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Li X, Zhao Z, Ke Y, Jiang Y, Liu Y, Liu Z. Links Between Cellular Energy Metabolism and Pain Sensation. Anesth Analg 2025; 140:616-627. [PMID: 39110636 PMCID: PMC11805490 DOI: 10.1213/ane.0000000000007096] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/26/2024] [Indexed: 02/09/2025]
Abstract
One of the functions of organism cells is to maintain energy homeostasis to promote metabolism and adapt to the environment. The 3 major pathways of cellular energy metabolism are glycolysis, the tricarboxylic acid (TCA) cycle, and oxidative phosphorylation (OXPHOS). Neurons, astrocytes, and microglia are crucial in allodynia, hyperalgesia, and sensitization in nociceptive pathways. This review focused on these 3 major cellular energy metabolism pathways, aiming to elucidate the relationship between neurocyte and pain sensation and present the reprogramming of energy metabolism on pain, as well as the cellular and molecular mechanism underlying various forms of pain. The clinical and preclinical drugs involved in pain treatment and molecular mechanisms via cellular energy metabolism were also discussed.
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Affiliation(s)
- Xiongjuan Li
- From the Department of Anesthesiology, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen, China
| | - Zhao Zhao
- From the Department of Anesthesiology, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen, China
| | - Yuwen Ke
- From the Department of Anesthesiology, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen, China
| | - Yonghan Jiang
- From the Department of Anesthesiology, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen, China
| | - Yuqiang Liu
- From the Department of Anesthesiology, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen, China
| | - Zhiheng Liu
- From the Department of Anesthesiology, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen, China
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Fabregat-Cid G, Cedeño DL, Harutyunyan A, Rodríguez-López R, Monsalve-Dolz V, Mínguez-Martí A, Hernández-Cádiz MJ, Escrivá-Matoses N, Villanueva-Pérez V, Asensio Samper JM, De Andrés J, Vallejo R. Effect of Conventional Spinal Cord Stimulation on Serum Protein Profile in Patients With Persistent Spinal Pain Syndrome: A Case-Control Study. Neuromodulation 2023; 26:1441-1449. [PMID: 37516956 DOI: 10.1016/j.neurom.2023.05.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2023] [Revised: 04/30/2023] [Accepted: 05/30/2023] [Indexed: 07/31/2023]
Abstract
BACKGROUND Spinal cord stimulation (SCS) provides pain relief for most patients with persistent spinal pain syndrome type 2 (PSPS 2). Evidence is mounting on molecular changes induced by SCS as one of the mechanisms to explain pain improvement. We report the SCS effect on serum protein expression in vivo in patients with PSPS 2. MATERIALS AND METHODS Serum proteins were identified and quantified using mass spectrometry. Proteins with significantly different expression among patients with PSPS 2 relative to controls, responders, and nonresponders to SCS, or significantly modulated by SCS relative to baseline, were identified. Those most correlated with the presence and time course of pain were selected using multivariate discriminant analysis. Bioinformatic tools were used to identify related biological processes. RESULTS Thirty patients with PSPS 2, of whom 23 responded to SCS, were evaluated, together with 14 controls with no pain who also had undergone lumbar spinal surgery. A significant improvement in pain intensity, disability, and quality of life was recorded among responders. Five proteins differed significantly at baseline between patients with PSPS 2 and controls, with three proteins, mostly involved in immune processes and inflammation, being downregulated and two, mostly involved in vitamin metabolism, synaptic transmission, and restorative processes, being upregulated. In addition, four proteins, mostly related to immune processes and inflammation, decreased significantly, and three, mostly related to iron metabolism and containment of synaptic sprouting, increased significantly during SCS. CONCLUSION This study identifies various biological processes that may underlie PSPS 2 pain and SCS therapeutic effects, including the modulation of neuroimmune response and inflammation, synaptic sprouting, vitamin and iron metabolism, and restorative processes.
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Affiliation(s)
- Gustavo Fabregat-Cid
- Multidisciplinary Pain Management Department, University General Hospital, Valencia, Spain; Surgery Department, Medical School, University of Valencia, Valencia, Spain.
| | | | - Anushik Harutyunyan
- Multidisciplinary Pain Management Department, University General Hospital, Valencia, Spain
| | | | - Vicente Monsalve-Dolz
- Multidisciplinary Pain Management Department, University General Hospital, Valencia, Spain
| | - Ana Mínguez-Martí
- Multidisciplinary Pain Management Department, University General Hospital, Valencia, Spain
| | | | | | | | - Juan Marcos Asensio Samper
- Multidisciplinary Pain Management Department, University General Hospital, Valencia, Spain; Surgery Department, Medical School, University of Valencia, Valencia, Spain
| | - José De Andrés
- Multidisciplinary Pain Management Department, University General Hospital, Valencia, Spain; Surgery Department, Medical School, University of Valencia, Valencia, Spain
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Deng HS, Xu LS, Ni HD, Wang YG, Li HB, He QL, Xu M, Yao M. Phosphoproteomic profiling of oxycodone‑treated spinal cord of rats with cancer‑induced bone pain. Mol Med Rep 2019; 20:4695-4705. [PMID: 31702022 DOI: 10.3892/mmr.2019.10702] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2018] [Accepted: 08/30/2019] [Indexed: 11/06/2022] Open
Abstract
Treatment of cancer‑induced bone pain (CIBP) is challenging in clinical settings. Oxycodone (OXY) is used to treat CIBP; however, a lack of understanding of the mechanisms underlying CIBP limits the application of OXY. In the present study, all rats were randomly divided into three groups: The sham group, the CIBP group, and the OXY group. Then, a rat model of CIBP was established by inoculation of Walker 256 tumor cells from rat tibia. Phosphoproteomic profiling of the OXY‑treated spinal dorsal cords of rats with CIBP was performed, and 1,679 phosphorylated proteins were identified, of which 160 proteins were significantly different between the CIBP and sham groups, and 113 proteins were significantly different between the CIBP and OXY groups. Gene Ontology analysis revealed that these proteins mainly clustered as synaptic‑associated cellular components; among these, disks large homolog 3 expression was markedly increased in rats with CIBP and was reversed by OXY treatment. Subsequent domain analysis of the differential proteins revealed several significant synaptic‑associated domains. In conclusion, synaptic‑associated cellular components may be critical in OXY‑induced analgesia in rats with CIBP.
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Affiliation(s)
- Hou-Sheng Deng
- Department of Anesthesiology and Pain Medicine, The First Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314001, P.R. China
| | - Long-Sheng Xu
- Department of Anesthesiology and Pain Medicine, The First Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314001, P.R. China
| | - Hua-Dong Ni
- Department of Anesthesiology and Pain Medicine, The First Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314001, P.R. China
| | - Yun-Gong Wang
- Department of Anesthesiology, Zhuzhou Central Hospital, Zhuzhou, Hunan 412000, P.R. China
| | - Hong-Bo Li
- Department of Anesthesiology and Pain Medicine, The First Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314001, P.R. China
| | - Qiu-Li He
- Department of Anesthesiology and Pain Medicine, The First Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314001, P.R. China
| | - Miao Xu
- Department of Anesthesiology and Pain Medicine, The First Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314001, P.R. China
| | - Ming Yao
- Department of Anesthesiology and Pain Medicine, The First Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314001, P.R. China
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Gomez-Varela D, Barry AM, Schmidt M. Proteome-based systems biology in chronic pain. J Proteomics 2019; 190:1-11. [DOI: 10.1016/j.jprot.2018.04.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2017] [Revised: 03/15/2018] [Accepted: 04/05/2018] [Indexed: 02/07/2023]
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Schwaid AG, Krasowka-Zoladek A, Chi A, Cornella-Taracido I. Comparison of the Rat and Human Dorsal Root Ganglion Proteome. Sci Rep 2018; 8:13469. [PMID: 30194433 PMCID: PMC6128859 DOI: 10.1038/s41598-018-31189-9] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Accepted: 07/31/2018] [Indexed: 01/09/2023] Open
Abstract
Dorsal root ganglion (DRG) are a key tissue in the nervous system that have a role in neurological disease, particularly pain. Despite the importance of this tissue, the proteome of DRG is poorly understood, and it is unknown whether the proteome varies between organisms or different DRG along the spine. Therefore, we profiled the proteome of human and rat DRG. We identified 5,245 proteins in human DRG and 4959 proteins in rat DRG. Across species the proteome is largely conserved with some notable differences. While the most abundant proteins in both rat and human DRG played a role in extracellular functions and myelin sheeth, proteins detected only in humans mapped to roles in immune function whereas those detected only in rat mapped to roles in localization and transport. The DRG proteome between human T11 and L2 vertebrae was nearly identical indicating DRG from different vertebrae are representative of one another. Finally, we asked if this data could be used to enhance translatability by identifying mechanisms that modulate cellular phenotypes representative of pain in different species. Based on our data we tested and discovered that MAP4K4 inhibitor treatment increased neurite outgrowth in rat DRG as in human SH-SY5Y cells.
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Affiliation(s)
| | | | - An Chi
- MRL, Merck & Co., Inc., Boston, MA, 02115, USA
| | - Ivan Cornella-Taracido
- MRL, Merck & Co., Inc., Boston, MA, 02115, USA.,Cedilla Therapeutics, Cambridge, MA, 02139, USA
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Yamanaka H, Kobayashi K, Okubo M, Noguchi K. Annexin A2 in primary afferents contributes to neuropathic pain associated with tissue type plasminogen activator. Neuroscience 2016; 314:189-99. [DOI: 10.1016/j.neuroscience.2015.11.058] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2015] [Revised: 11/21/2015] [Accepted: 11/25/2015] [Indexed: 02/07/2023]
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Li Q, Chen J, Chen Y, Cong X, Chen Z. Chronic sciatic nerve compression induces fibrosis in dorsal root ganglia. Mol Med Rep 2016; 13:2393-400. [PMID: 26820076 PMCID: PMC4768999 DOI: 10.3892/mmr.2016.4810] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2015] [Accepted: 12/15/2015] [Indexed: 01/10/2023] Open
Abstract
In the present study, pathological alterations in neurons of the dorsal root ganglia (DRG) were investigated in a rat model of chronic sciatic nerve compression. The rat model of chronic sciatic nerve compression was established by placing a 1 cm Silastic tube around the right sciatic nerve. Histological examination was performed via Masson's trichrome staining. DRG injury was assessed using Fluoro Ruby (FR) or Fluoro Gold (FG). The expression levels of target genes were examined using reverse transcription-quantitative polymerase chain reaction, western blot and immunohistochemical analyses. At 3 weeks post-compression, collagen fiber accumulation was observed in the ipsilateral area and, at 8 weeks, excessive collagen formation with muscle atrophy was observed. The collagen volume fraction gradually and significantly increased following sciatic nerve compression. In the model rats, the numbers of FR-labeled DRG neurons were significantly higher, relative to the sham-operated group, however, the numbers of FG-labeled neurons were similar. In the ipsilateral DRG neurons of the model group, the levels of transforming growth factor-β1 (TGF-β1) and connective tissue growth factor (CTGF) were elevated and, surrounding the neurons, the levels of collagen type I were increased, compared with those in the contralateral DRG. In the ipsilateral DRG, chronic nerve compression was associated with significantly higher levels of phosphorylated (p)-extracellular signal-regulated kinase 1/2, and significantly lower levels of p-c-Jun N-terminal kinase and p-p38, compared with those in the contralateral DRGs. Chronic sciatic nerve compression likely induced DRG pathology by upregulating the expression levels of TGF-β1, CTGF and collagen type I, with involvement of the mitogen-activated protein kinase signaling pathway.
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Affiliation(s)
- Qinwen Li
- Department of Orthopedics, The First People's Hospital of Yichang, Yichang, Hubei 443000, P.R. China
| | - Jianghai Chen
- Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Yanhua Chen
- Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Xiaobin Cong
- Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Zhenbing Chen
- Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
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Li S, Xue C, Yuan Y, Zhang R, Wang Y, Wang Y, Yu B, Liu J, Ding F, Yang Y, Gu X. The transcriptional landscape of dorsal root ganglia after sciatic nerve transection. Sci Rep 2015; 5:16888. [PMID: 26576491 PMCID: PMC4649668 DOI: 10.1038/srep16888] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2015] [Accepted: 10/21/2015] [Indexed: 11/12/2022] Open
Abstract
Following peripheral nerve injury, transcriptional responses are orchestrated to regulate the expression of numerous genes in the lesioned nerve, thus activating the intrinsic regeneration program. To better understand the molecular regulation of peripheral nerve regeneration, we aimed at investigating the transcriptional landscape of dorsal root ganglia (DRGs) after sciatic nerve transection in rats. The cDNA microarray analysis was used to identify thousands of genes that were differentially expressed at different time points post nerve injury (PNI). The results from Euclidean distance matrix, principal component analysis, and hierarchical clustering indicated that 2 nodal transitions in temporal gene expressions could segregate 3 distinct transcriptional phases within the period of 14 d PNI. The 3 phases were designated as “a stress response phase”, “a pre-regeneration phase”, and “a regeneration phase”, respectively, by referring to morphological observation of post-nerve-injury changes. The gene ontology (GO) analysis revealed the distinct features of biological process, cellular component, and molecular function at each transcriptional phase. Moreover, Ingenuity Pathway Analysis suggested that differentially expressed genes, mainly transcription factors and genes associated with neurite/axon growth, might be integrated into regulatory networks to mediate the regulation of peripheral nerve regeneration in a highly cooperative manner.
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Affiliation(s)
- Shiying Li
- Jiangsu Key Laboratory of Neuroregeneration, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, JS 226001, China
| | - Chengbin Xue
- Jiangsu Key Laboratory of Neuroregeneration, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, JS 226001, China
| | - Ying Yuan
- Jiangsu Key Laboratory of Neuroregeneration, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, JS 226001, China
| | - Ruirui Zhang
- Jiangsu Key Laboratory of Neuroregeneration, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, JS 226001, China
| | - Yaxian Wang
- Jiangsu Key Laboratory of Neuroregeneration, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, JS 226001, China
| | - Yongjun Wang
- Jiangsu Key Laboratory of Neuroregeneration, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, JS 226001, China
| | - Bin Yu
- Jiangsu Key Laboratory of Neuroregeneration, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, JS 226001, China
| | - Jie Liu
- Jiangsu Key Laboratory of Neuroregeneration, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, JS 226001, China
| | - Fei Ding
- Jiangsu Key Laboratory of Neuroregeneration, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, JS 226001, China
| | - Yuming Yang
- Jiangsu Key Laboratory of Neuroregeneration, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, JS 226001, China
| | - Xiaosong Gu
- Jiangsu Key Laboratory of Neuroregeneration, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, JS 226001, China
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Abstract
The transient receptor potential A1 (TRPA1) channel is essential for vertebrate pain. Even though TRPA1 activation by ligands has been studied extensively, the molecular machinery regulating TRPA1 is only poorly understood. Using an unbiased proteomics-based approach we uncovered the physical association of Annexin A2 (AnxA2) with native TRPA1 in mouse sensory neurons. AnxA2 is enriched in a subpopulation of sensory neurons and coexpressed with TRPA1. Furthermore, we observe an increase of TRPA1 membrane levels in cultured sensory neurons from AnxA2-deficient mice. This is reflected by our calcium imaging experiments revealing higher responsiveness upon TRPA1 activation in AnxA2-deficient neurons. In vivo these findings are associated with enhanced nocifensive behaviors specifically in TRPA1-dependent paradigms of acute and inflammatory pain, while heat and mechanical sensitivity as well as TRPV1-mediated pain are preserved in AnxA2-deficient mice. Our results support a model whereby AnxA2 limits the availability of TRPA1 channels to regulate nociceptive signaling in vertebrates.
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Toll-like receptor 4 signaling in trigeminal ganglion neurons contributes tongue-referred pain associated with tooth pulp inflammation. J Neuroinflammation 2013; 10:139. [PMID: 24267924 PMCID: PMC4222866 DOI: 10.1186/1742-2094-10-139] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2013] [Accepted: 11/14/2013] [Indexed: 01/08/2023] Open
Abstract
Background The purpose of the present study is to evaluate the mechanisms underlying tongue-referred pain associated with tooth pulp inflammation. Method Using mechanical and temperature stimulation following dental surgery, we have demonstrated that dental inflammation and hyperalgesia correlates with increased immunohistochemical staining of neurons for TLR4 and HSP70. Results Mechanical or heat hyperalgesia significantly enhanced in the ipsilateral tongue at 1 to 9 days after complete Freund’s adjuvant (CFA) application to the left lower molar tooth pulp compared with that of sham-treated or vehicle-applied rats. The number of fluorogold (FG)-labeled TLR4-immunoreactive (IR) cells was significantly larger in CFA-applied rats compared with sham-treated or vehicle-applied rats to the molar tooth. The number of heat shock protein (Hsp) 70-IR neurons in trigeminal ganglion (TG) was significantly increased on day 3 after CFA application compared with sham-treated or vehicle-applied rats to the molar tooth. About 9.2% of TG neurons were labeled with DiI applied to the molar tooth and FG injected into the tongue, and 15.4% of TG neurons were labeled with FG injected into the tongue and Alexa-labeled Hsp70-IR applied to the tooth. Three days after Hsp70 or lipopolysaccharide (LPS) application to the tooth in naive rats, mechanical or heat hyperalgesia was significantly enhanced compared with that of saline-applied rats. Following successive LPS-RS, an antagonist of TLR4, administration to the TG for 3 days, the enhanced mechanical or heat hyperalgesia was significantly reversed compared with that of saline-injected rats. Noxious mechanical responses of TG neurons innervating the tongue were significantly higher in CFA-applied rats compare with sham rats to the tooth. Hsp70 mRNA levels of the tooth pulp and TG were not different between CFA-applied rats and sham rats. Conclusions The present findings indicate that Hsp70 transported from the tooth pulp to TG neurons or expressed in TG neurons is released from TG neurons innervating inflamed tooth pulp, and is taken by TG neurons innervating the tongue, suggesting that the Hsp70-TLR4 signaling in TG plays a pivotal role in tongue-referred pain associated with tooth pulp inflammation.
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Liu TT, Bi HS, Lv SY, Wang XR, Yue SW. Inhibition of the expression and function of TRPV4 by RNA interference in dorsal root ganglion. Neurol Res 2013; 32:466-71. [DOI: 10.1179/174313209x408945] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
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Dubový P, Brázda V, Klusáková I, Hradilová-Svíženská I. Bilateral elevation of interleukin-6 protein and mRNA in both lumbar and cervical dorsal root ganglia following unilateral chronic compression injury of the sciatic nerve. J Neuroinflammation 2013; 10:55. [PMID: 23634725 PMCID: PMC3657546 DOI: 10.1186/1742-2094-10-55] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2012] [Accepted: 04/03/2013] [Indexed: 11/10/2022] Open
Abstract
Background Current research implicates interleukin (IL)-6 as a key component of the nervous-system response to injury with various effects. Methods We used unilateral chronic constriction injury (CCI) of rat sciatic nerve as a model for neuropathic pain. Immunofluorescence, ELISA, western blotting and in situ hybridization were used to investigate bilateral changes in IL-6 protein and mRNA in both lumbar (L4-L5) and cervical (C7-C8) dorsal root ganglia (DRG) following CCI. The operated (CCI) and sham-operated (sham) rats were assessed after 1, 3, 7, and 14 days. Withdrawal thresholds for mechanical hyperalgesia and latencies for thermal hyperalgesia were measured in both ipsilateral and contralateral hind and fore paws. Results The ipsilateral hind paws of all CCI rats displayed a decreased threshold of mechanical hyperalgesia and withdrawal latency of thermal hyperalgesia, while the contralateral hind and fore paws of both sides exhibited no significant changes in mechanical or thermal sensitivity. No significant behavioral changes were found in the hind and fore paws on either side of the sham rats, except for thermal hypersensitivity, which was present bilaterally at 3 days. Unilateral CCI of the sciatic nerve induced a bilateral increase in IL-6 immunostaining in the neuronal bodies and satellite glial cells (SGC) surrounding neurons of both lumbar and cervical DRG, compared with those of naive control rats. This bilateral increase in IL-6 protein levels was confirmed by ELISA and western blotting. More intense staining for IL-6 mRNA was detected in lumbar and cervical DRG from both sides of rats following CCI. The DRG removed from sham rats displayed a similar pattern of staining for IL-6 protein and mRNA as found in naive DRG, but there was a higher staining intensity in SGC. Conclusions Bilateral elevation of IL-6 protein and mRNA is not limited to DRG homonymous to the injured nerve, but also extended to DRG that are heteronymous to the injured nerve. The results for IL-6 suggest that the neuroinflammatory reaction of DRG to nerve injury is propagated alongside the neuroaxis from the lumbar to the remote cervical segments. This is probably related to conditioning of cervical DRG neurons to injury.
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Affiliation(s)
- Petr Dubový
- Central European Institute of Technology (CEITEC), Masaryk University, Kamenice 3, Brno, 62500, Czech Republic.
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Ju W, Li Q, Allette YM, Ripsch MS, White FA, Khanna R. Suppression of pain-related behavior in two distinct rodent models of peripheral neuropathy by a homopolyarginine-conjugated CRMP2 peptide. J Neurochem 2013; 124:869-79. [PMID: 23106100 DOI: 10.1111/jnc.12070] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2012] [Revised: 10/16/2012] [Accepted: 10/20/2012] [Indexed: 02/03/2023]
Abstract
The N-type voltage-gated calcium channel (CaV2.2) is a clinically endorsed target in chronic pain treatments. As directly targeting the channel can lead to multiple adverse side effects, targeting modulators of CaV2.2 may prove better. We previously identified ST1-104, a short peptide from the collapsin response mediator protein 2 (CRMP2), which disrupted the CaV2.2-CRMP2 interaction and suppressed a model of HIV-related neuropathy induced by anti-retroviral therapy but not traumatic neuropathy. Here, we report ST2-104 -a peptide wherein the cell-penetrating TAT motif has been supplanted with a homopolyarginine motif, which dose-dependently inhibits the CaV2.2-CRMP2 interaction and inhibits depolarization-evoked Ca(2+) influx in sensory neurons. Ca(2+) influx via activation of vanilloid receptors is not affected by either peptide. Systemic administration of ST2-104 does not affect thermal or tactile nociceptive behavioral changes. Importantly, ST2-104 transiently reduces persistent mechanical hypersensitivity induced by systemic administration of the anti-retroviral drug 2',3'-dideoxycytidine (ddC) and following tibial nerve injury (TNI). Possible mechanistic explanations for the broader efficacy of ST2-104 are discussed.
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Affiliation(s)
- Weina Ju
- Department of Pharmacology and Toxicology, Paul and Carole Stark Neurosciences Research Institute, Indianapolis, IN 46202, USA
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Zhang XJ, Leung FP, Hsiao WWL, Tan S, Li S, Xu HX, Sung JJY, Bian ZX. Proteome profiling of spinal cord and dorsal root ganglia in rats with trinitrobenzene sulfonic acid-induced colitis. World J Gastroenterol 2012; 18:2914-28. [PMID: 22736915 PMCID: PMC3380319 DOI: 10.3748/wjg.v18.i23.2914] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2011] [Revised: 09/24/2011] [Accepted: 04/12/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate proteomic changes in spinal cord and dorsal root ganglia (DRG) of rats with trinitrobenzene sulfonic acid (TNBS)-induced colitis.
METHODS: The colonic myeloperoxidase (MPO) activity and tumor necrosis factor-α (TNF-α) level were determined. A two-dimensional electrophoresis (2-DE)-based proteomic technique was used to profile the global protein expression changes in the DRG and spinal cord of the rats with acute colitis induced by intra-colonic injection of TNBS.
RESULTS: TNBS group showed significantly elevated colonic MPO activity and increased TNF-α level. The proteins derived from lumbosacral enlargement of the spinal cord and DRG were resolved by 2-DE; and 26 and 19 proteins that displayed significantly different expression levels in the DRG and spinal cord were identified respectively. Altered proteins were found to be involved in a number of biological functions, such as inflammation/immunity, cell signaling, redox regulation, sulfate transport and cellular metabolism. The overexpression of the protein similar to potassium channel tetramerisation domain containing protein 12 (Kctd 12) and low expression of proteasome subunit α type-1 (psma) were validated by Western blotting analysis.
CONCLUSION: TNBS-induced colitis has a profound impact on protein profiling in the nervous system. This result helps understand the neurological pathogenesis of inflammatory bowel disease.
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Interaction of transient receptor potential vanilloid 4 with annexin A2 and tubulin beta 5. Neurosci Lett 2012; 512:22-7. [DOI: 10.1016/j.neulet.2012.01.048] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2011] [Revised: 01/07/2012] [Accepted: 01/20/2012] [Indexed: 01/31/2023]
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Tam Tam S, Bastian I, Zhou XF, Vander Hoek M, Michael MZ, Gibbins IL, Haberberger RV. MicroRNA-143 expression in dorsal root ganglion neurons. Cell Tissue Res 2011; 346:163-73. [PMID: 22048787 DOI: 10.1007/s00441-011-1263-x] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2011] [Accepted: 10/06/2011] [Indexed: 12/20/2022]
Abstract
The unpleasant sensory and emotional experience of pain is initiated by excitation of primary afferent nociceptive neurons. Nerve damage or inflammation induces changes in nociceptive DRG neurons which contribute to both peripheral and central sensitization of pain-sensitive pathways. Recently, blockade of microRNA synthesis has been found to modulate the response of nociceptive neurons to inflammatory stimuli. However, little is known about the contributions of individual miRNAs to painful conditions. We compared miRNA expression in mouse sensory neurons and focussed on the localisation and control of miR-143. Using miRNA-arrays we compared the microRNA expression profile of intact lumbar DRG with one-day-old DRG cultures and found that nine miRNAs including miR-143 showed lower expression levels in cultures. Subsequent RT-qPCR confirmed array data and in-situ hybridisation localised miR-143 in the cytosol of sensory DRG neurons in situ and in vitro. Analysis of microbead-enriched neuron cultures showed significantly higher expression levels of miR-143 in isolectin B4 (I-B4) binding sensory neurons compared with neurons in the I-B4 negative flow-through fraction. In animal models of peripheral inflammation (injection of Complete Freund's Adjuvant, CFA) and nerve damage (transection of the sciatic nerve), we found that expression levels of miR-143 were significantly lower in DRGs ipsilateral to CFA injection or after nerve damage. Taken together, our data demonstrate for the first time miR-143 expression in nociceptive neurons. Since expression levels of miR-143 were higher in I-B4 positive neurons and declined in response to inflammation but not axotomy, miR-143 could selectively contribute to mRNA regulation in specific populations of nociceptors.
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Affiliation(s)
- S Tam Tam
- Department of Anatomy & Histology, Flinders University of South Australia, Adelaide, SA, Australia
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Alvarez P, Ferrari LF, Levine JD. Muscle pain in models of chemotherapy-induced and alcohol-induced peripheral neuropathy. Ann Neurol 2011; 70:101-9. [PMID: 21786301 DOI: 10.1002/ana.22382] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
OBJECTIVE While inflammatory pain is well described in skeletal muscle, neuropathic muscle pain remains to be clarified. We used 3 well-established rodent models of peripheral neuropathy to evaluate for muscle pain. METHODS In rats exposed to either of 2 neurotoxic cancer chemotherapies, paclitaxel or oxaliplatin, or to alcohol consumption, we assessed the evolution of mechanical hyperalgesia in skeletal muscle and skin, in the same animal. To explore the involvement of protein kinase C epsilon (PKCε), a second messenger implicated in some forms of neuropathic pain, antisense oligodeoxynucleotides (AS-ODNs) or mismatch ODNs (MM-ODNs) for PKCε were administered intrathecally. RESULTS Rats submitted to models of chemotherapy-induced and alcohol-induced neuropathy developed persistent muscle hyperalgesia, which evolved in parallel in muscle and skin. The administration of PKCε AS, which has been shown to mediate cutaneous hyperalgesia in paclitaxel and ethanol models of neuropathic pain, also inhibited muscle hyperalgesia induced by these agents. Stopping AS-ODN was associated with the reappearance of hyperalgesia at both sites. The AS-ODN to PKCε treatment was devoid of effect in both muscle and skin in the oxaliplatin neuropathy model. INTERPRETATION Our results support the suggestion that neuropathic muscle pain may be a greater clinical problem than generally appreciated.
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Affiliation(s)
- Pedro Alvarez
- Department of Oral and Maxillofacial Surgery, University of California, San Francisco, San Francisco, CA 94143-0440, USA
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18
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Abstract
Nitric oxide is generally considered a pronociceptive retrograde transmitter that, by activation of soluble guanylyl cyclase-mediated cGMP production and activation of cGMP-dependent protein kinase, drives nociceptive hypersensitivity. The duality of its functions, however, is increasingly recognized. This review summarizes nitric-oxide-mediated direct S-nitrosylation of target proteins that may modify nociceptive signaling, including glutamate receptors and G-protein-coupled receptors, transient receptor potential channels, voltage-gated channels, proinflammatory enzymes, transcription factors, and redoxins. S-Nitrosylation events require close proximity of nitric oxide production and target proteins and a permissive redox state in the vicinity. Despite the diversity of potential targets and effects, three major schemes arise that may affect nociceptive signaling: 1) S-Nitrosylation-mediated changes of ion channel gating properties, 2) modulation of membrane fusion and fission, and thereby receptor and channel membrane insertion, and 3) modulation of ubiquitination, and thereby protein degradation or transcriptional activity. In addition, S-Nitrosylation may alter the production of nitric oxide itself.
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Affiliation(s)
- Irmgard Tegeder
- Institut für Klinische Pharmakologie, Klinikum der Goethe-Universität Frankfurt, Theodor Stern Kai 7, Haus 74; 60590 Frankfurt am Main, Germany.
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Kamagata C, Tsuboko Y, Okabe T, Sato C, Sakamoto A. Proteomic analysis of rat brains in a model of neuropathic pain following exposure to electroconvulsive stimulation. ACTA ACUST UNITED AC 2011; 32:91-102. [PMID: 21551944 DOI: 10.2220/biomedres.32.91] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Some reports have shown that electroconvulsive shock therapy is effective for treating refractory neuropathic pain. However, its mechanism of action remains unknown. This study analyzes changes in protein expression in the brainstems of neuropathic pain model rats with or without electroconvulsive stimulation (ECS). A neuropathic pain model rat is produced by chronic constrictive injury (CCI) of the sciatic nerve. An ECS was administered to rodents once daily for 6 days after the CCI operation. After ECS, the latency to withdrawal from thermal stimulation was significantly increased. The expression of several proteins was changed after CCI. Ten proteins that increased after CCI then had decreased expression levels (close to control) after ECS, and 8 proteins that decreased after CCI then had increased expression levels (close to control) after ECS. In conclusion, ECS improved thermal hypersensitivity in a rat CCI model. Proteomic analysis showed that altered expression levels of proteins in the brainstem of CCI model rats returned to close to control levels after ECS, including many proteins associated with pain. This trend suggests an association of ECS with improved hypersensitivity, and these results may help elucidate the mechanism of this effect.
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Affiliation(s)
- Chihiro Kamagata
- Department of Anesthesiology, Nippon Medical School, Sendagi, Bunkyo-ku, Tokyo, Japan.
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20
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Vasileiou I, Giaginis C, Klonaris C, Theocharis S. Insight into pain-inducing and -related gene expression: a challenge for development of novel targeted therapeutic approaches. Fundam Clin Pharmacol 2011; 25:48-62. [PMID: 20070377 DOI: 10.1111/j.1472-8206.2009.00809.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The multidimensional issue of pain in relation to the need for efficient treatment has been the focus of extensive research. Gaining insight into the molecular mechanisms of pain and identifying specific genes and proteins as possible drug targets is strongly required considering that not all patients can be adequately treated with the currently available drugs. This up-to-date review aimed to summarize the findings of recent proteomic and genomic approaches in different types of pain to comment on their potential role in pain signaling pathways and to evaluate their possible contribution to the development of novel and possibly more targeted pain therapeutic strategies. Although pain treatment strategies have been greatly improved during the past century, no ideal targeted pain treatment has been developed. The development of modern and accurate platforms of technology for the study of genetics and physiology of pain has led to the identification of an increased number of altered genes and proteins that are involved in pain-related pathways. Through genomics and proteomics, pain-related genes and proteins, respectively, may be identified as diagnostic markers or drug targets improving therapeutic strategies. Furthermore, such molecular mediators of pain may reveal novel strategies for individualized pain management. The utilization of unique experimental approaches (through specific animal models) as well as powered genetic association studies conducted on appropriate populations is more than essential.
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Affiliation(s)
- Ioanna Vasileiou
- Department of Forensic Medicine & Toxicology, Medical School, National & Kapodistrian University of Athens, Athens, Greece
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21
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Wang C, Zhou J, Wang S, Ye M, Jiang C, Fan G, Zou H. Combined Comparative and Chemical Proteomics on the Mechanisms of levo-Tetrahydropalmatine-Induced Antinociception in the Formalin Test. J Proteome Res 2010; 9:3225-34. [DOI: 10.1021/pr1001274] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Affiliation(s)
- Chen Wang
- Department of Pharmaceutical Analysis, School of Pharmacy, Second Military Medical University, No.325 Guohe Road, Shanghai 200433, People's Republic of China, Division of Biotechnology, Dalian Institute of Chemical Physics, CAS, No.457 Zhongshan Road, Dalian 116023, People's Republic of China, Laboratory of Stress Medicine, Department of Nautical Medicine, Second Military Medical University, No.800 Xiangyin Road, Shanghai 200433, People's Republic of China, and Shanghai Key Laboratory for Pharmaceutical
| | - Jiangrui Zhou
- Department of Pharmaceutical Analysis, School of Pharmacy, Second Military Medical University, No.325 Guohe Road, Shanghai 200433, People's Republic of China, Division of Biotechnology, Dalian Institute of Chemical Physics, CAS, No.457 Zhongshan Road, Dalian 116023, People's Republic of China, Laboratory of Stress Medicine, Department of Nautical Medicine, Second Military Medical University, No.800 Xiangyin Road, Shanghai 200433, People's Republic of China, and Shanghai Key Laboratory for Pharmaceutical
| | - Shuowen Wang
- Department of Pharmaceutical Analysis, School of Pharmacy, Second Military Medical University, No.325 Guohe Road, Shanghai 200433, People's Republic of China, Division of Biotechnology, Dalian Institute of Chemical Physics, CAS, No.457 Zhongshan Road, Dalian 116023, People's Republic of China, Laboratory of Stress Medicine, Department of Nautical Medicine, Second Military Medical University, No.800 Xiangyin Road, Shanghai 200433, People's Republic of China, and Shanghai Key Laboratory for Pharmaceutical
| | - Mingliang Ye
- Department of Pharmaceutical Analysis, School of Pharmacy, Second Military Medical University, No.325 Guohe Road, Shanghai 200433, People's Republic of China, Division of Biotechnology, Dalian Institute of Chemical Physics, CAS, No.457 Zhongshan Road, Dalian 116023, People's Republic of China, Laboratory of Stress Medicine, Department of Nautical Medicine, Second Military Medical University, No.800 Xiangyin Road, Shanghai 200433, People's Republic of China, and Shanghai Key Laboratory for Pharmaceutical
| | - Chunlei Jiang
- Department of Pharmaceutical Analysis, School of Pharmacy, Second Military Medical University, No.325 Guohe Road, Shanghai 200433, People's Republic of China, Division of Biotechnology, Dalian Institute of Chemical Physics, CAS, No.457 Zhongshan Road, Dalian 116023, People's Republic of China, Laboratory of Stress Medicine, Department of Nautical Medicine, Second Military Medical University, No.800 Xiangyin Road, Shanghai 200433, People's Republic of China, and Shanghai Key Laboratory for Pharmaceutical
| | - Guorong Fan
- Department of Pharmaceutical Analysis, School of Pharmacy, Second Military Medical University, No.325 Guohe Road, Shanghai 200433, People's Republic of China, Division of Biotechnology, Dalian Institute of Chemical Physics, CAS, No.457 Zhongshan Road, Dalian 116023, People's Republic of China, Laboratory of Stress Medicine, Department of Nautical Medicine, Second Military Medical University, No.800 Xiangyin Road, Shanghai 200433, People's Republic of China, and Shanghai Key Laboratory for Pharmaceutical
| | - Hanfa Zou
- Department of Pharmaceutical Analysis, School of Pharmacy, Second Military Medical University, No.325 Guohe Road, Shanghai 200433, People's Republic of China, Division of Biotechnology, Dalian Institute of Chemical Physics, CAS, No.457 Zhongshan Road, Dalian 116023, People's Republic of China, Laboratory of Stress Medicine, Department of Nautical Medicine, Second Military Medical University, No.800 Xiangyin Road, Shanghai 200433, People's Republic of China, and Shanghai Key Laboratory for Pharmaceutical
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Current World Literature. Curr Opin Neurol 2009; 22:321-9. [DOI: 10.1097/wco.0b013e32832cf9cb] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Hamza M, Dionne RA. 2020 Foresight: Envisioning Therapeutic Innovations for Pain. DRUG DISCOVERY TODAY. THERAPEUTIC STRATEGIES 2009; 6:113-119. [PMID: 21712969 PMCID: PMC3123531 DOI: 10.1016/j.ddstr.2010.10.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/31/2023]
Affiliation(s)
- May Hamza
- National Institute of Nursing Research, NIH Bethesda, MD
- Dept. of Pharmacology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
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