- Joana Barroso
- Department of Physiology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois; Department of Physical Medicine and Rehabilitation, Northwestern University, Feinberg School of Medicine, Chicago, Illinois; Center for Chronic Pain and Drug Abuse, Northwestern University, Feinberg School of Medicine, Chicago, Illinois
| | - Paulo Branco
- Department of Physiology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois; Center for Chronic Pain and Drug Abuse, Northwestern University, Feinberg School of Medicine, Chicago, Illinois
| | - Apkar Vania Apkarian
- Department of Physiology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois; Department of Physical Medicine and Rehabilitation, Northwestern University, Feinberg School of Medicine, Chicago, Illinois; Center for Chronic Pain and Drug Abuse, Northwestern University, Feinberg School of Medicine, Chicago, Illinois; Department of Anesthesiology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois.
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Synaptamide Improves Cognitive Functions and Neuronal Plasticity in Neuropathic Pain. Int J Mol Sci 2021; 22:ijms222312779. [PMID: 34884587 PMCID: PMC8657620 DOI: 10.3390/ijms222312779] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 11/24/2021] [Accepted: 11/24/2021] [Indexed: 01/14/2023] Open
Abstract
Neuropathic pain arises from damage or dysfunction of the peripheral or central nervous system and manifests itself in a wide variety of sensory symptoms and cognitive disorders. Many studies demonstrate the role of neuropathic pain-induced neuroinflammation in behavioral disorders. For effective neuropathic pain treatment, an integrative approach is required, which simultaneously affects several links of pathogenesis. One promising candidate for this role is synaptamide (N-docosahexaenoylethanolamine), which is an endogenous metabolite of docosahexaenoic acid. In this study, we investigated the activity of synaptamide on mice behavior and hippocampal plasticity in neuropathic pain induced by spared nerve injury (SNI). We found a beneficial effect of synaptamide on the thermal allodynia and mechanical hyperalgesia dynamics. Synaptamide prevented working and long-term memory impairment. These results are probably based on the supportive effect of synaptamide on SNI-impaired hippocampal plasticity. Nerve ligation caused microglia activation predominantly in the contralateral hippocampus, while synaptamide inhibited this effect. The treatment reversed dendritic tree degeneration, dendritic spines density reduction on CA1-pyramidal neurons, neurogenesis deterioration, and hippocampal long-term potentiation (LTP) impairment. In addition, synaptamide inhibits changes in the glutamatergic receptor expression. Thus, synaptamide has a beneficial effect on hippocampal functioning, including synaptic plasticity and hippocampus-dependent cognitive processes in neuropathic pain.
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Plasma inflammatory cytokines and treatment-resistant depression with comorbid pain: improvement by ketamine. J Neuroinflammation 2021; 18:200. [PMID: 34526064 PMCID: PMC8444441 DOI: 10.1186/s12974-021-02245-5] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Accepted: 08/22/2021] [Indexed: 12/13/2022] Open
Abstract
Background Treatment-resistant depression (TRD) and pain frequently coexist clinically. Ketamine has analgesic and antidepressant effects, but few studies have evaluated individual differences in antidepressant outcomes to repeated ketamine in TRD patients with comorbid pain. Our aims were to determine the difference in ketamine’s antidepressant effects in TRD patients with or without pain and then to examine whether inflammatory cytokines might contribute to ketamine’s effect. Methods Sixty-six patients with TRD received six infusions of ketamine. Plasma levels of 19 inflammatory cytokines were assessed at baseline and post-infusion (day 13 and day 26) using the Luminex assay. Plasma inflammatory cytokines of sixty healthy controls (HCs) were also examined. Results TRD patients with pain had a higher antidepressant response rate (χ2 = 4.062, P = 0.044) and remission rate (χ2 = 4.062, P = 0.044) than patients without pain. Before ketamine treatment, GM-CSF and IL-6 levels were higher in the pain group than in the non-pain and HC groups. In the pain group, levels of TNF-α and IL-6 at day 13 and GM-CSF, fractalkine, IFN-γ, IL-10, MIP-3α, IL-12P70, IL-17α, IL-1β, IL-2, IL-4, IL-23, IL-5, IL-6, IL-7, MIP-1β, and TNF-α at day 26 were lower than those at baseline; in the non-pain group, TNF-α levels at day 13 and day 26 were lower than those at baseline. In the pain group, the changes of IL-6 were associated with improvement in pain intensity (β = 0.333, P = 0.001) and depressive symptoms (β = 0.478, P = 0.005) at day 13. Path analysis showed the direct (β = 2.995, P = 0.028) and indirect (β = 0.867, P = 0.042) effects of changes of IL-6 on improvement in depressive symptoms both were statistically significant. Conclusion This study suggested that an elevated inflammatory response plays a critical role in individual differences in TRD patients with or without pain. Ketamine showed great antidepressant and analgesic effects in TRD patients with pain, which may be related to its effects on modulating inflammation. Trial registration ChiCTR, ChiCTR-OOC-17012239. Registered on 26 May 2017 Supplementary Information The online version contains supplementary material available at 10.1186/s12974-021-02245-5.
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Fullerene C60 nanoparticle attenuates pain and tumor necrosis factor-α protein expression in hippocampus following diabetic neuropathy in rats. PHYSIOLOGY AND PHARMACOLOGY 2021. [DOI: 10.52547/phypha.26.4.5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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McIlwrath SL, Starr ME, High AE, Saito H, Westlund KN. Effect of acetyl-L-carnitine on hypersensitivity in acute recurrent caerulein-induced pancreatitis and microglial activation along the brain’s pain circuitry. World J Gastroenterol 2021; 27:794-814. [PMID: 33727771 PMCID: PMC7941858 DOI: 10.3748/wjg.v27.i9.794] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 12/08/2020] [Accepted: 01/15/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Acute pancreatitis (AP) and recurring AP are serious health care problems causing excruciating pain and potentially lethal outcomes due to sepsis. The validated caerulein- (CAE) induced mouse model of acute/recurring AP produces secondary persistent hypersensitivity and anxiety-like behavioral changes for study.
AIM To determine efficacy of acetyl-L-carnitine (ALC) to reduce pain-related behaviors and brain microglial activation along the pain circuitry in CAE-pancreatitis.
METHODS Pancreatitis was induced with 6 hly intraperitoneal (i.p.) injections of CAE (50 µg/kg), 3 d a week for 6 wk in male C57BL/6J mice. Starting in week 4, mice received either vehicle or ALC until experiment’s end. Mechanical hyper-sensitivity was assessed with von Frey filaments. Heat hypersensitivity was determined with the hotplate test. Anxiety-like behavior was tested in week 6 using elevated plus maze and open field tests. Microglial activation in brain was quantified histologically by immunostaining for ionized calcium-binding adaptor molecule 1 (Iba1).
RESULTS Mice with CAE-induced pancreatitis had significantly reduced mechanical withdrawal thresholds and heat response latencies, indicating ongoing pain. Treatment with ALC attenuated inflammation-induced hypersensitivity, but hypersensitivity due to abdominal wall injury caused by repeated intraperitoneal injections persisted. Animals with pancreatitis displayed spontaneous anxiety-like behavior in the elevated plus maze compared to controls. Treatment with ALC resulted in increased numbers of rearing activity events, but time spent in “safety” was not changed. After all the abdominal injections, pancreata were translucent if excised at experiment’s end and opaque if excised on the subsequent day, indicative of spontaneous healing. Post mortem histopathological analysis performed on pancreas sections stained with Sirius Red and Fast Green identified wide-spread fibrosis and acinar cell atrophy in sections from mice with CAE-induced pancreatitis that was not rescued by treatment with ALC. Microglial Iba1 immunostaining was significantly increased in hippocampus, thalamus (intralaminar nuclei), hypothalamus, and amygdala of mice with CAE-induced pancreatitis compared to naïve controls but unchanged in the primary somatosensory cortex compared to naïves.
CONCLUSION CAE-induced pancreatitis caused increased pain-related behaviors, pancreatic fibrosis, and brain microglial changes. ALC alleviated CAE-induced mechanical and heat hypersensitivity but not abdominal wall injury-induced hypersensitivity caused by the repeated injections.
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Affiliation(s)
- Sabrina L McIlwrath
- Research Service, New Mexico Veterans Affairs Healthcare System, Albuquerque, NM 87108, United States
| | - Marlene E Starr
- Department of Surgery, University of Kentucky, Lexington, KY 40536, United States
| | - Abigail E High
- College of Liberal Arts, University of Texas, Austin, TX 78712, United States
| | - Hiroshi Saito
- Department of Surgery, University of Kentucky, Lexington, KY 40536, United States
| | - Karin N Westlund
- Research Service, New Mexico Veterans Affairs Healthcare System, Albuquerque, NM 87108, United States
- Department of Anesthesiology and Critical Care Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, United States
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Solorza J, Oliva CA, Castillo K, Amestica G, Maldifassi MC, López-Cortés XA, Barra R, Stehberg J, Piesche M, Sáez-Briones P, González W, Arenas-Salinas M, Mariqueo TA. Effects of Interleukin-1β in Glycinergic Transmission at the Central Amygdala. Front Pharmacol 2021; 12:613105. [PMID: 33746753 PMCID: PMC7973117 DOI: 10.3389/fphar.2021.613105] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Accepted: 01/19/2021] [Indexed: 01/22/2023] Open
Abstract
Interleukin-1β (IL-1β) is an important cytokine that modulates peripheral and central pain sensitization at the spinal level. Among its effects, it increases spinal cord excitability by reducing inhibitory Glycinergic and GABAergic neurotransmission. In the brain, IL-1β is released by glial cells in regions associated with pain processing during neuropathic pain. It also has important roles in neuroinflammation and in regulating NMDA receptor activity required for learning and memory. The modulation of glycine-mediated inhibitory activity via IL-1β may play a critical role in the perception of different levels of pain. The central nucleus of the amygdala (CeA) participates in receiving and processing pain information. Interestingly, this nucleus is enriched in the regulatory auxiliary glycine receptor (GlyR) β subunit (βGlyR); however, no studies have evaluated the effect of IL-1β on glycinergic neurotransmission in the brain. Hence, we hypothesized that IL-1β may modulate GlyR-mediated inhibitory activity via interactions with the βGlyR subunit. Our results show that the application of IL-1β (10 ng/ml) to CeA brain slices has a biphasic effect; transiently increases and then reduces sIPSC amplitude of CeA glycinergic currents. Additionally, we performed molecular docking, site-directed mutagenesis, and whole-cell voltage-clamp electrophysiological experiments in HEK cells transfected with GlyRs containing different GlyR subunits. These data indicate that IL-1β modulates GlyR activity by establishing hydrogen bonds with at least one key amino acid residue located in the back of the loop C at the ECD domain of the βGlyR subunit. The present results suggest that IL-1β in the CeA controls glycinergic neurotransmission, possibly via interactions with the βGlyR subunit. This effect could be relevant for understanding how IL-1β released by glia modulates central processing of pain, learning and memory, and is involved in neuroinflammation.
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Affiliation(s)
- Jocelyn Solorza
- Center for Medical Research, Laboratory of Neuropharmacology, School of Medicine, Universidad de Talca, Talca, Chile.,Centro de Bioinformática, Simulación y Modelado (CBSM), Facultad de Ingeniería, Universidad de Talca, Talca, Chile
| | - Carolina A Oliva
- Institute of Biomedical Sciences, Faculty of Medicine, Universidad Andrés Bello, Santiago, Chile
| | - Karen Castillo
- Centro Interdisciplinario de Neurociencia de Valparaíso, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile
| | - Gabriela Amestica
- Center for Medical Research, Laboratory of Neuropharmacology, School of Medicine, Universidad de Talca, Talca, Chile
| | - María Constanza Maldifassi
- Centro Interdisciplinario de Neurociencia de Valparaíso, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile
| | - Xaviera A López-Cortés
- Department of Computer Science and Industries, Faculty of Engineering Science, Universidad Católica del Maule, Talca, Chile
| | - Rafael Barra
- Centro de Investigación Biomédica y Aplicada (CIBAP), Escuela de Medicina, Facultad de Ciencias Médicas, Universidad de Santiago de Chile (USACH), Santiago, Chile
| | - Jimmy Stehberg
- Faculty of Biological Sciences and Faculty of Medicine, Instituto de Ciencias Biomédicas, Universidad Andres Bello, Santiago, Chile
| | - Matthias Piesche
- Laboratory of Biomedical Research, Medicine Faculty, Universidad Católica del Maule, Talca, Chile.,Oncology Center, Medicine Faculty, Universidad Católica del Maule, Talca, Chile
| | - Patricio Sáez-Briones
- Laboratory of Neuropharmacology and Behavior, School of Medicine, Faculty of Medical Sciences, Universidad de Santiago de Chile (USACH), Santiago, Chile
| | - Wendy González
- Centro de Bioinformática, Simulación y Modelado (CBSM), Facultad de Ingeniería, Universidad de Talca, Talca, Chile.,Millennium Nucleus of Ion Channels-Associated Diseases (MiNICAD), Universidad de Talca, Talca, Chile
| | - Mauricio Arenas-Salinas
- Centro de Bioinformática, Simulación y Modelado (CBSM), Facultad de Ingeniería, Universidad de Talca, Talca, Chile
| | - Trinidad A Mariqueo
- Center for Medical Research, Laboratory of Neuropharmacology, School of Medicine, Universidad de Talca, Talca, Chile
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Mai CL, Tan Z, Xu YN, Zhang JJ, Huang ZH, Wang D, Zhang H, Gui WS, Zhang J, Lin ZJ, Meng YT, Wei X, Jie YT, Grace PM, Wu LJ, Zhou LJ, Liu XG. CXCL12-mediated monocyte transmigration into brain perivascular space leads to neuroinflammation and memory deficit in neuropathic pain. Theranostics 2021; 11:1059-1078. [PMID: 33391521 PMCID: PMC7738876 DOI: 10.7150/thno.44364] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Accepted: 10/26/2020] [Indexed: 12/19/2022] Open
Abstract
Emerging clinical and experimental evidence demonstrates that neuroinflammation plays an important role in cognitive impairment associated with neuropathic pain. However, how peripheral nerve challenge induces remote inflammation in the brain remains largely unknown. Methods: The circulating leukocytes and plasma C-X-C motif chemokine 12 (CXCL12) and brain perivascular macrophages (PVMs) were analyzed by flow cytometry, Western blotting, ELISA, and immunostaining in spared nerve injury (SNI) mice. The memory function was evaluated with a novel object recognition test (NORT) in mice and with Montreal Cognitive Assessment (MoCA) in chronic pain patients. Results: The classical monocytes and CXCL12 in the blood, PVMs in the perivascular space, and gliosis in the brain, particularly in the hippocampus, were persistently increased following SNI in mice. Using the transgenic CCR2RFP/+ and CX3CR1GFP/+ mice, we discovered that at least some of the PVMs were recruited from circulating monocytes. The SNI-induced increase in hippocampal PVMs, gliosis, and memory decline were substantially prevented by either depleting circulating monocytes via intravenous injection of clodronate liposomes or blockade of CXCL12-CXCR4 signaling. On the contrary, intravenous injection of CXCL12 at a pathological concentration in naïve mice mimicked SNI effects. Significantly, we found that circulating monocytes and plasma CXCL12 were elevated in chronic pain patients, and both of them were closely correlated with memory decline. Conclusion: CXCL12-mediated monocyte recruitment into the perivascular space is critical for neuroinflammation and the resultant cognitive impairment in neuropathic pain.
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Affiliation(s)
- Chun-Lin Mai
- Department of Physiology and Pain Research Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
| | - Zhi Tan
- Department of Physiology and Pain Research Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
| | - Ya-Nan Xu
- Department of Physiology and Pain Research Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
| | - Jing-Jun Zhang
- Department of Anesthesiology and Pain Clinic, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, China
| | - Zhen-Hua Huang
- Division of Emergency Medicine, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, China
| | - Dong Wang
- Department of Clinical Laboratory, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Hui Zhang
- Department of Anesthesiology, Guangdong Second Provincial General Hospital, Guangzhou, 510317, China
| | - Wen-Shan Gui
- Department of Physiology and Pain Research Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
| | - Jun Zhang
- Department of Physiology and Pain Research Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
| | - Zhen-Jia Lin
- Department of Physiology and Pain Research Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
| | - Ying-Tong Meng
- Department of Physiology and Pain Research Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
| | - Xiao Wei
- Department of Physiology and Pain Research Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
| | - Ying-Tao Jie
- Department of Physiology and Pain Research Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
| | - Peter M. Grace
- Department of Critical Care & Respiratory Care Research (PMG), University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Long-Jun Wu
- Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA
| | - Li-Jun Zhou
- Department of Physiology and Pain Research Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
- Guangdong Province Key Laboratory of Brain Function and Disease, Guangzhou 510080, China
| | - Xian-Guo Liu
- Department of Physiology and Pain Research Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
- Guangdong Province Key Laboratory of Brain Function and Disease, Guangzhou 510080, China
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Cioato SG, Medeiros LF, Lopes BC, de Souza A, Medeiros HR, Assumpção JAF, Caumo W, Roesler R, Torres ILS. Antinociceptive and neurochemical effects of a single dose of IB-MECA in chronic pain rat models. Purinergic Signal 2020; 16:573-584. [PMID: 33161497 PMCID: PMC7855191 DOI: 10.1007/s11302-020-09751-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Accepted: 10/18/2020] [Indexed: 12/31/2022] Open
Abstract
This study aimed to evaluate the effect of a single administration of IB-MECA, an A3 adenosine receptor agonist, upon the nociceptive response and central biomarkers of rats submitted to chronic pain models. A total of 136 adult male Wistar rats were divided into two protocols: (1) chronic inflammatory pain (CIP) using complete Freund's adjuvant and (2) neuropathic pain (NP) by chronic constriction injury of the sciatic nerve. Thermal and mechanical hyperalgesia was measured using von Frey (VF), Randal-Selitto (RS), and hot plate (HP) tests. Rats were treated with a single dose of IB-MECA (0.5 μmol/kg i.p.), a vehicle (dimethyl sulfoxide-DMSO), or positive control (morphine, 5 mg/kg i.p.). Interleukin 1β (IL-1β), brain-derived neurotrophic factor (BDNF), and nerve growth factor (NGF) levels were measured in the brainstem and spinal cord using enzyme-linked immunosorbent assay (ELISA). The establishment of the chronic pain (CIP or NP) model was observed 14 days after induction by a decreased nociceptive threshold in all three tests (GEE, P < 0.05). The antinociceptive effect of a single dose of IB-MECA was observed in both chronic pain models, but this was more effective in NP model. There was an increase in IL-1β levels promoted by CIP. NP model promoted increase in the brainstem BDNF levels, which was reversed by IB-MECA.
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Affiliation(s)
- Stefania Giotti Cioato
- Laboratório de Farmacologia da Dor e Neuromodulação, Investigações Pré-clínicas, Centro de Pesquisa Experimental (CPE), Hospital de Clínicas de Porto Alegre (HCPA), Universidade Federal do Rio Grande do Sul (UFRGS), Rua Ramiro Barcelos, 2350, Porto Alegre, RS, 90035-007, Brazil
- Unidade de Experimentação Animal, Grupo de Pesquisa e Pós-Graduação, HCPA, Porto Alegre, RS, Brazil
- Programa de Pós-Graduação em Ciências Biológicas, Farmacologia e Terapêutica, Instituto de Ciências Básicas da Saúde (ICBS), UFRGS, Porto Alegre, RS, Brazil
| | - Liciane Fernandes Medeiros
- Laboratório de Farmacologia da Dor e Neuromodulação, Investigações Pré-clínicas, Centro de Pesquisa Experimental (CPE), Hospital de Clínicas de Porto Alegre (HCPA), Universidade Federal do Rio Grande do Sul (UFRGS), Rua Ramiro Barcelos, 2350, Porto Alegre, RS, 90035-007, Brazil
- Unidade de Experimentação Animal, Grupo de Pesquisa e Pós-Graduação, HCPA, Porto Alegre, RS, Brazil
- Programa de Pós-Graduação em Ciências Biológicas, Farmacologia e Terapêutica, Instituto de Ciências Básicas da Saúde (ICBS), UFRGS, Porto Alegre, RS, Brazil
- Programa de Pós-Graduação em Saúde e Desenvolvimento Humano, Universidade La Salle, Canoas, RS, Brazil
| | - Bettega Costa Lopes
- Laboratório de Farmacologia da Dor e Neuromodulação, Investigações Pré-clínicas, Centro de Pesquisa Experimental (CPE), Hospital de Clínicas de Porto Alegre (HCPA), Universidade Federal do Rio Grande do Sul (UFRGS), Rua Ramiro Barcelos, 2350, Porto Alegre, RS, 90035-007, Brazil
- Unidade de Experimentação Animal, Grupo de Pesquisa e Pós-Graduação, HCPA, Porto Alegre, RS, Brazil
- Programa de Pós-Graduação em Ciências Biológicas: Fisiologia, ICBS, UFRGS, Porto Alegre, RS, Brazil
| | - Andressa de Souza
- Laboratório de Farmacologia da Dor e Neuromodulação, Investigações Pré-clínicas, Centro de Pesquisa Experimental (CPE), Hospital de Clínicas de Porto Alegre (HCPA), Universidade Federal do Rio Grande do Sul (UFRGS), Rua Ramiro Barcelos, 2350, Porto Alegre, RS, 90035-007, Brazil
- Programa de Pós-Graduação em Saúde e Desenvolvimento Humano, Universidade La Salle, Canoas, RS, Brazil
| | - Helouise Richardt Medeiros
- Laboratório de Farmacologia da Dor e Neuromodulação, Investigações Pré-clínicas, Centro de Pesquisa Experimental (CPE), Hospital de Clínicas de Porto Alegre (HCPA), Universidade Federal do Rio Grande do Sul (UFRGS), Rua Ramiro Barcelos, 2350, Porto Alegre, RS, 90035-007, Brazil
- Unidade de Experimentação Animal, Grupo de Pesquisa e Pós-Graduação, HCPA, Porto Alegre, RS, Brazil
- Programa de Pós-Graduação em Medicina, Ciências Médicas, UFRGS, Porto Alegre, RS, Brazil
| | - José Antônio Fagundes Assumpção
- Laboratório de Farmacologia da Dor e Neuromodulação, Investigações Pré-clínicas, Centro de Pesquisa Experimental (CPE), Hospital de Clínicas de Porto Alegre (HCPA), Universidade Federal do Rio Grande do Sul (UFRGS), Rua Ramiro Barcelos, 2350, Porto Alegre, RS, 90035-007, Brazil
- Unidade de Experimentação Animal, Grupo de Pesquisa e Pós-Graduação, HCPA, Porto Alegre, RS, Brazil
- Programa de Pós-Graduação em Ciências Biológicas, Farmacologia e Terapêutica, Instituto de Ciências Básicas da Saúde (ICBS), UFRGS, Porto Alegre, RS, Brazil
| | - Wolnei Caumo
- Programa de Pós-Graduação em Medicina, Ciências Médicas, UFRGS, Porto Alegre, RS, Brazil
| | - Rafael Roesler
- Programa de Pós-Graduação em Ciências Biológicas, Farmacologia e Terapêutica, Instituto de Ciências Básicas da Saúde (ICBS), UFRGS, Porto Alegre, RS, Brazil
- Programa de Pós-Graduação em Medicina, Ciências Médicas, UFRGS, Porto Alegre, RS, Brazil
- Cancer and Neurobiology Laboratory, Experimental Research Center, HCPA, Porto Alegre, RS, Brazil
| | - Iraci L S Torres
- Laboratório de Farmacologia da Dor e Neuromodulação, Investigações Pré-clínicas, Centro de Pesquisa Experimental (CPE), Hospital de Clínicas de Porto Alegre (HCPA), Universidade Federal do Rio Grande do Sul (UFRGS), Rua Ramiro Barcelos, 2350, Porto Alegre, RS, 90035-007, Brazil.
- Unidade de Experimentação Animal, Grupo de Pesquisa e Pós-Graduação, HCPA, Porto Alegre, RS, Brazil.
- Programa de Pós-Graduação em Ciências Biológicas, Farmacologia e Terapêutica, Instituto de Ciências Básicas da Saúde (ICBS), UFRGS, Porto Alegre, RS, Brazil.
- Programa de Pós-Graduação em Medicina, Ciências Médicas, UFRGS, Porto Alegre, RS, Brazil.
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The influence of rat strain on the development of neuropathic pain and comorbid anxio-depressive behaviour after nerve injury. Sci Rep 2020; 10:20981. [PMID: 33262364 PMCID: PMC7708988 DOI: 10.1038/s41598-020-77640-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Accepted: 11/13/2020] [Indexed: 12/16/2022] Open
Abstract
Back-translating the clinical manifestations of human disease burden into animal models is increasingly recognized as an important facet of preclinical drug discovery. We hypothesized that inbred rat strains possessing stress hyper-reactive-, depressive- or anxiety-like phenotypes may possess more translational value than common outbred strains for modeling neuropathic pain. Rats (inbred: LEW, WKY, F344/ICO and F344/DU, outbred: Crl:SD) were exposed to Spared Nerve Injury (SNI) and evaluated routinely for 6 months on behaviours related to pain (von Frey stimulation and CatWalk-gait analysis), anxiety (elevated plus maze, EPM) and depression (sucrose preference test, SPT). Markers of stress reactivity together with spinal/brain opioid receptor expression were also measured. All strains variously developed mechanical allodynia after SNI with the exception of stress-hyporesponsive LEW rats, despite all strains displaying similar functional gait-deficits after injury. However, affective changes reflective of anxiety- and depressive-like behaviour were only observed for F344/DU in the EPM, and for Crl:SD in SPT. Although differences in stress reactivity and opioid receptor expression occurred, overall they were relatively unaffected by SNI. Thus, anxio-depressive behaviours did not develop in all strains after nerve injury, and correlated only modestly with degree of pain sensitivity or with genetic predisposition to stress and/or affective disturbances.
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Tyrtyshnaia AA, Egorova EL, Starinets AA, Ponomarenko AI, Ermolenko EV, Manzhulo IV. N-Docosahexaenoylethanolamine Attenuates Neuroinflammation and Improves Hippocampal Neurogenesis in Rats with Sciatic Nerve Chronic Constriction Injury. Mar Drugs 2020; 18:md18100516. [PMID: 33076443 PMCID: PMC7602669 DOI: 10.3390/md18100516] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 10/10/2020] [Accepted: 10/13/2020] [Indexed: 02/06/2023] Open
Abstract
Chronic neuropathic pain is a condition that causes both sensory disturbances and a variety of functional disorders, indicating the involvement of various brain structures in pain pathogenesis. One of the factors underlying chronic neuropathic pain is neuroinflammation, which is accompanied by microglial activation and pro-inflammatory factor release. N-docosahexaenoylethanolamine (DHEA, synaptamide) is an endocannabinoid-like metabolite synthesized endogenously from docosahexaenoic acid. Synaptamide exhibits anti-inflammatory activity and improves neurite outgrowth, neurogenesis, and synaptogenesis within the hippocampus. This study aims to evaluate the effects of synaptamide obtained by the chemical modification of DHA, extracted from the Far Eastern raw material Berryteuthis magister on neuroinflammatory response and hippocampal neurogenesis changes during neuropathic pain. The study of microglial protein and cytokine concentrations was performed using immunohistochemistry and ELISA. The brain lipid analysis was performed using the liquid chromatography-mass spectrometry technique. Behavioral experiments showed that synaptamide prevented neuropathic pain-associated sensory and behavioral changes, such as thermal allodynia, impaired locomotor activity, working and long-term memory, and increased anxiety. Synaptamide attenuated microglial activation, release of proinflammatory cytokines, and decrease in hippocampal neurogenesis. Lipid analysis revealed changes in the brain N-acylethanolamines composition and plasmalogen concentration after synaptamide administration. In conclusion, we show here that synaptamide may have potential for use in preventing or treating neuropathic cognitive pain and emotional effects.
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Campos ACP, Antunes GF, Matsumoto M, Pagano RL, Martinez RCR. Neuroinflammation, Pain and Depression: An Overview of the Main Findings. Front Psychol 2020; 11:1825. [PMID: 32849076 PMCID: PMC7412934 DOI: 10.3389/fpsyg.2020.01825] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Accepted: 07/02/2020] [Indexed: 12/23/2022] Open
Abstract
Chronic pain is a serious public health problem with a strong affective-motivational component that makes it difficult to treat. Most patients with chronic pain suffer from severe depression; hence, both conditions coexist and exacerbate one another. Brain inflammatory mediators are critical for maintaining depression-pain syndrome and could be substrates for it. The goal of our paper was to review clinical and preclinical findings to identify the neuroinflammatory profile associated with the cooccurrence of pain and depression. In addition, we aimed to explore the regulatory effect of neuronal reorganization on the inflammatory response in pain and depression. We conducted a quantitative review supplemented by manual screening. Our results revealed inflammatory signatures in different preclinical models and clinical articles regarding depression-pain syndrome. We also identified that improvements in depressive symptoms and amelioration of pain can be modulated through direct targeting of inflammatory mediators, such as cytokines and molecular inhibitors of the inflammatory cascade. Additionally, therapeutic targets that improve and regulate the synaptic environment and its neurotransmitters may act as anti-inflammatory compounds, reducing local damage-associated molecular patterns and inhibiting the activation of immune and glial cells. Taken together, our data will help to better elucidate the neuroinflammatory profile in pain and depression and may help to identify pharmacological targets for effective management of depression-pain syndrome.
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Affiliation(s)
| | | | - Marcio Matsumoto
- Anesthesiology Medical Center, Hospital Sirio-Libanes, São Paulo, Brazil
| | | | - Raquel Chacon Ruiz Martinez
- Division of Neuroscience, Hospital Sirio-Libanes, São Paulo, Brazil.,LIM 23, Institute of Psychiatry, University of São Paulo School of Medicine, São Paulo, Brazil
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Tyrtyshnaia A, Manzhulo I, Konovalova S, Zagliadkina A. Neuropathic Pain Causes a Decrease in the Dendritic Tree Complexity of Hippocampal CA3 Pyramidal Neurons. Cells Tissues Organs 2020; 208:89-100. [DOI: 10.1159/000506812] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2019] [Accepted: 02/26/2020] [Indexed: 11/19/2022] Open
Abstract
The International Pain Association defines neuropathic pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage.” Recent studies show that chronic neuropathic pain causes both morphological and functional changes within brain structures. Due to the impact of supraspinal centers on pain signal processing, patients with chronic pain often suffer from depression, anxiety, memory impairment, and learning disabilities. Changes in hippocampal neuronal and glial plasticity can play a substantial role in the development of these symptoms. Given the special role of the CA3 hippocampal area in chronic stress reactions, we suggested that this region may undergo significant morphological changes as a result of persistent pain. Since the CA3 area is involved in the implementation of hippocampus-dependent memory, changes in the neuronal morphology can cause cognitive impairment observed in chronic neuropathic pain. This study aimed to elucidate the structural and plastic changes within the hippocampus associated with dendritic tree atrophy of CA3 pyramidal neurons in mice with chronic sciatic nerve constriction. Behavioral testing revealed impaired working and long-term memory in mice with a chronic constriction injury. Using the Golgi-Cox method, we revealed a decrease in the number of branches and dendritic length of CA3 pyramidal neurons. The dendritic spine number was decreased, predominantly due to a reduction in mushroom spines. An immunohistochemical study showed changes in astro- and microglial activity, which could affect the morphology of neurons both directly and indirectly via the regulation of neurotrophic factor synthesis. Using ELISA, we found a decrease in brain-derived neurotrophic factor production and an increase in neurotrophin-3 production. Morphological and biochemical changes in the CA3 area are accompanied by impaired working and long-term memory of animals. Thus, we can conclude that morphological and biochemical changes within the CA3 hippocampal area may underlie the cognitive impairment in neuropathic pain.
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Mokhtari T, Tu Y, Hu L. Involvement of the hippocampus in chronic pain and depression. BRAIN SCIENCE ADVANCES 2020. [DOI: 10.26599/bsa.2019.9050025] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
Increases in depressive behaviors have been reported in patients experiencing chronic pain. In these patients, the symptoms of pain and depression commonly coexist, impairing their lives and challenging effective treatment. The hippocampus may play a role in both chronic pain and depression. A reduction in the volume of the hippocampus is related to reduced neurogenesis and neuroplasticity in cases of chronic pain and depression. Moreover, an increase of proinflammatory factors and a reduction of neurotrophic factors have been reported to modulate the hippocampal neurogenesis and neuroplasticity in chronic pain and depression. This review discusses the mechanisms underlying the depressive-like behavior accompanying chronic pain, emphasizing the structural and functional changes in the hippocampus. We also discuss the hypothesis that pro-inflammatory factors and neurotrophic factors expressed in the hippocampus may serve as a therapeutic target for comorbid chronic pain and depression.
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Affiliation(s)
- Tahmineh Mokhtari
- CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing 100101, China
- Department of Psychology, University of Chinese Academy of Sciences, Beijing 100101, China
| | - Yiheng Tu
- Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA
| | - Li Hu
- CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing 100101, China
- Department of Psychology, University of Chinese Academy of Sciences, Beijing 100101, China
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Li R, Dang S, Yao M, Zhao C, Zhang W, Cui J, Wang J, Wen A. Osthole alleviates neuropathic pain in mice by inhibiting the P2Y 1-receptor-dependent JNK signaling pathway. Aging (Albany NY) 2020; 12:7945-7962. [PMID: 32365053 PMCID: PMC7244062 DOI: 10.18632/aging.103114] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Accepted: 04/11/2020] [Indexed: 04/14/2023]
Abstract
There are many reports about natural products relieving neuralgia. Osthole is the main component of Angelica biserrata Yuan et Shan, a natural product that treats rheumatism through the elimination of inflammation and the alleviation of pain that has a long history in the clinic. The analgesic mechanism of osthole is complicated and confusing. Astrocytes have attracted increasing attention from pain researchers. Inhibitors targeting astrocytes are thought to be promising treatments for neuropathic pain. Whether osthole can alleviate neuropathic pain through astrocytes has not been elucidated in detail. In this study, CCI surgery was used to establish the neuropathic pain model in mice. The CCI mice were treated with osthole (5, 10, or 20 mg/kg/day) for 14 days in vivo. Mechanical allodynia and heat hyperalgesia were measured to evaluate the therapeutic effect of osthole. In mechanism research, the activation of astrocytes; the protein expression of P2Y1R and p-JNK in astrocytes; the release of inflammatory factors; the variations in mEPSPs and eEPSPs; and the levels of GluA1, GluN2B, p-ERK, p-CREB and c-Fos in neurons were observed. The P2Y1R inhibitor MRS2179 and the p-JNK inhibitor SP600125 were used to demonstrate how osthole works in neuropathic pain. In addition, astrocytes and neurons were used to estimate the direct effect of osthole on astrocyte-neuron interactions and signal transmission in vitro. Our findings suggest that osthole treatment obviously relieved mechanical allodynia and heat hyperalgesia in CCI mice. P2Y1R is involved in CCI-induced pain hypersensitivity, and P2Y1R is required for osthole-induced p-JNK downregulation in the spinal cord. Osthole inhibited astrocyte activation and reduced inflammatory factor expression. After osthole treatment, mEPSP frequency and eEPSP amplitude were decreased in spinal lamina I-II neurons. Downstream signaling molecules such as pGluA1, pGluN2B, p-ERK, p-CREB and c-Fos were also reduced very quickly in osthole-treated neuralgic mice. Our conclusion is that osthole alleviates neuropathic pain in mice via the P2Y1-receptor-dependent JNK signaling pathway in spinal astrocytes, and osthole could be considered a potential pharmacotherapy to alleviate neuropathic pain.
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Affiliation(s)
- Ruili Li
- Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Shajie Dang
- Department of Anesthesiology, Shaanxi Provincial Cancer Hospital, Xi’an, Shaanxi 71061, China
| | - Minna Yao
- Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Chao Zhao
- Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Wei Zhang
- Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Jia Cui
- Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Jingwen Wang
- Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Aidong Wen
- Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
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Hestehave S, Abelson KSP, Brønnum Pedersen T, Munro G. Stress sensitivity and cutaneous sensory thresholds before and after neuropathic injury in various inbred and outbred rat strains. Behav Brain Res 2019; 375:112149. [DOI: 10.1016/j.bbr.2019.112149] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Revised: 07/21/2019] [Accepted: 08/12/2019] [Indexed: 12/13/2022]
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32
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HCN channel antagonist ZD7288 ameliorates neuropathic pain and associated depression. Brain Res 2019; 1717:204-213. [DOI: 10.1016/j.brainres.2019.03.036] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2018] [Revised: 03/19/2019] [Accepted: 03/30/2019] [Indexed: 12/11/2022]
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Hippocampal PKR/NLRP1 Inflammasome Pathway Is Required for the Depression-Like Behaviors in Rats with Neuropathic Pain. Neuroscience 2019; 412:16-28. [DOI: 10.1016/j.neuroscience.2019.05.025] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2018] [Revised: 03/28/2019] [Accepted: 05/13/2019] [Indexed: 01/08/2023]
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Jiang HX, Ke BW, Liu J, Ma G, Hai KR, Gong DY, Yang Z, Zhou C. Inhibition of Fatty Acid Amide Hydrolase Improves Depressive-Like Behaviors Independent of Its Peripheral Antinociceptive Effects in a Rat Model of Neuropathic Pain. Anesth Analg 2019; 129:587-597. [DOI: 10.1213/ane.0000000000003563] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Yao PW, Wang SK, Chen SX, Xin WJ, Liu XG, Zang Y. Upregulation of tumor necrosis factor-alpha in the anterior cingulate cortex contributes to neuropathic pain and pain-associated aversion. Neurobiol Dis 2019; 130:104456. [PMID: 31028871 DOI: 10.1016/j.nbd.2019.04.012] [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] [Received: 12/14/2018] [Revised: 04/10/2019] [Accepted: 04/23/2019] [Indexed: 10/26/2022] Open
Abstract
Injury associated pain involves subjective perception and emotional experience. The anterior cingulate cortex (ACC) is a key area involved in the affective component of pain processing. However, the neuroimmune mechanisms underlying enhanced ACC excitability following peripheral nerve injury are still not fully understood. Our previous work has shown that tumor necrosis factor-alpha (TNF-α) overexpression leads to peripheral afferent hyperexcitability and synaptic transmission potentiation in spinal cord. Here, we aimed to reveal the potential role of ACC TNF-α in ACC hyperexcitability and neuropathic pain. c-Fos, a widely used neuronal activity marker, was induced especially in contralateral ACC early [postoperative (PO) 1 h] and later (PO day 7 and 10) during the development of neuropathic pain. Spared nerve injury (SNI) elevated TNF-α level in contralateral ACC from PO day 5 to 14, delayed relative to decreased ipsilateral paw withdrawal threshold apparent from PO day 1 to 14. Microinjection of anti-TNF-α antibody into the ACC completely eliminated c-Fos overexpression and greatly attenuated pain aversion and mechanical allodynia induced by SNI, suggesting an important role of ACC TNF-α in the pain aversiveness and pain maintenance. Furthermore, modulating ACC pyramidal neurons via a Gi-coupled human M4 muscarinic receptor (hM4Di) or a Gq-coupled human M3 muscarinic receptor (hM3Dq), a type of designer receptors exclusively activated by designer drugs (DREADD), greatly changed the ACC TNF-α level and the mechanical paw withdrawal threshold. The positive interactions between TNF-α and ACC neurons might modulate the cytokine microenvironment thus contribute to the neuropathic pain.
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Affiliation(s)
- Pei-Wen Yao
- Pain Research Center and Department of Physiology, Zhongshan Medical School, Sun Yat-Sen University, 74 Zhongshan Rd. 2, Guangzhou 510080, PR China
| | - Shao-Kun Wang
- Pain Research Center and Department of Physiology, Zhongshan Medical School, Sun Yat-Sen University, 74 Zhongshan Rd. 2, Guangzhou 510080, PR China
| | - Shao-Xia Chen
- Pain Research Center and Department of Physiology, Zhongshan Medical School, Sun Yat-Sen University, 74 Zhongshan Rd. 2, Guangzhou 510080, PR China; Department of Anesthesiology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Road East, Guangzhou 510060, PR China
| | - Wen-Jun Xin
- Pain Research Center and Department of Physiology, Zhongshan Medical School, Sun Yat-Sen University, 74 Zhongshan Rd. 2, Guangzhou 510080, PR China
| | - Xian-Guo Liu
- Pain Research Center and Department of Physiology, Zhongshan Medical School, Sun Yat-Sen University, 74 Zhongshan Rd. 2, Guangzhou 510080, PR China
| | - Ying Zang
- Pain Research Center and Department of Physiology, Zhongshan Medical School, Sun Yat-Sen University, 74 Zhongshan Rd. 2, Guangzhou 510080, PR China.
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36
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Humo M, Lu H, Yalcin I. The molecular neurobiology of chronic pain-induced depression. Cell Tissue Res 2019; 377:21-43. [PMID: 30778732 DOI: 10.1007/s00441-019-03003-z] [Citation(s) in RCA: 84] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Accepted: 02/01/2019] [Indexed: 12/18/2022]
Abstract
The increasing number of individuals with comorbidities poses an urgent need to improve the management of patients with multiple co-existing diseases. Among these comorbidities, chronic pain and mood disorders, two long-lasting disabling conditions that significantly reduce the quality of life, could be cited first. The recent development of animal models accelerated the studies focusing on the underlying mechanisms of the chronic pain and depression/anxiety comorbidity. This review provides an overview of clinical and pre-clinical studies performed over the past two decades addressing the molecular aspects of the comorbid relationship of chronic pain and depression. We thus focused on the studies that investigated the molecular characteristics of the comorbid relationship between chronic pain and mood disorders, especially major depressive disorders, from the genetic and epigenetic point of view to key neuromodulators which have been shown to play an important role in this comorbidity.
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Affiliation(s)
- Muris Humo
- Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique et Université de Strasbourg, 67000, Strasbourg, France
| | - Han Lu
- Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique et Université de Strasbourg, 67000, Strasbourg, France.,Faculty of Biology and Bernstein Center Freiburg, University of Freiburg, D-79104, Freiburg, Germany
| | - Ipek Yalcin
- Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique et Université de Strasbourg, 67000, Strasbourg, France.
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The Elevated Serum Level of IFN- γ in Patients with Failed Back Surgery Syndrome Remains Unchanged after Spinal Cord Stimulation. DISEASE MARKERS 2019; 2019:2606808. [PMID: 30755780 PMCID: PMC6348905 DOI: 10.1155/2019/2606808] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Revised: 11/08/2018] [Accepted: 11/25/2018] [Indexed: 01/10/2023]
Abstract
Objectives We investigated the influence of spinal cord stimulation (SCS) on IFN-γ, IL-1β, IL-6, TNF-α, IL-10, and TGF-β serum levels in failed back surgery syndrome (FBSS) patients. The study will try to give new insights into the mechanism of SCS action and the role of IFN-γ and other cytokines in neuropathic pain (NP) development. Materials and Methods Clinical and biochemical assessment was conducted in four groups of patients: group 0 consisted of 24 FBSS patients qualified to SCS therapy, group 1 included 17 patients who were one month after implantation, group 2 featured 12 patients who were 3 months after the implantation, and group C (the control group) with no NP. Clinical status was assessed with the use of Numeric Rating Scale (NRS), the Pain Rating Index of McGill Pain Questionnaire (SF-MPQ), the Oswestry Disability Index (ODI), and Beck Depression Inventory (BDI). The plasma concentrations of IFN-γ were ascertained by an immunoenzymatic method. Results We found a significant difference between the patients before SCS and controls' serum level of IFN-γ. Similarly, a significantly higher level of TNF-α and significantly lower level of IL-10 in FBSS patients than controls were observed. The significant differences were not observed between SCS patients 3 months after the procedure and controls' serum level of IFN-γ and other cytokines. We noticed a positive correlation between IFN-γ concentration with NRS back value before SCS and positive correlation between IFN-γ concentration after SCS with NRS leg value before SCS. Higher IFN-γ concentrations accompanied higher NRS values. Levels of TGF-β and IL-10 may correlate with physical ability and depressive behavior. Conclusions SCS did not influence serum cytokine levels significantly. Serum concentration of IFN-γ may be recognized as an occasional pain factor because of its significantly higher level in FBSS patients versus controls and higher IFN-γ value accompanying higher pain intensity.
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38
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Jurga AM, Rojewska E, Makuch W, Mika J. Lipopolysaccharide from Rhodobacter sphaeroides (TLR4 antagonist) attenuates hypersensitivity and modulates nociceptive factors. PHARMACEUTICAL BIOLOGY 2018; 56:275-286. [PMID: 29656686 PMCID: PMC6130482 DOI: 10.1080/13880209.2018.1457061] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/03/2023]
Abstract
CONTEXT Accumulating evidence has demonstrated that Toll-like receptors (TLRs), especially TLR4 localized on microglia/macrophages, may play a significant role in nociception. OBJECTIVE We examine the role of TLR4 in a neuropathic pain model. Using behavioural/biochemical methods, we examined the influence of TLR4 antagonist on levels of hypersensitivity and nociceptive factors whose contribution to neuropathy development has been confirmed. MATERIALS AND METHODS Behavioural (von Frey's/cold plate) tests were performed with Wistar male rats after intrathecal administration of a TLR4 antagonist (LPS-RS ULTRAPURE (LPS-RSU), 20 μG: lipopolysaccharide from Rhodobacter sphaeroides, InvivoGen, San Diego, CA) 16 H and 1 h before chronic constriction injury (cci) to the sciatic nerve and then daily for 7 d. three groups were used: an intact group and two cci-exposed groups that received vehicle or LPS-RSU. tissue [spinal cord/dorsal root ganglia (DRG)] for western blot analysis was collected on day 7. RESULTS The pharmacological blockade of TLR4 diminished mechanical (from ca. 40% to 16% that in the INTACT group) and thermal (from ca. 51% to 32% that in the INTACT group) hypersensitivity despite the enhanced activation of IBA-1-positive cells in DRG. Moreover, LPS-RSU changed the ratio between IL-18/IL-18BP and MMP-9/TIMP-1 in favour of the increase of antinociceptive factors IL-18BP (25%-spinal; 96%-DRG) and TIMP-1 (15%-spinal; 50%-DRG) and additionally led to an increased IL-6 (40%-spinal; 161%-DRG), which is known to have analgesic properties in neuropathy. CONCLUSIONS Our results provide evidence that LPS-RSU influences pain through the expression of TLR4. TLR4 blockade has analgesic properties and restores the balance between nociceptive factors, which indicates its engagement in neuropathy development.
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Affiliation(s)
- Agnieszka M. Jurga
- Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland
| | - Ewelina Rojewska
- Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland
| | - Wioletta Makuch
- Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland
| | - Joanna Mika
- Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland
- CONTACT Joanna MikaDepartment of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Str., 31343Krakow, Poland
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Abstract
Pain has a strong emotional component and is defined by its unpleasantness. Chronic pain represents a complex disorder with anxio-depressive symptoms and cognitive deficits. Underlying mechanisms are still not well understood but an important role for interactions between prefrontal cortical areas and subcortical limbic structures has emerged. Evidence from preclinical studies in the rodent brain suggests that neuroplastic changes in prefrontal (anterior cingulate, prelimbic and infralimbic) cortical and subcortical (amygdala and nucleus accumbens) brain areas and their interactions (corticolimbic circuitry) contribute to the complexity and persistence of pain and may be predetermining factors as has been proposed in recent human neuroimaging studies.
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Affiliation(s)
- Jeremy M Thompson
- Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, School of Medicine, Lubbock, TX, United States
| | - Volker Neugebauer
- Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, School of Medicine, Lubbock, TX, United States; Center of Excellence for Translational Neuroscience and Therapeutics, Texas Tech University Health Sciences Center, Lubbock, TX, United States.
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40
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Hestehave S, Abelson KSP, Brønnum Pedersen T, Munro G. The analgesic efficacy of morphine varies with rat strain and experimental pain model: implications for target validation efforts in pain drug discovery. Eur J Pain 2018; 23:539-554. [PMID: 30318662 PMCID: PMC6587867 DOI: 10.1002/ejp.1327] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Revised: 09/07/2018] [Accepted: 10/10/2018] [Indexed: 11/25/2022]
Abstract
Background Translating efficacy of analgesic drugs from animal models to humans remains challenging. Reasons are multifaceted, but lack of sufficiently rigorous preclinical study design criteria and phenotypically relevant models may be partly responsible. To begin to address this fundamental issue, we assessed the analgesic efficacy of morphine in three inbred rat strains (selected based on stress reactivity and affective/pain phenotypes), and outbred Sprague Dawley (SD) rats supplied from two vendors. Methods Sensitivity to morphine (0.3–6.0 mg/kg, s.c.) was evaluated in the hot plate test of acute thermal nociception, the Complete Freund's Adjuvant (CFA) model of inflammatory‐induced mechanical hyperalgesia, and in a locomotor motility assay in male rats from the following strains; Lewis (LEW), Fischer (F344), Wistar Kyoto (WKY), and SD's from Envigo and Charles River. Results F344 and SD rats were similarly sensitive to morphine in hot plate and CFA‐induced inflammatory hyperalgesia (Minimum Effective Dose (MED) = 3.0 mg/kg). WKY rats developed a less robust mechanical hypersensitivity after CFA injection, and were less sensitive to morphine in both pain tests (MED = 6.0 mg/kg). LEW rats were completely insensitive to morphine in the hot plate test, in contrast to the reversal of CFA‐induced hyperalgesia (MED = 3.0 mg/kg). All strains exhibited a dose‐dependent reduction in locomotor activity at 3.0–6.0 mg/kg. Conclusion Sensory phenotyping in response to acute thermal and inflammatory‐induced pain, and sensitivity to morphine in various inbred and outbred rat strains indicates that different pathophysiological mechanisms are engaged after injury. This could have profound implications for translating preclinical drug discovery efforts into pain patients. Significance The choice of rat strain used in preclinical pain research can profoundly affect the outcome of experiments in relation to (a) nociceptive threshold responses, and (b) efficacy to analgesic treatment, in assays of acute and tonic inflammatory nociceptive pain.
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Affiliation(s)
- Sara Hestehave
- Department of Experimental Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,H. Lundbeck A/S, Valby, Denmark
| | - Klas S P Abelson
- Department of Experimental Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | | | - Gordon Munro
- Department of Neurology, Danish Headache Center, Glostrup Research Institute, Glostrup, Copenhagen, Denmark
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Fiore NT, Austin PJ. Glial-cytokine-neuronal Adaptations in the Ventral Hippocampus of Rats with Affective Behavioral Changes Following Peripheral Nerve Injury. Neuroscience 2018; 390:119-140. [DOI: 10.1016/j.neuroscience.2018.08.010] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Revised: 08/01/2018] [Accepted: 08/07/2018] [Indexed: 12/17/2022]
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42
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Zhang H, Li F, Li WW, Stary C, Clark JD, Xu S, Xiong X. The inflammasome as a target for pain therapy. Br J Anaesth 2018; 117:693-707. [PMID: 27956668 DOI: 10.1093/bja/aew376] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
The interleukin-1 family of cytokines are potent inducers of inflammation and pain. Proteolytic activation of this family of cytokines is under the control of several innate immune receptors that coordinate to form large multiprotein signalling platforms, termed inflammasomes. Recent evidence suggests that a wide range of inflammatory diseases, cancers, and metabolic and autoimmune disorders, in which pain is a common complaint, may be coordinated by inflammasomes. Activation of inflammasomes results in cleavage of caspase-1, which subsequently induces downstream initiation of several potent pro-inflammatory cascades. Therefore, it has been proposed that targeting inflammasome activity may be a novel and effective therapeutic strategy for these pain-related diseases. The purpose of this narrative review article is to provide the reader with an overview of the activation and regulation of inflammasomes and to investigate the potential therapeutic role of inflammasome inhibition in the treatment of diseases characterized by pain, including the following: complex regional pain syndrome, gout, rheumatoid arthritis, inflammatory pain, neuropathic pain, chronic prostatitis, chronic pelvic pain syndrome, and fibromyalgia. We conclude that the role of the inflammasome in pain-associated diseases is likely to be inflammasome subtype and disease specific. The currently available evidence suggests that disease-specific targeting of the assembly and activity of the inflammasome complex may be a novel therapeutic opportunity for the treatment of refractory pain in many settings.
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Affiliation(s)
- H Zhang
- Department of Anesthesiology, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong, PR China
| | - F Li
- Department of Anesthesiology, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong, PR China
| | - W-W Li
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - C Stary
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - J D Clark
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - S Xu
- Department of Anesthesiology, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong, PR China
| | - X Xiong
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, PR China
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43
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Kelly CJ, Martina M. Circuit-selective properties of glutamatergic inputs to the rat prelimbic cortex and their alterations in neuropathic pain. Brain Struct Funct 2018; 223:2627-2639. [PMID: 29550939 DOI: 10.1007/s00429-018-1648-7] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2017] [Accepted: 03/12/2018] [Indexed: 11/24/2022]
Abstract
Functional deactivation of the prefrontal cortex (PFC) is a critical step in the neuropathic pain phenotype. We performed optogenetic circuit dissection to study the properties of ventral hippocampal (vHipp) and thalamic (MDTh) inputs to L5 pyramidal cells in acute mPFC slices and to test whether alterations in these inputs contribute to mPFC deactivation in neuropathic pain. We found that: (1) both the vHipp and MDTh inputs elicit monosynaptic excitatory and polysynaptic inhibitory currents. (2) The strength of the excitatory MDTh input is uniform, while the vHipp input becomes progressively stronger along the dorsal-ventral axis. (3) Synaptic current kinetics suggests that the MDTh inputs contact distal, while the vHipp inputs contact proximal dendritic sections. (4) The longer delay of inhibitory currents in response to vHipp compared to MDTh inputs suggests that they are activated by feedback and feed-forward circuitries, respectively. (5) One week after a peripheral neuropathic injury, both glutamatergic inputs are modified: MDTh responses are smaller, without evidence of presynaptic changes, while the probability of release at vHipp-mPFC synapses becomes lower, without significant change in current amplitude. Thus, dysregulation of both these inputs likely contributes to the mPFC deactivation in neuropathic pain and may impair PFC-dependent cognitive tasks.
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Affiliation(s)
- Crystle J Kelly
- Department of Physiology, Northwestern University, Feinberg School of Medicine, 303 E Chicago Avenue, Chicago, IL, 60611, USA
| | - Marco Martina
- Department of Physiology, Northwestern University, Feinberg School of Medicine, 303 E Chicago Avenue, Chicago, IL, 60611, USA.
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Cao S, Qin B, Zhang Y, Yuan J, Fu B, Xie P, Song G, Li Y, Yu T. Herpes zoster chronification to postherpetic neuralgia induces brain activity and grey matter volume change. Am J Transl Res 2018; 10:184-199. [PMID: 29423004 PMCID: PMC5801357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2017] [Accepted: 12/25/2017] [Indexed: 06/08/2023]
Abstract
OBJECTIVE Herpes zoster (HZ) can develop into postherpetic neuralgia (PHN), which is a chronic neuropathic pain (NP). Whether the chronification from HZ to PHN induced brain functional or structural change is unknown and no study compared the changes of the same brains of patients who transited from HZ to PHN. We minimized individual differences and observed whether the chronification of HZ to PHN induces functional and pain duration dependent grey matter volume (GMV) change in HZ-PHN patients. METHODS To minimize individual differences induced error, we enrolled 12 patients with a transition from HZ to PHN. The functional and structural changes of their brains between the two states were identified with resting-state functional MRI (rs-fMRI) technique (i.e., the regional homogeneity (ReHo) and fractional aptitude of low-frequency fluctuation (fALFF) method) and the voxel based morphometry (VBM) technology respectively. The correlations between MRI parameters (i.e., ΔReHo, ΔfALFF and ΔVBM) and Δpain duration were analyzed too. RESULTS Compared with HZ brains, PHN brains exhibited abnormal ReHo, fALFF and VBM values in pain matrix (the frontal lobe, parietal lobe, thalamus, limbic lobe and cerebellum) as well as the occipital lobe and temporal lobe. Nevertheless, the activity of vast area of cerebellum and frontal lobe significantly increased while that of occipital lobe and limbic lobe showed apparent decrease when HZ developed to PHN. In addition, PHN brain showed decreased GMV in the frontal lobe, the parietal lobe and the occipital lobe but increased in the cerebellum and the temporal lobe. Correlation analyses showed that some of the ReHo, fALFF and VBM differential areas (such as the cerebellum posterior lobe, the thalamus extra-nuclear and the middle temporal gyrus) correlated well with Δpain duration. CONCLUSIONS HZ chronification induced functional and structural change in cerebellum, occipital lobe, temporal lobe, parietal lobe and limbic lobe. These changes may be correlated with HZ-PHN chronification. In addition, these changes could be reasons of refractory chronic pain of PHN.
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Affiliation(s)
- Song Cao
- Department of Pain Medicine, The First Affiliated Hospital of Zunyi Medical UniversityZunyi, Guizhou, China
- Guizhou Key Laboratory of Anesthesia and Organ Protection, Zunyi Medical UniversityZunyi, Guizhou, China
| | - Bangyong Qin
- Department of Pain Medicine, The First Affiliated Hospital of Zunyi Medical UniversityZunyi, Guizhou, China
| | - Yi Zhang
- Guizhou Key Laboratory of Anesthesia and Organ Protection, Zunyi Medical UniversityZunyi, Guizhou, China
| | - Jie Yuan
- Guizhou Key Laboratory of Anesthesia and Organ Protection, Zunyi Medical UniversityZunyi, Guizhou, China
| | - Bao Fu
- Guizhou Key Laboratory of Anesthesia and Organ Protection, Zunyi Medical UniversityZunyi, Guizhou, China
| | - Peng Xie
- Guizhou Key Laboratory of Anesthesia and Organ Protection, Zunyi Medical UniversityZunyi, Guizhou, China
| | - Ganjun Song
- Department of Radiology, The First Affiliated Hospital of Zunyi Medical UniversityZunyi, Guizhou, China
| | - Ying Li
- Department of Pain Medicine, The First Affiliated Hospital of Zunyi Medical UniversityZunyi, Guizhou, China
| | - Tian Yu
- Guizhou Key Laboratory of Anesthesia and Organ Protection, Zunyi Medical UniversityZunyi, Guizhou, China
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Haghparast A, Shafiei I, Alizadeh AM, Ezzatpanah S, Haghparast A. Blockade of the orexin receptors in the CA1 region of hippocampus decreased the lateral hypothalamic-induced antinociceptive responses in the model of orofacial formalin test in the rats. Peptides 2018; 99:217-222. [PMID: 29042271 DOI: 10.1016/j.peptides.2017.10.006] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Revised: 10/01/2017] [Accepted: 10/11/2017] [Indexed: 12/30/2022]
Abstract
The role of hippocampus and lateral hypothalamus (LH) in modulation of formalin-induced nociception has been established. The present study aims to examine the role of orexin receptors in the Cornu Ammonis 1 (CA1) region of hippocampus in modulation of the LH-induced antinociception in the orofacial formalin test. Male Wistar rats were unilaterally implanted with two cannulae into the LH and CA1. Intra-LH microinjection of carbachol was done 5min after intra-CA1 administration of SB-334867 (OX1R antagonist) or TCS OX2 29 (OX2R antagonist). After 5min, 50μl of 1% formalin was subcutaneously injected into the upper lip for inducing the nociceptive behaviors. Solely intra-LH administration of carbachol reduced early and late phases of formalin-induced orofacial nociception in a dose-dependent manner. The antinociception evoked by intra-LH injection of carbachol (0.5μl of 250nM carbachol) was antagonized by intra-CA1 administration of 0.5μl of 3, 10 and 30nM solutions of SB-334867 or TCS OX2 29 during the early and late phases of orofacial formalin test. This effect was more remarkable during the late phase in comparison to the early phase. In addition, anti-analgesic effect of SB-334867 was more than TCS OX2 29 during the early and late phases. The results suggest the interpretation that a neural pathway from the LH to the CA1 probably contributes to the modulation of formalin-induced orofacial nociception through recruitment of both CA1 orexin receptors. Clinical studies are recommended to study the probable effectiveness of orexinergic system in modulation of the orofacial nociceptive responses.
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Affiliation(s)
- Amir Haghparast
- School of Dentistry, International Branch of Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Iman Shafiei
- Prosthetic Department, School of Dentistry, Tehran University of Medical Sciences, Tehran, Iran
| | - Amir-Mohammad Alizadeh
- Department of Neuroscience, Research Group Neurophysiology, KU Leuven, O&N II Herestraat 49, 3000, Leuven, Belgium
| | - Somayeh Ezzatpanah
- Department of Work Psychology and Physiology, National Institute of Occupational Health, Oslo, Norway
| | - Abbas Haghparast
- Neuroscience Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, P.O. Box: 19615-1178, Tehran, Iran.
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46
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Ding CP, Guo YJ, Li HN, Wang JY, Zeng XY. Red nucleus interleukin-6 participates in the maintenance of neuropathic pain through JAK/STAT3 and ERK signaling pathways. Exp Neurol 2017; 300:212-221. [PMID: 29183675 DOI: 10.1016/j.expneurol.2017.11.012] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Revised: 11/21/2017] [Accepted: 11/24/2017] [Indexed: 12/18/2022]
Abstract
We previously reported that interleukin-6 (IL-6) in the red nucleus (RN) is up-regulated at 3weeks after spared nerve injury (SNI), and plays facilitated role in the later maintenance of neuropathic pain. The current study aimed to reveal the roles of different signaling pathways, including Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3), extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK) and phosphatidylinositide 3-kinase/protein kinase B (PI3K/AKT), in RN IL-6-mediated pain modulation. In accord with the increase of IL-6 in the RN following SNI, the protein levels of phospho-STAT3 (p-STAT3), p-ERK and p-JNK were also up-regulated in the RN contralateral to the nerve injury side at 3weeks after SNI. The increases of p-STAT3 and p-ERK (but not p-JNK) were associated with IL-6 and could be blocked by anti-IL-6 antibody. Microinjection of JAK2 inhibitor AG490, ERK inhibitor PD98059 and also JNK inhibitor SP600125 into the RN significantly increased the paw withdrawal threshold (PWT) and alleviated SNI-induced mechanical allodynia. Further studies showed that microinjection of recombinant rat IL-6 (rrIL-6, 20ng) into the RN of normal rats significantly decreased the PWT of rats and increased the local protein levels of p-STAT3 and p-ERK, but not p-JNK. Pre-treatment with AG490 and PD98059 could prevent IL-6-induced mechanical allodynia. Whereas, p-p38 MAPK and p-AKT did not show any expression changes in the RN of rats with SNI or rats treated with rrIL-6. These results suggest that RN IL-6 participates in the later maintenance of SNI-induced neuropathic pain and plays facilitated role through activating JAK/STAT3 and ERK signaling pathways.
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Affiliation(s)
- Cui-Ping Ding
- Department of Laboratory Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China; Department of Pathogenic Biology and Immunology, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, China
| | - Yi-Jie Guo
- Department of Pathogenic Biology and Immunology, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, China
| | - Hao-Nan Li
- Department of Pathogenic Biology and Immunology, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, China
| | - Jun-Yang Wang
- Department of Pathogenic Biology and Immunology, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, China
| | - Xiao-Yan Zeng
- Department of Laboratory Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
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47
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Enhanced delivery of IL-1 receptor antagonist to the central nervous system as a novel anti-transferrin receptor-IL-1RA fusion reverses neuropathic mechanical hypersensitivity. Pain 2017; 158:660-668. [PMID: 28009628 PMCID: PMC5359788 DOI: 10.1097/j.pain.0000000000000810] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Delivery of an interleukin-1 antagonist across the blood–brain barrier results in analgesia in the Seltzer model of neuropathic pain. Neuropathic pain is a major unmet medical need, with only 30% to 35% of patients responding to the current standard of care. The discovery and development of novel therapeutics to address this unmet need have been hampered by poor target engagement, the selectivity of novel molecules, and limited access to the relevant compartments. Biological therapeutics, either monoclonal antibodies (mAbs) or peptides, offer a solution to the challenge of specificity as the intrinsic selectivity of these kinds of molecules is significantly higher than traditional medicinal chemistry–derived approaches. The interleukin-1 receptor system within the spinal cord has been implicated in the amplification of pain signals, and its central antagonism provides relief of neuropathic pain. Targeting the IL-1 system in the spinal cord with biological drugs, however, raises the even greater challenge of delivery to the central compartment. Targeting the transferrin receptor with monoclonal antibodies has proved successful in traversing the endothelial cell–derived blood–brain barrier and delivering proteins to the central nervous system. In this study, we describe a novel construct exemplifying an engineered solution to overcome these challenges. We have generated a novel anti–transferrin receptor-interleukin-1 receptor antagonist fusion that transports to the central nervous system and delivers efficacy in a model of nerve ligation–induced hypersensitivity. Approaches such as these provide promise for novel and selective analgesics that target the central compartment.
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48
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Laumet G, Zhou W, Dantzer R, Edralin JD, Huo X, Budac DP, O’Connor JC, Lee AW, Heijnen CJ, Kavelaars A. Upregulation of neuronal kynurenine 3-monooxygenase mediates depression-like behavior in a mouse model of neuropathic pain. Brain Behav Immun 2017; 66:94-102. [PMID: 28709913 PMCID: PMC5650931 DOI: 10.1016/j.bbi.2017.07.008] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Revised: 07/10/2017] [Accepted: 07/10/2017] [Indexed: 12/18/2022] Open
Abstract
Pain and depression often co-occur, but the underlying mechanisms have not been elucidated. Here, we used the spared nerve injury (SNI) model in mice to induce both neuropathic pain and depression-like behavior. We investigated whether brain interleukin (IL)-1 signaling and activity of kynurenine 3-monoxygenase (KMO), a key enzyme for metabolism of kynurenine into the neurotoxic NMDA receptor agonist quinolinic acid, are necessary for comorbid neuropathic pain and depression-like behavior. SNI mice showed increased expression levels of Il1b and Kmo mRNA in the contralateral side of the brain. The SNI-induced increase of Kmo mRNA was associated with increased KMO protein and elevated quinolinic acid and reduced kynurenic acid in the contralateral hippocampus. The increase in KMO-protein in response to SNI mostly took place in hippocampal NeuN-positive neurons rather than microglia. Inhibition of brain IL-1 signaling by intracerebroventricular administration of IL-1 receptor antagonist after SNI prevented the increase in Kmo mRNA and depression-like behavior measured by forced swim test. However, inhibition of brain IL-1 signaling has no effect on mechanical allodynia. In addition, intracerebroventricular administration of the KMO inhibitor Ro 61-8048 abrogated depression-like behavior without affecting mechanical allodynia after SNI. We show for the first time that the development of depression-like behavior in the SNI model requires brain IL-1 signaling and activation of neuronal KMO, while pain is independent of this pathway. Inhibition of KMO may represent a promising target for treating depression.
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Affiliation(s)
- Geoffroy Laumet
- Laboratory of Neuroimmunology, Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Wenjun Zhou
- Laboratory of Neuroimmunology, Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Robert Dantzer
- Laboratory of Neuroimmunology, Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Jules D. Edralin
- Laboratory of Neuroimmunology, Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - XiaoJiao Huo
- Laboratory of Neuroimmunology, Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - David P. Budac
- Bioanalysis and Physiology, Lundbeck Research, Paramus, NJ, USA
| | - Jason C. O’Connor
- Department of Pharmacology, The University of Texas Health Science Center and Audie L. Murphy VA Hospital, South Texas Veteran’s Heath Care System, San Antonio, TX, USA
| | - Anna W. Lee
- Neuroinflammation Disease Biology Unit, Lundbeck Research USA, Paramus, NJ, USA at the time the analysis of kynurenine metabolites was carried out
| | - Cobi J. Heijnen
- Laboratory of Neuroimmunology, Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Annemieke Kavelaars
- Laboratory of Neuroimmunology, Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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Fan Y, Hu L, Zhu S, Han Y, Liu W, Yang Y, Li Q. Paeoniflorin attenuates postoperative pain by suppressing Matrix Metalloproteinase‐9/2 in mice. Eur J Pain 2017; 22:272-281. [DOI: 10.1002/ejp.1116] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/28/2017] [Indexed: 12/21/2022]
Affiliation(s)
- Y.‐x. Fan
- Jiangsu Provincial Key Lab of Cardiovascular Diseases and Molecular Intervention Department of Pharmacology Nanjing Medical University China
- Department of Pharmacy Sir Run Run Shaw Hospital Affiliated to Nanjing Medical University China
| | - L. Hu
- Jiangsu Provincial Key Lab of Cardiovascular Diseases and Molecular Intervention Department of Pharmacology Nanjing Medical University China
| | - S.‐h. Zhu
- Jiangsu Provincial Key Lab of Cardiovascular Diseases and Molecular Intervention Department of Pharmacology Nanjing Medical University China
| | - Y. Han
- Jiangsu Province Key Laboratory of Anesthesiology School of Anesthesiology Xuzhou Medical University China
| | - W.‐t. Liu
- Jiangsu Provincial Key Lab of Cardiovascular Diseases and Molecular Intervention Department of Pharmacology Nanjing Medical University China
| | - Y.‐j. Yang
- Jiangsu Key Laboratory of Oral Disease Nanjing Medical University China
| | - Q.‐p. Li
- Jiangsu Provincial Key Lab of Cardiovascular Diseases and Molecular Intervention Department of Pharmacology Nanjing Medical University China
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50
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Tyrtyshnaia AA, Manzhulo IV, Sultanov RM, Ermolenko EV. Adult hippocampal neurogenesis in neuropathic pain and alkyl glycerol ethers treatment. Acta Histochem 2017; 119:812-821. [PMID: 29107326 DOI: 10.1016/j.acthis.2017.10.007] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Revised: 10/02/2017] [Accepted: 10/23/2017] [Indexed: 12/31/2022]
Abstract
Neuropathic pain manifested by a number of sensory symptoms is often accompanied by disorders of higher nervous activity, such as memory impairment, depression, anxiety, anhedonia, etc. This emphasizes the involvement of supraspinal structures including the hippocampus in neuropathic pain pathogenesis. In the present study, we focused on the impact of chronic neuropathic pain on hippocampal neurogenesis and microglial state. In addition, we test the effect of alkyl glycerol ethers on hippocampal neuronal and microglial plasticity as well as behavioral parameters. Neuropathic pain was induced using the model of sciatic nerve chronic constriction injury. We found an impairment of working memory and locomotor activity in animals with neuropathic pain, which was prevented by alkyl glycerol ethers treatment. Sciatic nerve ligation in mice contributed to the decrease in hippocampal neurogenesis intensity. Alkyl glycerol ethers administration significantly reduced this effect. Neuropathic pain-associated neurogenesis reduction was accompanied by an increased percentage of Iba1-labeled area in the CA1 hippocampal region on the 14th and 28th days after surgery. In addition, we observed a decrease in hippocampal pro-inflammatory microglia marker CD86 immunostaining on day 28 after surgery in alkyl glycerol ethers-treated mice with sciatic nerve ligation. These results are consistent with data on pro- and anti-inflammatory cytokines expression in the hippocampus. Alkyl glycerol ethers administration increased IL-10 and decreased IL-1β hippocampal expression in animals with neuropathic pain. Taken together, these data suggest that neuropathic pain-behavior in rodents is accompanied by changes in microglia polarization, thereby contributing to neurogenesis impairment and cognitive disturbances. Alkyl glycerol ethers prevented M1 microglial activation, contributing to the maintenance of normal neurogenesis levels within the hippocampus and normalizing working memory.
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Affiliation(s)
- Anna A Tyrtyshnaia
- National Scientific Center of Marine Biology, Far Eastern Branch, Russian Academy of Sciences, Palchevskogo Str, 17, Vladivostok, 690041, Russian Federation; School of Biomedicine, Far Eastern Federal University, Sukhanova 8, Vladivostok, 690091, Russian Federation.
| | - Igor V Manzhulo
- National Scientific Center of Marine Biology, Far Eastern Branch, Russian Academy of Sciences, Palchevskogo Str, 17, Vladivostok, 690041, Russian Federation; School of Biomedicine, Far Eastern Federal University, Sukhanova 8, Vladivostok, 690091, Russian Federation.
| | - Ruslan M Sultanov
- National Scientific Center of Marine Biology, Far Eastern Branch, Russian Academy of Sciences, Palchevskogo Str, 17, Vladivostok, 690041, Russian Federation.
| | - Ekaterina V Ermolenko
- National Scientific Center of Marine Biology, Far Eastern Branch, Russian Academy of Sciences, Palchevskogo Str, 17, Vladivostok, 690041, Russian Federation.
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