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Aguilera-Lizarraga J, Lim TK, Pattison LA, Paine LW, Bulmer DC, Smith ESJ. Pro-inflammatory mediators sensitise transient receptor potential melastatin 3 cation channel (TRPM3) function in mouse sensory neurons. Neuropharmacology 2025; 271:110391. [PMID: 40024472 DOI: 10.1016/j.neuropharm.2025.110391] [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: 09/10/2024] [Revised: 02/24/2025] [Accepted: 02/26/2025] [Indexed: 03/04/2025]
Abstract
Pro-inflammatory mediators can directly activate pain-sensing neurons, known as nociceptors. Additionally, these mediators can sensitise ion channels and receptors expressed by these cells through transcriptional and post-translational modulation, leading to nociceptor hypersensitivity. A well-characterised group of ion channels that subserve nociceptor sensitisation is the transient receptor potential (TRP) superfamily of cation channels. For example, the roles of TRP channels vanilloid 1 (TRPV1) and ankyrin 1 (TRPA1) in nociceptor sensitisation and inflammatory pain have been extensively documented. In the case of TRP melastatin 3 (TRPM3), however, despite the increasing recognition of this channel's role in inflammatory pain, the mediators driving its sensitisation during inflammation remain poorly characterised. Here, using Ca2+ imaging, we found that an inflammatory soup of bradykinin, interleukin 1β (IL-1β) and tumour necrosis factor α (TNFα) sensitised TRPM3 function in isolated mouse sensory neurons; IL-1β and TNFα, but not bradykinin, independently potentiated TRPM3 function. TRPM3 expression and translocation to the membrane remained unchanged upon individual or combined exposure to these inflammatory mediators, which suggests that post-translational modification might occur. Finally, using the complete Freund's adjuvant-induced model of knee inflammation, we found that systemic pharmacological blockade of TRPM3 does not alleviate inflammatory pain (as assessed through evaluation of digging behaviour and dynamic weight bearing), which contrasts with previous reports using different pain models. We propose that the nuances of the immune response may determine the relative contribution of TRPM3 to nociceptive signalling in different neuro-immune contexts. Collectively, our findings improve insight into the role of TRPM3 sensitisation in inflammatory pain.
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Affiliation(s)
| | - Tony K Lim
- Department of Pharmacology, University of Cambridge, Cambridge, UK
| | - Luke A Pattison
- Department of Pharmacology, University of Cambridge, Cambridge, UK
| | - Luke W Paine
- Department of Pharmacology, University of Cambridge, Cambridge, UK
| | - David C Bulmer
- Department of Pharmacology, University of Cambridge, Cambridge, UK
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Hwang SM, Rahman MM, Go EJ, Roh J, Park R, Lee SG, Nahm M, Berta T, Kim YH, Park CK. Modulation of pain sensitivity by Ascl1- and Lhx6-dependent GABAergic neuronal function in streptozotocin diabetic mice. Mol Ther 2025; 33:786-804. [PMID: 39741412 PMCID: PMC11852955 DOI: 10.1016/j.ymthe.2024.12.039] [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: 05/07/2024] [Revised: 11/24/2024] [Accepted: 12/27/2024] [Indexed: 01/03/2025] Open
Abstract
Painful diabetic neuropathy commonly affects the peripheral nervous system in individuals with diabetes. However, the pathological processes and mechanisms underlying diabetic neuropathic pain remain unclear. We aimed to identify the overall profiles and screen for genes potentially involved in pain mechanisms using transcriptome analysis of the dorsal root ganglion of diabetic mice treated with streptozotocin (STZ). Using RNA sequencing, we identified differentially expressed genes between streptozotocin-treated diabetic mice and controls, focusing on altered GABAergic neuron-related genes and inflammatory pathways. Behavioral and molecular analyses revealed a marked reduction in GABAergic neuronal markers (GAD65, GAD67, VGAT) and increased pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) in the diabetic group compared with controls. Intrathecal administration of lentiviral vectors expressing transcription factors Ascl1 and Lhx6 reversed pain hypersensitivity and restored normal expression of GABAergic genes and inflammatory mediators. Protein-protein interaction network analysis revealed five key proteins influenced by Ascl1 and Lhx6 treatment, including those in the JunD/FosB/C-fos signaling pathway. These findings suggest that Ascl1 and Lhx6 mitigate diabetic neuropathic pain by modulating GABAergic neuronal function, pro-inflammatory responses, and pain-related channels (TRPV1, Nav1.7). These results provide a basis for developing transcription factor-based therapies targeting GABAergic neurons for diabetic neuropathic pain relief.
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Affiliation(s)
- Sung-Min Hwang
- Gachon Pain Center and Department of Physiology, Gachon University College of Medicine, Incheon, Republic of Korea
| | - Md Mahbubur Rahman
- Gachon Pain Center and Department of Physiology, Gachon University College of Medicine, Incheon, Republic of Korea
| | - Eun Jin Go
- Gachon Pain Center and Department of Physiology, Gachon University College of Medicine, Incheon, Republic of Korea
| | - Jueun Roh
- Gachon Pain Center and Department of Physiology, Gachon University College of Medicine, Incheon, Republic of Korea
| | - Rayoung Park
- Bio-IT Foundry Center of Chonnam National University and FromDATA, Buk-Gu, Gwangju, South Korea
| | - Sung-Gwon Lee
- Section of Genetics and Physiology, Laboratory of Molecular and Cellular Biology, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, MD, USA
| | - Minyeop Nahm
- Dementia Research Group, Korea Brain Research Institute, Daegu, Republic of Korea
| | - Temugin Berta
- Pain Research Center, Department of Anesthesiology, University of Cincinnati Medical Center, Cincinnati, OH, USA
| | - Yong Ho Kim
- Gachon Pain Center and Department of Physiology, Gachon University College of Medicine, Incheon, Republic of Korea.
| | - Chul-Kyu Park
- Gachon Pain Center and Department of Physiology, Gachon University College of Medicine, Incheon, Republic of Korea.
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LI S, WANG S, YIN Y, DE G, LI C, WANG Z, CAO W. Electroacupuncture alleviates zymosan-induced colorectal hypersensitivity. J TRADIT CHIN MED 2025; 45:32-38. [PMID: 39957156 PMCID: PMC11764946 DOI: 10.19852/j.cnki.jtcm.20220425.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Accepted: 03/22/2022] [Indexed: 02/18/2025]
Abstract
OBJECTIVE this study to investigate the mechanism underlying the electroacupuncture (EA) alleviates colorectal hypersensitivity, a feature of irritable bowel syndrome (IBS). METHODS The colorectal hypersensitivity model was established by treating mice with zymosan. Electrophysiological techniques, Western blotting and immunofluorescence staining were used to detect the changes of the sensitive state of the colorectum and the response in spinal ganglion and spinal cord after acupuncture intervention. RESULTS colorectal distension studies revealed that repetitive applied electroacupuncture treatment on mice could significant alleviates colorectal intensity. Western blotting studies with nerve growth factor (NGF) in the colorectum, substance P (SP) in the spinal ganglion, protein kinase C gamma (PKCγ) in the spinal cord, and transient receptor potential vanilloid 1 (TRPV1) showed that electroacupuncture suppressed zymosan-induced expression of TRPV1, NGF and SP in multiple tissues. Immunofluorescence labeling results showed that EA attenuated the expression of NGF in the colorectum, SP in the spinal ganglion, PKCγ in the spinal cord, and TRPV1 in all three tissues in zymosan-treated mice. Moreover, the number of neurons double-positive for TRPV1/Isolectin B4 (IB4) and TRPV1/Neurofilament (NF) 200 was increased in the spinal ganglion. CONCLUSION these results provide molecular-level evidence that EA alleviates zymosan-induced colorectal hypersensitivity by altering the expression of pain-associated proteins in the colorectum and spinal cord. EA has a potential to be therapeutic intervention option for IBS treatment.
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Affiliation(s)
- Siting LI
- 1 Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Shaojun WANG
- 1 Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Yehui YIN
- 1 Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Gejing DE
- 2 Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Caicai LI
- 1 Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Ziyan WANG
- 1 Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Wenjie CAO
- 1 Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing 100700, China
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Kitzerow O, Christensen S, Hong J, Adam RJ, Zucker IH, Jensen‐Smith H, Wang H. Anatomical mapping of neural lineages expressing the transient receptor potential vanilloid type 1 receptor using a modified and combined PACT and CUBIC protocol for rapid tissue clearance. Acta Physiol (Oxf) 2025; 241:e14275. [PMID: 39821962 PMCID: PMC11737471 DOI: 10.1111/apha.14275] [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: 04/13/2024] [Revised: 11/13/2024] [Accepted: 01/01/2025] [Indexed: 01/19/2025]
Abstract
AIM Tissue clearance is a rapidly evolving technology that allows for the three-dimensional imaging of intact biological tissues. Preexisting tissue-clearing techniques, such as Passive Clarity Technique (PACT) and Clear Unobstructed Brain Imaging Cocktails and Computational Analysis (CUBIC), clear tissues adequately but have distinct disadvantages, such as taking extensive time to clear tissues and degradation of endogenous tissue fluorescence. We developed a new tissue-clearing technique combining PACT and CUBIC protocols to map the neural lineages expressing the transient receptor potential vanilloid type 1 (TRPV1) receptor. METHODS To test the effectiveness of this modified protocol, a TdTomato reporter mouse line was crossed with a separate mouse line containing Cre recombinase under the control of the TRPV1 promoter, which would result in TRPV1 cell lineages expressing green fluorescence protein (GFP). RESULTS Compared to the PACT protocol that requires several weeks to months for tissue clearance, our approach reached a satisfactory clearance within 3 days in all neural tissues as well as several non-neural tissues such as colon, duodenum, and pancreas. Compared to the CUBIC approach, all tissues reserved strong GFP fluorescence. Robust GFP fluorescence was visualized in sensory neuronal soma but not in sympathetic ganglia neuronal soma. On the other hand, GFP fluorescence in the TRPV1 cells appeared to be expressed throughout the epithelium of the duodenum and colon and the arteriole smooth muscle in all non-neuronal tissues. CONCLUSION This study shows that our combined PACT and CUBIC (CPC) protocol can clear tissues in significantly less time while preserving tissue integrity and fluorescence.
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Affiliation(s)
- Oliver Kitzerow
- Department of Genetics Cell Biology and AnatomyUniversity of Nebraska Medical CenterOmahaNebraskaUSA
- Deptrtment of AnesthesiologyUniversity of Nebraska Medical CenterOmahaNebraskaUSA
- Department of Medical EducationCreighton UniversityOmahaNebraskaUSA
| | - Samuel Christensen
- Deptrtment of AnesthesiologyUniversity of Nebraska Medical CenterOmahaNebraskaUSA
| | - Juan Hong
- Deptrtment of AnesthesiologyUniversity of Nebraska Medical CenterOmahaNebraskaUSA
| | - Ryan J. Adam
- Deptrtment of AnesthesiologyUniversity of Nebraska Medical CenterOmahaNebraskaUSA
| | - Irving H. Zucker
- Department of Cellular and Integrative PhysiologyUniversity of Nebraska Medical CenterOmahaNebraskaUSA
| | - Heather Jensen‐Smith
- Department of Genetics Cell Biology and AnatomyUniversity of Nebraska Medical CenterOmahaNebraskaUSA
- Fred and Pamela Buffett Cancer CenterUniversity of Nebraska Medical CenterOmahaNebraskaUSA
| | - Han‐Jun Wang
- Deptrtment of AnesthesiologyUniversity of Nebraska Medical CenterOmahaNebraskaUSA
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Peng BG, Li YC, Yang L. Role of neurogenic inflammation in intervertebral disc degeneration. World J Orthop 2025; 16:102120. [PMID: 39850033 PMCID: PMC11752484 DOI: 10.5312/wjo.v16.i1.102120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 11/29/2024] [Accepted: 12/20/2024] [Indexed: 01/13/2025] Open
Abstract
In healthy intervertebral discs (IVDs), nerves and blood vessels are present only in the outer annulus fibrosus, while in degenerative IVDs, a large amount of nerve and blood vessel tissue grows inward. Evidence supports that neurogenic inflammation produced by neuropeptides such as substance P and calcitonin gene related peptide released by the nociceptive nerve fibers innervating the IVDs plays a crucial role in the process of IVD degeneration. Recently, non-neuronal cells, including IVD cells and infiltrating immune cells, have emerged as important players in neurogenic inflammation. IVD cells and infiltrating immune cells express functional receptors for neuropeptides through which they receive signals from the nervous system. In return, IVD cells and immune cells produce neuropeptides and nerve growth factor, which stimulate nerve fibers. This communication generates a positive bidirectional feedback loop that can enhance the inflammatory response of the IVD. Recently emerging transient receptor potential channels have been recognized as contributors to neurogenic inflammation in the degenerative IVDs. These findings suggest that neurogenic inflammation involves complex pathophysiological interactions between sensory nerves and multiple cell types in the degenerative IVDs. Clarifying the mechanism of neurogenic inflammation in IVD degeneration may provide in-depth understanding of the pathology of discogenic low back pain.
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Affiliation(s)
- Bao-Gan Peng
- Department of Orthopaedics, The Third Medical Center, General Hospital of the Chinese People’s Liberation Army, Beijing 100039, China
| | - Yong-Chao Li
- Department of Orthopaedics, The Third Medical Center, General Hospital of the Chinese People’s Liberation Army, Beijing 100039, China
| | - Liang Yang
- Department of Orthopeadics, Featured Medical Center of Chinese People’s Armed Police Forces, Tianjin 300000, China
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Wang R, Yue C, Cong F, Lou Y, Liu Y, Xu C, Li X, Huang Y. A sustained-release gel alleviates neuropathic pain in SNI mice by reversing Glu/GABA imbalance and chloride efflux disorders. Int J Biol Macromol 2025; 286:138501. [PMID: 39647722 DOI: 10.1016/j.ijbiomac.2024.138501] [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: 08/05/2024] [Revised: 12/01/2024] [Accepted: 12/05/2024] [Indexed: 12/10/2024]
Abstract
Impaired spinal GABAergic inhibitory neuronal system is one popular target for developing new drugs or procedures for treatment of neuropathic pain, but effective and transferable methods are still lacking. We designed an assembled, temperature sensitive and sustained releasing hydrogel to repair the impaired GABAergic neural system by reversing imbalance of glutamic acid (Glu) and γ-aminobutyric acid (GABA) and healing impaired Cl- extrusion capacity of neurons. Hydrogel solution is a mixture of pluronic F-127, recombinant glutamate decarboxylase 67 (rGAD67) protein and CLP257, a K+-Cl- cotransporter isoform 2 (KCC2) enhancer. The temperature sensitive properties, gel properties and slow-releasing properties of the drug system were determined in vitro. After intrathecal injected in sural spared nerve injury mice model, the hydrogel solution turned into gel, capturing Glu and transforming it into GABA. CLP257 released from gel reversed the suppressed expression of KCC2 in spinal cord, maintaining a low intracellular Cl- concentration in neurons and allowing the normal work of GABA receptors. Combination of rGAD67 and CLP257 showed synergistic effects in alleviating hyperalgesia, altering glia activation, and inhibiting cell apoptosis and inflammatory response. In conclusion, the in situ assembled gel is a long-term effective tool for repairing damaged GABAergic inhibitory system and alleviating neuropathic pain.
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Affiliation(s)
- Ran Wang
- Department of Pain, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China; Department of Anesthesiology, Perioperative and Pain Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China
| | - Chunyan Yue
- Medical School and School of Life Science, Nanjing University, Nanjing 210008, China; Institute of Drug R&D, Medical School, Nanjing University, Nanjing 210008, China
| | - Feng Cong
- Department of Pain, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China; Department of Anesthesiology, the People's Hospital of Rugao, Rugao, China
| | - Youpan Lou
- Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, China
| | - Yanan Liu
- Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, China
| | - Chenjie Xu
- Department of Anesthesiology, Perioperative and Pain Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China.
| | - Xihan Li
- School of Life Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China.
| | - Ying Huang
- Department of Pain, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China.
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Datta I, Erridge S, Holvey C, Coomber R, Guru R, Holden W, Darweish Medniuk A, Sajad M, Searle R, Usmani A, Varma S, Rucker JJ, Platt M, Sodergren MH. UK medical cannabis registry: A clinical outcome analysis of medical cannabis therapy in chronic pain patients with and without co-morbid sleep impairment. Pain Pract 2025; 25:e13438. [PMID: 39545361 DOI: 10.1111/papr.13438] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2024]
Abstract
INTRODUCTION Chronic pain (CP) affects 35.0%-51.3% of the UK population, with 67%-88% reporting sleep disturbances. Cannabis-based medicinal products (CBMPs) have shown therapeutic potential in managing CP. Evidence suggests poor sleep worsens pain perception; therefore, this study aimed to assess patient-reported outcome measures (PROMs) following CBMP treatment in CP patients with and without co-morbid sleep impairment. METHODS A prospective cohort study of CP patients from the UK Medical Cannabis Registry was conducted. Participants were separated by baseline single-item sleep quality scale (SQS) score into sleep impaired (SQS ≤3) and unimpaired (SQS ≥4) cohorts. The primary outcome assessed changes in PROMs from baseline to 1-, 3-, 6-, and 12-months. Participants completed the following: SQS, General Anxiety Disorder-7, EQ-5D-5L, Brief Pain Inventory (BPI), and Short-Form McGill Pain Questionnaire-2. Significance was defined as p < 0.050. RESULTS 1139 participants met the inclusion criteria (sleep impaired: n = 517, 45.4%; sleep unimpaired: n = 622, 54.61%). The sleep impaired cohort showed improvements in all PROMs at each follow-up (p < 0.010). The sleep unimpaired cohort showed similar results (p < 0.050), except in SQS and ED-5Q-5L: self-care and anxiety/depression scores (p > 0.050). However, the sleep impaired cohort observed greater improvements in BPI pain severity (p < 0.050) and SQS (p < 0.001) than the sleep unimpaired cohort at all follow-ups. 2817 adverse events were self-reported between both cohorts (p = 0.197). DISCUSSION These findings align with literature that shows associated improvements in pain outcomes following CBMP administration. Sleep impaired individuals were more likely to experience greater pain severity improvements. However, this was not confirmed on multivariate logistic regression analysis and instead may be confounded by baseline pain severity. CONCLUSION Whilst these results show promise for the effects of CBMPs on CP, they must be examined within the limitations of the study design. These findings provide further evidence to support the design of subsequent randomized controlled trials to verify causality between CBMPs and pain outcomes.
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Affiliation(s)
- Ishita Datta
- Department of Surgery and Cancer, Medical Cannabis Research Group, Imperial College London, London, UK
| | - Simon Erridge
- Department of Surgery and Cancer, Medical Cannabis Research Group, Imperial College London, London, UK
- Curaleaf Clinic, London, UK
| | | | - Ross Coomber
- Curaleaf Clinic, London, UK
- St. George's Hospital NHS Trust, London, UK
| | - Rahul Guru
- Curaleaf Clinic, London, UK
- Cardiff and Vale University Health Board, Cardiff, UK
| | | | | | | | | | | | | | - James J Rucker
- Curaleaf Clinic, London, UK
- Department of Psychological Medicine, Kings College London, London, UK
- South London and Maudsley NHS Foundation Trust, London, UK
| | | | - Mikael H Sodergren
- Department of Surgery and Cancer, Medical Cannabis Research Group, Imperial College London, London, UK
- Curaleaf Clinic, London, UK
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Go EJ, Hwang SM, Jo H, Rahman MM, Park J, Lee JY, Jo YY, Lee BG, Jung Y, Berta T, Kim YH, Park CK. GLP-1 and its derived peptides mediate pain relief through direct TRPV1 inhibition without affecting thermoregulation. Exp Mol Med 2024; 56:2449-2464. [PMID: 39482537 PMCID: PMC11612315 DOI: 10.1038/s12276-024-01342-8] [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: 04/07/2024] [Revised: 04/07/2024] [Accepted: 08/13/2024] [Indexed: 11/03/2024] Open
Abstract
Hormonal regulation during food ingestion and its association with pain prompted the investigation of the impact of glucagon-like peptide-1 (GLP-1) on transient receptor potential vanilloid 1 (TRPV1). Both endogenous and synthetic GLP-1, as well as a GLP-1R antagonist, exendin 9-39, reduced heat sensitivity in naïve mice. GLP-1-derived peptides (liraglutide, exendin-4, and exendin 9-39) effectively inhibited capsaicin (CAP)-induced currents and calcium responses in cultured sensory neurons and TRPV1-expressing cell lines. Notably, exendin 9-39 alleviated CAP-induced acute pain, as well as chronic pain induced by complete Freund's adjuvant (CFA) and spared nerve injury (SNI), in mice without causing hyperthermia associated with other TRPV1 inhibitors. Electrophysiological analyses revealed that exendin 9-39 binds to the extracellular side of TRPV1, functioning as a noncompetitive inhibitor of CAP. Exendin 9-39 did not affect proton-induced TRPV1 activation, suggesting its selective antagonism. Among the exendin 9-39 fragments, exendin 20-29 specifically binds to TRPV1, alleviating pain in both acute and chronic pain models without interfering with GLP-1R function. Our study revealed a novel role for GLP-1 and its derivatives in pain relief, suggesting exendin 20-29 as a promising therapeutic candidate.
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Affiliation(s)
- Eun Jin Go
- Gachon Pain Center and Department of Physiology, College of Medicine, Gachon University, Incheon, 21999, Republic of Korea
| | - Sung-Min Hwang
- Gachon Pain Center and Department of Physiology, College of Medicine, Gachon University, Incheon, 21999, Republic of Korea
| | - Hyunjung Jo
- Gachon Pain Center and Department of Physiology, College of Medicine, Gachon University, Incheon, 21999, Republic of Korea
| | - Md Mahbubur Rahman
- Gachon Pain Center and Department of Physiology, College of Medicine, Gachon University, Incheon, 21999, Republic of Korea
| | - Jaeik Park
- Gachon Pain Center and Department of Physiology, College of Medicine, Gachon University, Incheon, 21999, Republic of Korea
| | - Ji Yeon Lee
- Department of Anesthesiology and Pain Medicine, Gil Medical Center, Gachon University, Incheon, 21565, Republic of Korea
| | - Youn Yi Jo
- Department of Anesthesiology and Pain Medicine, Gil Medical Center, Gachon University, Incheon, 21565, Republic of Korea
| | - Byung-Gil Lee
- Lee Gil Ya Cancer and Diabetes Institute Gachon University, Incheon, 21999, Republic of Korea
| | - YunJae Jung
- Lee Gil Ya Cancer and Diabetes Institute Gachon University, Incheon, 21999, Republic of Korea
| | - Temugin Berta
- Pain Research Center, Department of Anesthesiology, University of Cincinnati Medical Center, Cincinnati, OH, USA
| | - Yong Ho Kim
- Gachon Pain Center and Department of Physiology, College of Medicine, Gachon University, Incheon, 21999, Republic of Korea.
| | - Chul-Kyu Park
- Gachon Pain Center and Department of Physiology, College of Medicine, Gachon University, Incheon, 21999, Republic of Korea.
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Salib AMN, Crane MJ, Jamieson AM, Lipscombe D. Peripheral Ca V2.2 Channels in the Skin Regulate Prolonged Heat Hypersensitivity during Neuroinflammation. eNeuro 2024; 11:ENEURO.0311-24.2024. [PMID: 39433408 PMCID: PMC11599794 DOI: 10.1523/eneuro.0311-24.2024] [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: 07/13/2024] [Revised: 09/13/2024] [Accepted: 09/26/2024] [Indexed: 10/23/2024] Open
Abstract
Neuroinflammation can lead to chronic maladaptive pain affecting millions of people worldwide. Neurotransmitters, cytokines, and ion channels are implicated in neuroimmune cell signaling, but their roles in specific behavioral responses are not fully elucidated. Voltage-gated CaV2.2 channel activity in skin controls rapid and transient heat hypersensitivity induced by intradermal (i.d.) capsaicin via IL-1ɑ cytokine signaling. CaV2.2 channels are not, however, involved in mechanical hypersensitivity that developed in the i.d. capsaicin animal model. Here, we show that CaV2.2 channels are also critical for heat hypersensitivity induced by i.d. complete Freund adjuvant (CFA). i.d. CFA, a model of chronic neuroinflammation, involves ongoing cytokine signaling for days leading to pronounced edema and hypersensitivity to sensory stimuli. Peripheral CaV2.2 channel activity in the skin was required for the full development and week-long time course of heat hypersensitivity induced by i.d. CFA, but paw edema and mechanical hypersensitivity were independent of CaV2.2 channel activity. CFA induced increases in several cytokines in hindpaw fluid including IL-6 which was also dependent on CaV2.2 channel activity. Using IL-6-specific neutralizing antibodies in vivo, we show that IL-6 contributes to heat hypersensitivity and that neutralizing both IL-1ɑ and IL-6 was even more effective at reducing the magnitude and duration of CFA-induced heat hypersensitivity. Our findings demonstrate a functional link between CaV2.2 channel activity and the release of IL-6 in the skin and show that CaV2.2 channels have a privileged role in the induction and maintenance of heat hypersensitivity during chronic forms of neuroinflammation in the skin.
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Affiliation(s)
- Anne-Mary N Salib
- Departments of Neuroscience, Brown University, Providence, Rhode Island 02912
- Carney Institute for Brain Science, Brown University, Providence, Rhode Island 02912
| | - Meredith J Crane
- Molecular Microbiology and Immunology, Brown University, Providence, Rhode Island 02912
| | - Amanda M Jamieson
- Molecular Microbiology and Immunology, Brown University, Providence, Rhode Island 02912
| | - Diane Lipscombe
- Departments of Neuroscience, Brown University, Providence, Rhode Island 02912
- Carney Institute for Brain Science, Brown University, Providence, Rhode Island 02912
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Alexander SN, Green AR, Debner EK, Ramos Freitas LE, Abdelhadi HMK, Szabo-Pardi TA, Burton MD. The influence of sex on neuroimmune communication, pain, and physiology. Biol Sex Differ 2024; 15:82. [PMID: 39439003 PMCID: PMC11494817 DOI: 10.1186/s13293-024-00660-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Accepted: 10/02/2024] [Indexed: 10/25/2024] Open
Abstract
With the National Institutes of Health's mandate to consider sex as a biological variable (SABV), there has been a significant increase of studies utilizing both sexes. Historically, we have known that biological sex and hormones influence immunological processes and now studies focusing on interactions between the immune, endocrine, and nervous systems are revealing sex differences that influence pain behavior and various molecular and biochemical processes. Neuroendocrine-immune interactions represent a key integrative discipline that will reveal critical processes in each field as it pertains to novel mechanisms in sex differences and necessary therapeutics. Here we appraise preclinical and clinical literature to discuss these interactions and key pathways that drive cell- and sex-specific differences in immunity, pain, and physiology.
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Affiliation(s)
- Shevon N Alexander
- Neuroimmunology and Behavior Laboratory, Department of Neuroscience, School of Behavioral and Brain Sciences, Center for Advanced Pain Studies, University of Texas at Dallas, 800 W. Campbell Road, BSB 10.537, Richardson, TX, 75080, USA
| | - Audrey R Green
- Neuroimmunology and Behavior Laboratory, Department of Neuroscience, School of Behavioral and Brain Sciences, Center for Advanced Pain Studies, University of Texas at Dallas, 800 W. Campbell Road, BSB 10.537, Richardson, TX, 75080, USA
| | - Emily K Debner
- Neuroimmunology and Behavior Laboratory, Department of Neuroscience, School of Behavioral and Brain Sciences, Center for Advanced Pain Studies, University of Texas at Dallas, 800 W. Campbell Road, BSB 10.537, Richardson, TX, 75080, USA
| | - Lindsey E Ramos Freitas
- Neuroimmunology and Behavior Laboratory, Department of Neuroscience, School of Behavioral and Brain Sciences, Center for Advanced Pain Studies, University of Texas at Dallas, 800 W. Campbell Road, BSB 10.537, Richardson, TX, 75080, USA
| | - Hanna M K Abdelhadi
- Neuroimmunology and Behavior Laboratory, Department of Neuroscience, School of Behavioral and Brain Sciences, Center for Advanced Pain Studies, University of Texas at Dallas, 800 W. Campbell Road, BSB 10.537, Richardson, TX, 75080, USA
| | - Thomas A Szabo-Pardi
- Neuroimmunology and Behavior Laboratory, Department of Neuroscience, School of Behavioral and Brain Sciences, Center for Advanced Pain Studies, University of Texas at Dallas, 800 W. Campbell Road, BSB 10.537, Richardson, TX, 75080, USA
| | - Michael D Burton
- Neuroimmunology and Behavior Laboratory, Department of Neuroscience, School of Behavioral and Brain Sciences, Center for Advanced Pain Studies, University of Texas at Dallas, 800 W. Campbell Road, BSB 10.537, Richardson, TX, 75080, USA.
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11
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Salib AMN, Crane MJ, Jamieson AM, Lipscombe D. Peripheral Ca V2.2 channels in skin regulate prolonged heat hypersensitivity during neuroinflammation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.07.13.603149. [PMID: 39071304 PMCID: PMC11275762 DOI: 10.1101/2024.07.13.603149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/30/2024]
Abstract
Neuroinflammation can lead to chronic maladaptive pain affecting millions of people worldwide. Neurotransmitters, cytokines, and ion channels are implicated in neuro-immune cell signaling but their roles in specific behavioral responses are not fully elucidated. Voltage-gated CaV2.2 channel activity in skin controls rapid and transient heat hypersensitivity induced by intradermal capsaicin via IL-1α cytokine signaling. CaV2.2 channels are not, however, involved in mechanical hypersensitivity that developed in the same animal model. Here, we show that CaV2.2 channels are also critical for heat hypersensitivity induced by the intradermal (id) Complete Freund's Adjuvant (CFA) model of chronic neuroinflammation that involves ongoing cytokine signaling for days. Ongoing CFA-induced cytokine signaling cascades in skin lead to pronounced edema, and hypersensitivity to sensory stimuli. Peripheral CaV2.2 channel activity in skin is required for the full development and week-long time course of heat hypersensitivity induced by id CFA. CaV2.2 channels, by contrast, are not involved in paw edema and mechanical hypersensitivity. CFA induced increases in cytokines in hind paws including IL-6 which was dependent on CaV2.2 channel activity. Using IL-6 specific neutralizing antibodies, we show that IL-6 contributes to heat hypersensitivity and, neutralizing both IL-1α and IL-6 was even more effective at reducing the magnitude and duration of CFA-induced heat hypersensitivity. Our findings demonstrate a functional link between CaV2.2 channel activity and the release of IL-6 in skin and show that CaV2.2 channels have a privileged role in the induction and maintenance of heat hypersensitivity during chronic forms of neuroinflammation in skin.
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Affiliation(s)
- Anne-Mary N Salib
- Department of Neuroscience & the Carney Institute for Brain Science Brown University, Providence, RI 02912, USA
| | - Meredith J Crane
- Department of Molecular Microbiology and Immunology, Brown University, Providence, RI 02912, USA
| | - Amanda M Jamieson
- Department of Molecular Microbiology and Immunology, Brown University, Providence, RI 02912, USA
| | - Diane Lipscombe
- Department of Neuroscience & the Carney Institute for Brain Science Brown University, Providence, RI 02912, USA
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12
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MO X, CHEN Y, YIN Q, CHEN H, BAN Q, LI J, CHEN S, YAO J. Transient receptor potential vanilloid 1 involved in the analgesic effects of total flavonoids extracted from Longxuejie (). J TRADIT CHIN MED 2024; 44:437-447. [PMID: 38767627 PMCID: PMC11077159 DOI: 10.19852/j.cnki.jtcm.20240423.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Accepted: 07/06/2023] [Indexed: 05/22/2024]
Abstract
OBJECTIVE To evaluate the analgesic effects of total flavonoids of Longxuejie (Resina Dracaenae Cochinchinensis) (TFDB) and explore the possible analgesic mechanism associated with transient receptor potential vanilloid 1 (TRPV1). METHODS Whole-cell patch clamp technique was used to observe the effects of TFDB on capsaicin-induced TRPV1 currents. Rat experiments in vivo were used to observe the analgesic effects of TFDB. Western blot and immunofluorescence experiments were used to test the change of TRPV1 expression in DRG neurons induced by TFDB. RESULTS Results showed that TFDB inhibited capsaicin-induced TRPV1 receptor currents in acutely isolated dorsal root ganglion (DRG) neurons of rats and the half inhibitory concentration was (16.7 ± 1.6) mg/L. TFDB (2-20 mg/kg) showed analgesic activity in the phase Ⅱ of formalin test and (0.02-2 mg per paw) reduced capsaicin-induced licking times of rats. TFDB (20 mg/kg) was fully efficacious on complete Freund's adjuvant (CFA)-induced inflammatory thermal hyperalgesia and capsaicin could weaken the analgesic effects. The level of TRPV1 expressions of DRG neurons was also decreased in TFDB-treated CFA-inflammatory pain rats. CONCLUSION All these results indicated that the analgesic effect of TFDB may contribute to their modulations on both function and expression of TRPV1 channels in DRG neurons.
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Affiliation(s)
- Xiaoqiang MO
- 1 Department of Stomatology, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise 533000, China
- 2 College of General Practitioners, Youjiang Medical University for Nationalities, Baise 533000, China
| | - Yating CHEN
- 3 College of Biomedical Engineering, South-Central Minzu University, Key Laboratory of Cognitive Science of State Ethnic Affairs Commission, Hubei Key Laboratory of Medical Information Analysis and Tumor Diagnosis and Treatment, Wuhan 430074, China
| | - Qian YIN
- 3 College of Biomedical Engineering, South-Central Minzu University, Key Laboratory of Cognitive Science of State Ethnic Affairs Commission, Hubei Key Laboratory of Medical Information Analysis and Tumor Diagnosis and Treatment, Wuhan 430074, China
| | - Haibo CHEN
- 1 Department of Stomatology, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise 533000, China
| | - Qiang BAN
- 1 Department of Stomatology, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise 533000, China
| | - Jun LI
- 4 College of Pharmacy, South-Central Minzu University, Wuhan 430074, China
| | - Su CHEN
- 3 College of Biomedical Engineering, South-Central Minzu University, Key Laboratory of Cognitive Science of State Ethnic Affairs Commission, Hubei Key Laboratory of Medical Information Analysis and Tumor Diagnosis and Treatment, Wuhan 430074, China
| | - Jinguang YAO
- 1 Department of Stomatology, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise 533000, China
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13
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Park CK, Go EJ, Jo H, Hwang SM, Rahman MM, Park J, Lee JY, Jo YY, Jung Y, Berta T, Kim YH. GLP-1 and Its Derived Peptides Mediate Pain Relief Through Direct TRPV1 Inhibition Without Affecting Thermoregulation. RESEARCH SQUARE 2024:rs.3.rs-4233732. [PMID: 38798444 PMCID: PMC11118710 DOI: 10.21203/rs.3.rs-4233732/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/29/2024]
Abstract
Hormonal regulation during food ingestion and its association with pain prompted the investigation of the impact of glucagon-like peptide-1 (GLP-1) on the transient receptor potential vanilloid 1 (TRPV1). Both endogenous and synthetic GLP-1 and an antagonist of GLP-1, exendin 9-39, reduced heat sensitivity in naïve mice. GLP-1-derived peptides (liraglutide, exendin-4, and exendin 9-39) effectively inhibited capsaicin (CAP)-induced currents and calcium responses in cultured sensory neurons and TRPV1-expressing cell lines. Notably, the exendin 9-39 alleviated CAP-induced acute pain, as well as chronic pain induced by complete Freund's adjuvant (CFA) and spared nerve injury (SNI) in mice, without causing hyperthermia associated with other TRPV1 inhibitors. Electrophysiological analyses revealed that exendin 9-39 binds to the extracellular side of TRPV1, functioning as a noncompetitive inhibitor of CAP. Exendin 9-39 did not affect proton-induced TRPV1 activation, suggesting its selective antagonism. Among exendin 9-39 fragments, exendin 20-29 specifically binds to TRPV1, alleviating pain in both acute and chronic pain models without interfering with GLP-1R function. Our study revealed a novel role for GLP-1 and its derivatives in pain relief, proposing exendin 20-29 as a promising therapeutic candidate.
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14
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Pontearso M, Slepicka J, Bhattacharyya A, Spicarova D, Palecek J. Dual effect of anandamide on spinal nociceptive transmission in control and inflammatory conditions. Biomed Pharmacother 2024; 173:116369. [PMID: 38452657 DOI: 10.1016/j.biopha.2024.116369] [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: 11/23/2023] [Revised: 02/26/2024] [Accepted: 02/28/2024] [Indexed: 03/09/2024] Open
Abstract
Anandamide (AEA) is an important modulator of nociception in the spinal dorsal horn, acting presynaptically through Cannabinoid (CB1) and Transient receptor potential vanilloid (TRPV1) receptors. The role of AEA (1 µM, 10 µM, and 30 µM) application on the modulation of nociceptive synaptic transmission under control and inflammatory conditions was studied by recording miniature excitatory postsynaptic currents (mEPSCs) from neurons in spinal cord slices. Inhibition of the CB1 receptors by PF514273, TRPV1 by SB366791, and the fatty acid amide hydrolase (FAAH) by URB597 was used. Under naïve conditions, the AEA application did not affect the mEPSCs frequency (1.43±0.12 Hz) when all the recorded neurons were considered. The mEPSC frequency increased (180.0±39.2%) only when AEA (30 µM) was applied with PF514273 and URB597. Analysis showed that one sub-population of neurons had synaptic input inhibited (39.1% of neurons), the second excited (43.5%), whereas 8.7% showed a mixed effect and 8.7% did not respond to the AEA. With inflammation, the AEA effect was highly inhibitory (72.7%), while the excitation was negligible (9.1%), and 18.2% were not modulated. After inflammation, more neurons (45.0%) responded even to low AEA by mEPSC frequency increase with PF514273/URB597 present. AEA-induced dual (excitatory/inhibitory) effects at the 1st nociceptive synapse should be considered when developing analgesics targeting the endocannabinoid system. These findings contrast the clear inhibitory effects of the AEA precursor 20:4-NAPE application described previously and suggest that modulation of endogenous AEA production may be more favorable for analgesic treatments.
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Affiliation(s)
- Monica Pontearso
- Laboratory of Pain Research, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Jakub Slepicka
- Laboratory of Pain Research, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Anirban Bhattacharyya
- Laboratory of Pain Research, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Diana Spicarova
- Laboratory of Pain Research, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Jiri Palecek
- Laboratory of Pain Research, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic.
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15
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Brewer CL, Kauer JA. Low-Frequency Stimulation of Trpv1-Lineage Peripheral Afferents Potentiates the Excitability of Spino-Periaqueductal Gray Projection Neurons. J Neurosci 2024; 44:e1184232023. [PMID: 38050062 PMCID: PMC10860615 DOI: 10.1523/jneurosci.1184-23.2023] [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: 06/26/2023] [Revised: 10/19/2023] [Accepted: 11/09/2023] [Indexed: 12/06/2023] Open
Abstract
High-threshold dorsal root ganglion (HT DRG) neurons fire at low frequencies during inflammatory injury, and low-frequency stimulation (LFS) of HT DRG neurons selectively potentiates excitatory synapses onto spinal neurons projecting to the periaqueductal gray (spino-PAG). Here, in male and female mice, we have identified an underlying peripheral sensory population driving this plasticity and its effects on the output of spino-PAG neurons. We provide the first evidence that Trpv1-lineage sensory neurons predominantly induce burst firing, a unique mode of neuronal activity, in lamina I spino-PAG projection neurons. We modeled inflammatory injury by optogenetically stimulating Trpv1+ primary afferents at 2 Hz for 2 min (LFS), as peripheral inflammation induces 1-2 Hz firing in high-threshold C fibers. LFS of Trpv1+ afferents enhanced the synaptically evoked and intrinsic excitability of spino-PAG projection neurons, eliciting a stable increase in the number of action potentials (APs) within a Trpv1+ fiber-induced burst, while decreasing the intrinsic AP threshold and increasing the membrane resistance. Further experiments revealed that this plasticity required Trpv1+ afferent input, postsynaptic G protein-coupled signaling, and NMDA receptor activation. Intriguingly, an inflammatory injury and heat exposure in vivo also increased APs per burst, in vitro These results suggest that inflammatory injury-mediated plasticity is driven though Trpv1+ DRG neurons and amplifies the spino-PAG pathway. Spinal inputs to the PAG could play an integral role in its modulation of heat sensation during peripheral inflammation, warranting further exploration of the organization and function of these neural pathways.
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Affiliation(s)
- Chelsie L Brewer
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California 94305
| | - Julie A Kauer
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California 94305
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16
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Hsieh MC, Lai CY, Lin LT, Chou D, Yeh CM, Cheng JK, Wang HH, Lin KH, Lin TB, Peng HY. Melatonin Relieves Paclitaxel-Induced Neuropathic Pain by Regulating pNEK2-Dependent Epigenetic Pathways in DRG Neurons. ACS Chem Neurosci 2023; 14:4227-4239. [PMID: 37978917 DOI: 10.1021/acschemneuro.3c00616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2023] Open
Abstract
The neurohormone melatonin (MLT) demonstrates promising potential in ameliorating neuropathic pain induced by paclitaxel (PTX) chemotherapy. However, little is known about its protective effect on dorsal root ganglion (DRG) neurons in neuropathic pain resulting from the chemotherapeutic drug PTX. Here, PTX-treated rats revealed that intrathecal administration of MLT dose-dependently elevated hind paw withdrawal thresholds and latency, indicating that MLT significantly reversed PTX-induced neuropathic pain. Mechanistically, the analgesic effects of MLT were found to be mediated via melatonin receptor 2 (MT2), as pretreatment with an MT2 receptor antagonist inhibited these effects. Moreover, intrathecal MLT injection reversed the pNEK2-dependent epigenetic program induced by PTX. All of the effects caused by MLT were blocked by pretreatment with an MT2 receptor-selective antagonist, 4P-PDOT. Remarkably, multiple MLT administered during PTX treatment (PTX+MLTs) exhibited not only rapid but also lasting reversal of allodynia/hyperalgesia compared to single-bolus MLT administered after PTX treatment (PTX+MLT). In addition, PTX+MLTs exhibited greater efficacy in reversing PTX-induced alterations in pRSK2, pNEK2, JMJD3, H3K27me3, and TRPV1 expression and interaction in DRG neurons than PTX+MLT. These results indicated that MLT administered during PTX treatment reduced the incidence and/or severity of neuropathy and had a better inhibitory effect on the pNEK2-dependent epigenetic program compared to MLT administered after PTX treatment. In conclusion, MLT/MT2 is a promising therapy for the treatment of pNEK2-dependent painful neuropathy resulting from PTX treatment. MLT administered during PTX chemotherapy may be more effective in the prevention or reduction of PTX-induced neuropathy and maintaining quality.
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Affiliation(s)
- Ming-Chun Hsieh
- Department of Medicine, Mackay Medical College, New Taipei 252, Taiwan
| | - Cheng-Yuan Lai
- Institute of Biomedical Sciences, MacKay Medical College, New Taipei City 252, Taiwan
| | - Li-Ting Lin
- Institute of Biomedical Sciences, MacKay Medical College, New Taipei City 252, Taiwan
| | - Dylan Chou
- Department of Medicine, Mackay Medical College, New Taipei 252, Taiwan
| | - Chou-Ming Yeh
- Division of Thoracic Surgery, Department of Health, Taichung Hospital, Executive Yuan, Taichung 40343, Taiwan
- Central Taiwan University of Science and Technology, Taichung 40343, Taiwan
| | - Jen-Kun Cheng
- Department of Medicine, Mackay Medical College, New Taipei 252, Taiwan
- Department of Anesthesiology, Mackay Memorial Hospital, Taipei104, Taiwan
| | - Hsueh-Hsiao Wang
- Department of Medicine, Mackay Medical College, New Taipei 252, Taiwan
| | - Kuan-Hung Lin
- Institute of Biomedical Sciences, MacKay Medical College, New Taipei City 252, Taiwan
- Traditional Herbal Medicine Research Center, Taipei Medical University Hospital, Taipei110, Taiwan
- Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 252, Taiwan
| | - Tzer-Bin Lin
- Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei City 110, Taiwan
- Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei City 110, Taiwan
- Institute of New Drug Development, College of Medicine, China Medical University, Taichung 40604, Taiwan
| | - Hsien-Yu Peng
- Department of Medicine, Mackay Medical College, New Taipei 252, Taiwan
- Institute of Biomedical Sciences, MacKay Medical College, New Taipei City 252, Taiwan
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17
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Lee S, Lim NY, Kang MS, Jeong Y, Ahn JO, Choi JH, Chung JY. IL-31RA and TRPV1 Expression in Atopic Dermatitis Induced with Trinitrochlorobenzene in Nc/Nga Mice. Int J Mol Sci 2023; 24:13521. [PMID: 37686326 PMCID: PMC10488026 DOI: 10.3390/ijms241713521] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 08/26/2023] [Accepted: 08/28/2023] [Indexed: 09/10/2023] Open
Abstract
Atopic dermatitis (AD) is a common chronic inflammatory skin disease. Interleukin 31 (IL-31), a novel cytokine in AD, causes pruritus, typically characteristic of AD patients. The transient receptor potential vanilloid type 1 (TRPV1) is a cation channel activated by diverse noxious stimuli that has been studied in a variety of pruritic skin diseases. In this study, the AD animal model was generated by administering the hapten, trinitrochlorobenzene (TNCB), to Nc/Nga mice, and the degree of expression of the IL-31 receptor alpha (IL-31RA) and TRPV1 in the skin of these atopic models was evaluated. The Nc/Nga mice were divided into 3 groups: control, TNCB 2-weeks treated, and TNCB 8-weeks treated. After inducing AD, the skin lesions in each group were scored and compared, and the histology of the skin lesions and the IL-31RA and TRPV1 expression for each group were evaluated by analyzing immunohistochemistry. The results show a significant difference in the skin lesion scores between the groups. The immunohistochemistry evaluation highlighted the remarkable expression of IL-31RA and TRPV1 in the nerve fibers of the TNCB 8-weeks-treated group. We thus confirmed that the long-term application of TNCB induced chronic atopic-like dermatitis and that IL-31RA and TRPV1 were overexpressed in the peripheral nerve fibers in this AD model.
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Affiliation(s)
- Seokwoo Lee
- Department of Veterinary Internal Medicine and Institute of Veterinary Science, College of Veterinary Medicine, Kangwon National University, 1 Kangwondaehak-gil, Chuncheon-si 24341, Gangwon-do, Republic of Korea; (S.L.); (N.Y.L.); (Y.J.); (J.-O.A.)
| | - Na Yeon Lim
- Department of Veterinary Internal Medicine and Institute of Veterinary Science, College of Veterinary Medicine, Kangwon National University, 1 Kangwondaehak-gil, Chuncheon-si 24341, Gangwon-do, Republic of Korea; (S.L.); (N.Y.L.); (Y.J.); (J.-O.A.)
| | - Min Soo Kang
- Department of Veterinary Anatomy and Institute of Veterinary Science, College of Veterinary Medicine, Kangwon National University, 1 Kangwondaehak-gil, Chuncheon-si 24341, Gangwon-do, Republic of Korea; (M.S.K.); (J.H.C.)
| | - Yunho Jeong
- Department of Veterinary Internal Medicine and Institute of Veterinary Science, College of Veterinary Medicine, Kangwon National University, 1 Kangwondaehak-gil, Chuncheon-si 24341, Gangwon-do, Republic of Korea; (S.L.); (N.Y.L.); (Y.J.); (J.-O.A.)
| | - Jin-Ok Ahn
- Department of Veterinary Internal Medicine and Institute of Veterinary Science, College of Veterinary Medicine, Kangwon National University, 1 Kangwondaehak-gil, Chuncheon-si 24341, Gangwon-do, Republic of Korea; (S.L.); (N.Y.L.); (Y.J.); (J.-O.A.)
| | - Jung Hoon Choi
- Department of Veterinary Anatomy and Institute of Veterinary Science, College of Veterinary Medicine, Kangwon National University, 1 Kangwondaehak-gil, Chuncheon-si 24341, Gangwon-do, Republic of Korea; (M.S.K.); (J.H.C.)
| | - Jin-Young Chung
- Department of Veterinary Internal Medicine and Institute of Veterinary Science, College of Veterinary Medicine, Kangwon National University, 1 Kangwondaehak-gil, Chuncheon-si 24341, Gangwon-do, Republic of Korea; (S.L.); (N.Y.L.); (Y.J.); (J.-O.A.)
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18
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Lu HJ, Wu XB, Wei QQ. Ion channels in cancer-induced bone pain: from molecular mechanisms to clinical applications. Front Mol Neurosci 2023; 16:1239599. [PMID: 37664239 PMCID: PMC10469682 DOI: 10.3389/fnmol.2023.1239599] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Accepted: 08/07/2023] [Indexed: 09/05/2023] Open
Abstract
Cancer-induced bone pain (CIBP) caused by bone metastasis is one of the most prevalent diseases, and current treatments rely primarily on opioids, which have significant side effects. However, recent developments in pharmaceutical science have identified several new mechanisms for CIBP, including the targeted modification of certain ion channels and receptors. Ion channels are transmembrane proteins, which are situated on biological cell membranes, which facilitate passive transport of inorganic ions across membranes. They are involved in various physiological processes, including transmission of pain signals in the nervous system. In recent years, there has been an increasing interest in the role of ion channels in chronic pain, including CIBP. Therefore, in this review, we summarize the current literature on ion channels, related receptors, and drugs and explore the mechanism of CIBP. Targeting ion channels and regulating their activity might be key to treating pain associated with bone cancer and offer new treatment avenues.
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Affiliation(s)
- Huan-Jun Lu
- Institute of Pain Medicine and Special Environmental Medicine, Nantong University, Nantong, China
| | - Xiao-Bo Wu
- Institute of Pain Medicine and Special Environmental Medicine, Nantong University, Nantong, China
| | - Qian-Qi Wei
- Department of Infectious Diseases, General Hospital of Tibet Military Command, Xizang, China
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Spicarova D, Nerandzic V, Muzik D, Pontearso M, Bhattacharyya A, Nagy I, Palecek J. Inhibition of synaptic transmission by anandamide precursor 20:4-NAPE is mediated by TRPV1 receptors under inflammatory conditions. Front Mol Neurosci 2023; 16:1188503. [PMID: 37426071 PMCID: PMC10325575 DOI: 10.3389/fnmol.2023.1188503] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Accepted: 05/24/2023] [Indexed: 07/11/2023] Open
Abstract
Transient receptor potential ion channel, vanilloid subfamily, type 1 (TRPV1) cation channel, and cannabinoid receptor 1 (CB1) are essential in the modulation of nociceptive signaling in the spinal cord dorsal horn that underlies different pathological pain states. TRPV1 and CB1 receptors share the endogenous agonist anandamide (AEA), produced from N-arachidonoylphosphatidylethanolamine (20:4-NAPE). We investigated the effect of the anandamide precursor 20:4-NAPE on synaptic activity in naive and inflammatory conditions. Patch-clamp recordings of miniature excitatory postsynaptic currents (mEPSCs) from superficial dorsal horn neurons in rat acute spinal cord slices were used. Peripheral inflammation was induced by subcutaneous injection of carrageenan. Under naive conditions, mEPSCs frequency (0.96 ± 0.11 Hz) was significantly decreased after 20 μM 20:4-NAPE application (55.3 ± 7.4%). This 20:4-NAPE-induced inhibition was blocked by anandamide-synthesizing enzyme N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD) inhibitor LEI-401. In addition, the inhibition was prevented by the CB1 receptor antagonist PF 514273 (0.2 μM) but not by the TRPV1 receptor antagonist SB 366791 (10 μM). Under inflammatory conditions, 20:4-NAPE (20 μM) also exhibited a significant inhibitory effect (74.5 ± 8.9%) on the mEPSCs frequency that was prevented by the TRPV1 receptor antagonist SB 366791 but not by PF 514273 application. Our results show that 20:4-NAPE application has a significant modulatory effect on spinal cord nociceptive signaling that is mediated by both TRPV1 and CB1 presynaptic receptors, whereas peripheral inflammation changes the underlying mechanism. The switch between TRPV1 and CB1 receptor activation by the AEA precursor 20:4-NAPE during inflammation may play an important role in nociceptive processing, hence the development of pathological pain.
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Affiliation(s)
- Diana Spicarova
- Laboratory of Pain Research, Institute of Physiology of the Czech Academy of Sciences, Prague, Czechia
| | - Vladimir Nerandzic
- Laboratory of Pain Research, Institute of Physiology of the Czech Academy of Sciences, Prague, Czechia
| | - David Muzik
- Laboratory of Pain Research, Institute of Physiology of the Czech Academy of Sciences, Prague, Czechia
| | - Monica Pontearso
- Laboratory of Pain Research, Institute of Physiology of the Czech Academy of Sciences, Prague, Czechia
| | - Anirban Bhattacharyya
- Laboratory of Pain Research, Institute of Physiology of the Czech Academy of Sciences, Prague, Czechia
| | - Istvan Nagy
- Section of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Imperial College London, Faculty of Medicine, Chelsea and Westminster Hospital, London, United Kingdom
- Department of Physiology, University of Debrecen, Debrecen, Hungary
| | - Jiri Palecek
- Laboratory of Pain Research, Institute of Physiology of the Czech Academy of Sciences, Prague, Czechia
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20
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Niu M, Zhao F, Chen R, Li P, Bi L. The transient receptor potential channels in rheumatoid arthritis: Need to pay more attention. Front Immunol 2023; 14:1127277. [PMID: 36926330 PMCID: PMC10013686 DOI: 10.3389/fimmu.2023.1127277] [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: 12/19/2022] [Accepted: 02/06/2023] [Indexed: 03/06/2023] Open
Abstract
Rheumatoid arthritis (RA) is characterized by the augment of vascular permeability, increased inflammatory cells infiltration, dysregulated immune cells activation, pannus formation and unbearable pain hyperalgesia. Ca2+ affect almost every aspect of cellular functions, involving cell migration, signal transduction, proliferation, and apoptosis. Transient receptor potential channels (TRPs) as a type of non-selective permeable cation channels, can regulate Ca2+ entry and intracellular Ca2+ signal in cells including immune cells and neurons. Researches have demonstrated that TRPs in the mechanisms of inflammatory diseases have achieved rapid progress, while the roles of TRPs in RA pathogenesis and pain hyperalgesia are still not well understood. To solve this problem, this review presents the evidence of TRPs on vascular endothelial cells in joint swelling, neutrophils activation and their trans-endothelial migration, as well as their bridging role in the reactive oxygen species/TRPs/Ca2+/peptidyl arginine deiminases networks in accelerating citrullinated proteins formation. It also points out the distinct functions of TRPs subfamilies expressed in the nervous systems of joints in cold hyperalgesia and neuro-inflammation mutually influenced inflammatory pain in RA. Thus, more attention could be paid on the impact of TRPs in RA and TRPs are useful in researches on the molecular mechanisms of anti-inflammation and analgesic therapeutic strategies.
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Affiliation(s)
- Mengwen Niu
- Department of Rheumatology and Immunology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Feng Zhao
- Department of Rheumatology and Immunology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Rui Chen
- Department of Cardiology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Ping Li
- Department of Rheumatology and Immunology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Liqi Bi
- Department of Rheumatology and Immunology, China-Japan Union Hospital of Jilin University, Changchun, China
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21
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Aripaka SS, Bech-Azeddine R, Jørgensen LM, Mikkelsen JD. Transient receptor potential (TRP) channels mRNA transcripts in the lumbar intervertebral discs: biomarkers for inflammation, pain, disability, and clinical outcome. Mol Cell Biochem 2023; 478:121-130. [PMID: 35737198 DOI: 10.1007/s11010-022-04501-5] [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: 01/12/2022] [Accepted: 06/08/2022] [Indexed: 01/17/2023]
Abstract
Transient receptor potential (TRP) channels are widely expressed cation channels that play an essential role in mediating Ca2+ homeostasis and are considered potential regulators of inflammatory pain. This study investigates the expression of the TRP channel subtypes TRPV1, TRPV4, TRPC6, TRPM2, TRPM8 in lumbar intervertebral disc (IVD) biopsies from patients with chronic low back pain (LBP). We determined the expression of these TRP channel subtypes in the annulus fibrosus (AF) and the nucleus pulposus (NP) from 46 patients with LBP undergoing 1-2 level lumbar fusion surgery for degenerative disc disease. The mRNA transcripts were analyzed using quantitative real-time polymerase chain reaction (RT-qPCR), and the expression levels were compared against visual analog scale (VAS) and oswestry disability index (ODI) scores (0-100) for pain and disability. A significant positive correlation was demonstrated between VAS score and the mRNA expression of TRPV1, TRPC6, TRPM2, TRPM8 in the AF. We also found a significant positive correlation between ODI scores and expression of TRPV1 and TRPM8. Further, there is a significant positive correlation between TNF-α and TRPV1, TRPM2 and TRPM8 expression in the AF, and IL-6 to TRPV1 in the NP. Interestingly, when investigating treatment response via a 12-month postoperative follow-up ODI, we found a significant correlation between only TRPV1 expression at baseline and the follow-up ODI scores, which indicates this marker could predict the effectiveness of surgery. These results strongly suggest an association between pain, inflammatory mediators, and TRP channel expression in lumbar disc biopsies of patients with chronic LBP.
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Affiliation(s)
- Sanjay S Aripaka
- Neurobiology Research Unit, University Hospital Copenhagen, Rigshospitalet, 4-6, Inge Lehmanns vej, 2100, Copenhagen, Denmark.,Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Rachid Bech-Azeddine
- Center for Rheumatology and Spine Diseases, Copenhagen Spine Research Unit, Rigshospitalet, Glostrup, Copenhagen, Denmark.,Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Louise M Jørgensen
- Neurobiology Research Unit, University Hospital Copenhagen, Rigshospitalet, 4-6, Inge Lehmanns vej, 2100, Copenhagen, Denmark.,Center for Rheumatology and Spine Diseases, Copenhagen Spine Research Unit, Rigshospitalet, Glostrup, Copenhagen, Denmark.,Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens D Mikkelsen
- Neurobiology Research Unit, University Hospital Copenhagen, Rigshospitalet, 4-6, Inge Lehmanns vej, 2100, Copenhagen, Denmark. .,Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. .,Institute of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
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22
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Ness TJ, DeWitte C, Randich A. The Double Insult of Neonatal Cystitis Plus Adult Somatic Inflammation Results in Corticotropin Releasing Factor Type II Receptor-Dependent Bladder Hypersensitivity in Female Rats. THE JOURNAL OF PAIN 2022; 23:2167-2178. [PMID: 36089237 PMCID: PMC9729390 DOI: 10.1016/j.jpain.2022.08.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 08/23/2022] [Accepted: 08/26/2022] [Indexed: 01/04/2023]
Abstract
The spinal mechanisms of visceral hypersensitivity are poorly understood, particularly when there is an interaction with somatic systems. Recently we demonstrated that rats which were pretreated with neonatal bladder inflammation (NBI) and subsequently pretreated as adults with bladder re-inflammation had augmented reflex and neuronal responses to urinary bladder distension via a corticotropin-releasing factor receptor type II (CRFR2) mechanism. Another insult producing similar augmented responses is somatic inflammation induced by Complete Freund's Adjuvant (CFA) in the hindlimb. Using neurochemical measures and both reflex and neuronal responses to urinary bladder distension as endpoints, the present study probed the role of CRFR2-related mechanisms in bladder hyperalgesia secondary to NBI and CFA-induced hindlimb inflammation. ELISA measures of the lumbosacral spinal cord demonstrated increased CRFR2 protein following pretreatment with NBI+CFA. Intrathecal CRFR2 antagonists blocked the augmentation of visceromotor responses to distension following pretreatment with both NBI+CFA. Lumbosacral dorsal horn neuronal responses to bladder distension in rats pretreated with NBI+CFA were attenuated by the spinal topical administration of a CRFR2 antagonist. These findings are the first demonstration of a somatovisceral interaction working via CRFR2 receptors and support the therapeutic value of these agents in the treatment of painful bladder disorders, particularly when triggered by somatic events. (Word Count 199). PERSPECTIVE: Bladder hypersensitivity occurs following neonatal cystitis and an adult insult such as somatic inflammation. This paper demonstrates that CRFR2-related mechanisms are associated with this hypersensitivity. This supports the therapeutic value of these agents in the treatment of painful bladder disorders, particularly when triggered by somatic events.
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Affiliation(s)
- Timothy J Ness
- Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, Alabama.
| | - Cary DeWitte
- Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, Alabama
| | - Alan Randich
- Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, Alabama
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23
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A Guide to Preclinical Models of Zoster-Associated Pain and Postherpetic Neuralgia. Curr Top Microbiol Immunol 2022; 438:189-221. [PMID: 34524508 DOI: 10.1007/82_2021_240] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Reactivation of latent varicella-zoster virus (VZV) causes herpes zoster (HZ), which is commonly accompanied by acute pain and pruritus over the time course of a zosteriform rash. Although the rash and associated pain are self-limiting, a considerable fraction of HZ cases will subsequently develop debilitating chronic pain states termed postherpetic neuralgia (PHN). How VZV causes acute pain and the mechanisms underlying the transition to PHN are far from clear. The human-specific nature of VZV has made in vivo modeling of pain following reactivation difficult to study because no single animal can reproduce reactivated VZV disease as observed in the clinic. Investigations of VZV pathogenesis following primary infection have benefited greatly from human tissues harbored in immune-deficient mice, but modeling of acute and chronic pain requires an intact nervous system with the capability of transmitting ascending and descending sensory signals. Several groups have found that subcutaneous VZV inoculation of the rat induces prolonged and measurable changes in nociceptive behavior, indicating sensitivity that partially mimics the development of mechanical allodynia and thermal hyperalgesia seen in HZ and PHN patients. Although it is not a model of reactivation, the rat is beginning to inform how VZV infection can evoke a pain response and induce long-lasting alterations to nociception. In this review, we will summarize the rat pain models from a practical perspective and discuss avenues that have opened for testing of novel treatments for both zoster-associated pain and chronic PHN conditions, which remain in critical need of effective therapies.
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24
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Systemic Lipopolysaccharide Challenge Induces Inflammatory Changes in Rat Dorsal Root Ganglia: An Ex Vivo Study. Int J Mol Sci 2022; 23:ijms232113124. [DOI: 10.3390/ijms232113124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 10/21/2022] [Accepted: 10/26/2022] [Indexed: 11/09/2022] Open
Abstract
Inflammatory processes within the peripheral nervous system (PNS) are associated with symptoms of hyperalgesia and allodynia. Pro-inflammatory mediators, such as cytokines or prostaglandins, modulate the excitability of nociceptive neurons, called peripheral sensitization. Here, we aimed to examine if previously reported effects of in vitro stimulation with lipopolysaccharide (LPS) on primary cell cultures of dorsal root ganglia (DRG) reflect changes in a model of LPS-induced systemic inflammation in vivo. Male rats were intraperitoneally injected with LPS (100 µg/kg) or saline. Effects of systemic inflammation on expression of inflammatory mediators, neuronal Ca2+ responses, and activation of inflammatory transcription factors in DRG were assessed. Systemic inflammation was accompanied by an enhanced expression of pro-inflammatory cytokines and cyclooxygenase-2 in lumbar DRG. In DRG primary cultures obtained from LPS-treated rats enhanced neuronal capsaicin-responses were detectable. Moreover, we found an increased activation of inflammatory transcription factors in cultured macrophages and neurons after an in vivo LPS challenge compared to saline controls. Overall, our study emphasizes the role of inflammatory processes in the PNS that may be involved in sickness-behavior-associated hyperalgesia induced by systemic LPS treatment. Moreover, we present DRG primary cultures as tools to study inflammatory processes on a cellular level, not only in vitro but also ex vivo.
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25
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Petitjean H, Héberlé E, Hilfiger L, Łapieś O, Rodrigue G, Charlet A. TRP channels and monoterpenes: Past and current leads on analgesic properties. Front Mol Neurosci 2022; 15:945450. [PMID: 35966017 PMCID: PMC9373873 DOI: 10.3389/fnmol.2022.945450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 07/04/2022] [Indexed: 11/13/2022] Open
Abstract
The activation of the transient receptor potential (TRP) channels expressed by sensory neurons is essential to the transduction of thermal and mechanical sensory information. In the setting of chronic inflammatory conditions, the activation of the melastatin family member 8 (TRPM8), the TRP vanilloid 1 (TRPV1), and the TRP ankyrin 1 (TRPA1) is correlated with pain hypersensitivity reactions. Monoterpenes, among which pulegone and menthol, a major class of phytocompounds present in essential oils of medicinal plants, are known modulators of those TRP channels activity. In the present review, we correlate the monoterpene content of plants with their historical therapeutic properties. We then describe how monoterpenes exert their anti-inflammatory and antihyperalgesia effects through modulation of TRP channels activity. Finally, we discuss the importance and the potential of characterizing new plant extracts and reassessing studied plant extracts for the development of ethnopharmacology-based innovative treatments for chronic pain. This review suggests that monoterpene solutions, based on composition from traditional healing herbs, offer an interesting avenue for the development of new phytotherapeutic treatments to alleviate chronic inflammatory pain conditions.
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Affiliation(s)
| | | | - Louis Hilfiger
- Benephyt, Strasbourg, France
- Centre National de la Recherche Scientifique, University of Strasbourg, Institute of Cellular and Integrative Neuroscience, INCI UPR3212, Strasbourg, France
| | - Olga Łapieś
- Centre National de la Recherche Scientifique, University of Strasbourg, Institute of Cellular and Integrative Neuroscience, INCI UPR3212, Strasbourg, France
| | | | - Alexandre Charlet
- Centre National de la Recherche Scientifique, University of Strasbourg, Institute of Cellular and Integrative Neuroscience, INCI UPR3212, Strasbourg, France
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26
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Bogdan DM, Studholme K, DiBua A, Gordon C, Kanjiya MP, Yu M, Puopolo M, Kaczocha M. FABP5 deletion in nociceptors augments endocannabinoid signaling and suppresses TRPV1 sensitization and inflammatory pain. Sci Rep 2022; 12:9241. [PMID: 35655086 PMCID: PMC9163147 DOI: 10.1038/s41598-022-13284-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 05/23/2022] [Indexed: 11/09/2022] Open
Abstract
The endocannabinoid anandamide (AEA) produces antinociceptive effects by activating cannabinoid receptor 1 (CB1). However, AEA also serves as an agonist at transient receptor potential vanilloid receptor 1 (TRPV1) in nociceptive sensory neurons, which may exacerbate pain. This potential functional duality is highlighted by the failure of an inhibitor of the AEA catabolic enzyme fatty acid amide hydrolase (FAAH) to afford pain relief in a clinical trial. Consequently, it remains to be determined whether elevating AEA levels in nociceptors leads to antinociceptive or pro-nociceptive effects. Fatty acid binding protein 5 (FABP5) is an intracellular carrier that mediates AEA transport to FAAH for inactivation. Leveraging the abundant expression of FABP5 in TRPV1+ nociceptors, we employed a conditional knockout strategy to demonstrate that FABP5 deletion in nociceptors augments AEA levels, resulting in the emergence of antinociceptive effects mediated by CB1. Mechanistically, FABP5 deletion suppresses inflammation- and nerve growth factor-mediated TRPV1 sensitization via CB1, an effect mediated by calcineurin. Unexpectedly, inhibition of FAAH failed to blunt TRPV1 sensitization, uncovering functionally distinct outputs resulting from FABP5 and FAAH inhibition. Collectively, our results demonstrate that FABP5 serves a key role in governing endocannabinoid signaling in nociceptors to disrupt TRPV1 sensitization and pain, and position FABP5 as a therapeutic target for the development of analgesics.
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Affiliation(s)
- Diane M Bogdan
- Department of Anesthesiology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, 11794, USA
| | - Keith Studholme
- Department of Anesthesiology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, 11794, USA
| | - Adriana DiBua
- Department of Anesthesiology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, 11794, USA
| | - Chris Gordon
- Department of Anesthesiology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, 11794, USA
| | - Martha P Kanjiya
- Department of Anesthesiology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, 11794, USA
| | - Mei Yu
- Department of Anesthesiology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, 11794, USA
| | - Michelino Puopolo
- Department of Anesthesiology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, 11794, USA
- Stony Brook University Pain and Analgesia Research Center (SPARC), Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, 11794, USA
| | - Martin Kaczocha
- Department of Anesthesiology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, 11794, USA.
- Stony Brook University Pain and Analgesia Research Center (SPARC), Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, 11794, USA.
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27
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Chen Y, Lu R, Wang Y, Gan P. Shaoyao Gancao Decoction Ameliorates Paclitaxel-Induced Peripheral Neuropathy via Suppressing TRPV1 and TLR4 Signaling Expression in Rats. Drug Des Devel Ther 2022; 16:2067-2081. [PMID: 35795847 PMCID: PMC9252300 DOI: 10.2147/dddt.s357638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Accepted: 05/26/2022] [Indexed: 11/23/2022] Open
Abstract
Purpose Paclitaxel-induced peripheral neuropathy (PIPN) is increasingly becoming one of the most widespread adverse effects in the treatment of cancer patients, and further precipitate neuroinflammation in the nervous system. Interestingly, Shaoyao Gancao Decoction (SGD), a traditional Chinese analgesic prescription, has emerged as a primary adjuvant to chemotherapy in relieving side effects, especially in the case of PIPN. However, the underlying mechanism of SGD functioning in PIPN remains elusive. Accordingly, the current study set out to explore the potential axis implicated in the functioning of SGD in PIPN. Methods First, network pharmacology was adopted to predict the role of the transient receptor potential vanilloid type 1 (TRPV1) protein in treating PIPN with SGD. Subsequently, the effects of SGD treatment on mechanical allodynia and thermal hyperalgesia were evaluated in rat PIPN models. Based on the bioinformatics information and current literature, paclitaxel activates toll-like receptor 4 (TLR4) induces the sensitization of TRPV1 mechanistically. Thereafter, TLR4-myeloid-differentiation response gene 88 (MyD88) signaling and TRPV1 expression patterns in dorsal root ganglias (DRGs) were measured by means of Western blotting, qPCR and immunofluorescence. Results Initial bioinformatics reared a total of 105 bioactive compounds and 1075 target genes from SGD. In addition, 40 target genes intersected with PIPN were considered as potential therapeutic genes. Based on the network analysis, SGD was found to exert its analgesic effect by reducing the expression of TRPV1. Further experimentation validated that SGD exerted an analgesic effect on thermal hyperalgesia in PIPN models, such that this protective effect was associated with the suppression of TRPV1 and TLR4-MyD88 Signaling over-expression. Conclusion Collectively, our findings indicated that SGD ameliorates PIPN by inhibiting the over-expression of TLR4-MyD88 Signaling and TRPV1, and further highlights the use of SGD as a potential alternative treatment for PIPN.
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Affiliation(s)
- Yu Chen
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, People’s Republic of China
| | - Ruohuang Lu
- Department of Stomatology, Third Xiangya Hospital, Central South University, Changsha, People’s Republic of China
| | - Yang Wang
- Department of Integrated Traditional Chinese and Western Medicine, Institute of Integrative Medicine, Xiangya Hospital, Central South University, Changsha, People’s Republic of China
| | - Pingping Gan
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, People’s Republic of China
- Correspondence: Pingping Gan, Department of Oncology, Xiangya Hospital, Central South University, Changsha, People’s Republic of China, Tel +86 13874975101, Email
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28
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Zhu C, Wang M, Guo J, Su SL, Yu G, Yang Y, Zhou Y, Tang Z. Angelica dahurica Extracts Attenuate CFA-Induced Inflammatory Pain via TRPV1 in Mice. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2022; 2022:4684830. [PMID: 35656472 PMCID: PMC9152374 DOI: 10.1155/2022/4684830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 03/13/2022] [Accepted: 04/11/2022] [Indexed: 11/20/2022]
Abstract
Angelica dahurica, belonging to the family Apiaceae, is a well-known herbal medicine. The roots of Angelica dahurica are commonly used for the treatment of headache, toothache, abscess, furunculosis, and acne. However, little is known about their analgesic molecular mechanism underlying pain relief. In this study, we used behavioral tests to assess the analgesic effect of the ADE (Angelica dahurica extracts) on CFA (complete Freund's adjuvant)-induced inflammatory pain mice models. TRPV1 (Transient Receptor Potential Cation Channel Subfamily V Member 1) protein activity in dorsal root ganglion (DRG) was assessed with a calcium imaging assay. TRPV1 expression was detected with western blot and immunohistochemistry. Then, we examined the constituents of ADE using combined ultra-performance liquid chromatography-quadrupole time-of-light mass spectrometry (UPLC/Q-TOF-MS). Our results showed that ADE effectively attenuated mechanical and thermal hypersensitivities in CFA-induced inflammatory pain model in mice. ADE also significantly reduced the activity and the protein expression of TRPV1 in DRG from CFA mice. Therefore, ADE might be an attractive and suitable analgesic agent for the management of chronic inflammatory pain.
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Affiliation(s)
- Chan Zhu
- School of Medicine, Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, China
- Key Laboratory of Chinese Medicine for Prevention and Treatment of Neurological Diseases, Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, China
| | - Meiyuan Wang
- School of Medicine, Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, China
- Key Laboratory of Chinese Medicine for Prevention and Treatment of Neurological Diseases, Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, China
| | - Jun Guo
- School of Medicine, Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, China
- Key Laboratory of Chinese Medicine for Prevention and Treatment of Neurological Diseases, Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, China
| | - Shu Lan Su
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
| | - Guang Yu
- School of Medicine, Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, China
- Key Laboratory of Chinese Medicine for Prevention and Treatment of Neurological Diseases, Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, China
| | - Yan Yang
- School of Medicine, Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, China
- Key Laboratory of Chinese Medicine for Prevention and Treatment of Neurological Diseases, Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, China
| | - Yuan Zhou
- School of Medicine, Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, China
- Key Laboratory of Chinese Medicine for Prevention and Treatment of Neurological Diseases, Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, China
| | - Zongxiang Tang
- School of Medicine, Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, China
- Key Laboratory of Chinese Medicine for Prevention and Treatment of Neurological Diseases, Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, China
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29
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Xu X, Yuan Z, Zhang S, Li G, Zhang G. Regulation of TRPV1 channel in monosodium urate-induced gouty arthritis in mice. Inflamm Res 2022; 71:485-495. [PMID: 35298670 DOI: 10.1007/s00011-022-01561-7] [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: 10/20/2021] [Revised: 03/04/2022] [Accepted: 03/05/2022] [Indexed: 11/28/2022] Open
Abstract
OBJECTIVE The transient receptor potential vanilloid subtype 1 (TRPV1) channel is considered to play an important regulatory role in the process of pain. The purpose of this study is to observe the change characteristics of TRPV1 channel in MSU-induced gouty arthritis and to find a new target for clinical treatment of gout pain. METHODS Acute gouty arthritis was induced by injection of monosodium urate (MSU) crystals into the ankle joint of mice. The swelling degree was evaluated by measuring the circumference of the ankle joint. Mechanical hyperalgesia was conducted using the electronic von Frey. Calcium fluorescence and TRPV1 current were recorded by applying laser scanning confocal microscope and patch clamp in dorsal root ganglion (DRG) neurons, respectively. RESULTS MSU treatment resulted in significant inflammatory response and mechanical hyperalgesia. The peak swelling degree appeared at 12 h, and the minimum pain threshold appeared at 8 h after MSU treatment. The fluorescence intensity of capsaicin-induced calcium response and TRPV1 current were increased in DRG cells from MSU-treated mice. The number of cells that increased calcium response after MSU treatment was mainly distributed in small-diameter DRG cells. However, the action potential was not significantly changed in small-diameter DRG cells after MSU treatment. CONCLUSIONS These findings identified an important role of TRPV1 in mediating mechanical hyperalgesia in MSU-induced gouty arthritis and further suggest that TRPV1 can be regarded as a potential new target for the clinical treatment of gouty arthritis.
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Affiliation(s)
- Xiuqi Xu
- Department of Clinical Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China
| | - Ziqi Yuan
- Department of Clinical Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China
| | - Shijia Zhang
- School of Pharmacy, Xuzhou Medical University, Xuzhou, 221000, China
| | - Guang Li
- Key Laboratory of Medical Electrophysiology, Ministry of Education, Institute of Cardiovascular Research of Southwest Medical University, Luzhou, 646000, China
| | - Guangqin Zhang
- Department of Clinical Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China.
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30
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Grayson M, Arris D, Wu P, Merlo J, Ibrahim T, Mei C, Valenzuela V, Ganatra S, Ruparel S. Oral squamous cell carcinoma-released brain-derived neurotrophic factor contributes to oral cancer pain by peripheral tropomyosin receptor kinase B activation. Pain 2022; 163:496-507. [PMID: 34321412 PMCID: PMC8678394 DOI: 10.1097/j.pain.0000000000002382] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Accepted: 06/14/2021] [Indexed: 11/26/2022]
Abstract
ABSTRACT Oral cancer pain is debilitating and understanding mechanisms for it is critical to develop novel treatment strategies treatment strategies. Brain-derived neurotrophic factor (BDNF) signaling is elevated in oral tumor biopsies and is involved with tumor progression. Whether BDNF signaling in oral tumors contributes to cancer-induced pain is not known. The current study evaluates a novel peripheral role of BDNF-tropomyosin receptor kinase B (TrkB) signaling in oral cancer pain. Using human oral squamous cell carcinoma (OSCC) cells and an orthotopic mouse tongue cancer pain model, we found that BDNF levels were upregulated in superfusates and lysates of tumor tongues and that BDNF was expressed by OSCC cells themselves. Moreover, neutralization of BDNF or inhibition of TrkB activity by ANA12, within the tumor-bearing tongue reversed tumor-induced pain-like behaviors in a sex-dependent manner. Oral squamous cell carcinoma conditioned media also produced pain-like behaviors in naïve male mice that was reversed by local injection of ANA12. On a physiological level, using single-fiber tongue-nerve electrophysiology, we found that acutely blocking TrkB receptors reversed tumor-induced mechanical sensitivity of A-slow high threshold mechanoreceptors. Furthermore, single-cell reverse transcription polymerase chain reaction data of retrogradely labeled lingual neurons demonstrated expression of full-form TrkB and truncated TrkB in distinct neuronal subtypes. Last but not the least, intra-TG siRNA for TrkB also reversed tumor-induced orofacial pain behaviors. Our data suggest that TrkB activities on lingual sensory afferents are partly controlled by local release of OSCC-derived BDNF, thereby contributing to oral cancer pain. This is a novel finding and the first demonstration of a peripheral role for BDNF signaling in oral cancer pain.
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Affiliation(s)
- Max Grayson
- Department of Endodontics, University of Texas Health San Antonio, Texas, USA
| | - Dominic Arris
- Department of Pharmacology and Physiology, University of Texas Health San Antonio, Texas, USA
| | - Ping Wu
- Department of Endodontics, University of Texas Health San Antonio, Texas, USA
| | - Jaclyn Merlo
- Department of Microbiology and Immunology, University of Texas Health San Antonio, Texas, USA
| | - Tarek Ibrahim
- Department of Endodontics, University of Texas Health San Antonio, Texas, USA
| | - Chang Mei
- Department of Endodontics, University of Texas Health San Antonio, Texas, USA
| | - Vanessa Valenzuela
- Department of Endodontics, University of Texas Health San Antonio, Texas, USA
| | - Shilpa Ganatra
- Department of Endodontics, University of Texas Health San Antonio, Texas, USA
| | - Shivani Ruparel
- Department of Endodontics, University of Texas Health San Antonio, Texas, USA
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31
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Zhang Y, Zhang D, Qin C. Animal models and experimental medicine and the Nobel Prize in Physiology or Medicine 2021-TRPV and PIEZO receptors for temperature and touch sensation. Animal Model Exp Med 2021; 4:297-299. [PMID: 34977480 PMCID: PMC8690987 DOI: 10.1002/ame2.12196] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 11/16/2021] [Indexed: 11/25/2022] Open
Affiliation(s)
- Yu Zhang
- Institute of Laboratory Animal SciencesChinese Academy of Medical SciencesBeijingChina
- Comparative Medicine CenterPeking Union Medical CollegeBeijingChina
- NHC Key Laboratory of Human Disease Comparative MedicineBeijingChina
- Beijing Engineering Research Center for Experimental Animal Models of Human Critical DiseasesBeijingChina
- Chinese Association for Laboratory Animal SciencesBeijingChina
| | - Dongyuan Zhang
- Institute of Laboratory Animal SciencesChinese Academy of Medical SciencesBeijingChina
- Comparative Medicine CenterPeking Union Medical CollegeBeijingChina
- NHC Key Laboratory of Human Disease Comparative MedicineBeijingChina
- Beijing Engineering Research Center for Experimental Animal Models of Human Critical DiseasesBeijingChina
- Chinese Association for Laboratory Animal SciencesBeijingChina
| | - Chuan Qin
- Institute of Laboratory Animal SciencesChinese Academy of Medical SciencesBeijingChina
- Comparative Medicine CenterPeking Union Medical CollegeBeijingChina
- NHC Key Laboratory of Human Disease Comparative MedicineBeijingChina
- Beijing Engineering Research Center for Experimental Animal Models of Human Critical DiseasesBeijingChina
- Chinese Association for Laboratory Animal SciencesBeijingChina
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32
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Li X, Ye Y, Zhou W, Shi Q, Wang L, Li T. Anti-Inflammatory Effects of BoNT/A Against Complete Freund's Adjuvant-Induced Arthritis Pain in Rats: Transcriptome Analysis. Front Pharmacol 2021; 12:735075. [PMID: 34803684 PMCID: PMC8602683 DOI: 10.3389/fphar.2021.735075] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 10/11/2021] [Indexed: 01/01/2023] Open
Abstract
Arthritis is the most common cause to lead to chronic pain. Botulinum toxin type A (BoNT/A) has been widely used to treat chronic pain. In our previous study, we confirmed the anti-inflammatory and antinociceptive effects of BoNT/A in the Complete Freund’s Adjuvant (CFA)-induced arthritis model, but the underlying anti-inflammatory mechanism was not fully elucidated. The purpose of this study was to investigate the anti-inflammatory effects and mechanisms of BoNT/A on arthritis using transcriptomic analysis. The BoNT/A was injected into the rat ankle joint on day 21 after CFA injection. The von Frey and hot plate tests were applied to assess the pain-related behaviors at different time points. Five days after BoNT/A treatment, gene expression profiling in dorsal root ganglion (DRG) was performed using RNA sequencing (RNA-seq). The differentially expressed genes (DEGs) were analyzed by various tools. The mechanical allodynia and thermal hyperalgesia were significantly reversed after BoNT/A injection. RNA-seq revealed 97 DEGs between the CFA group and Sham group; these DEGs were enriched inflammatory response, IL-17 signaling pathway, etc. There are 71 DEGs between the CFA+BoNT/A group and the CFA group; these DEGs related to response to peptide, PI3K-Akt signaling pathway, ECM–receptor interactions, etc. Three key genes were significantly decreased after CFA-induced arthritis pain, while BoNT/A increased the expression of these genes. The identification of S100A9, S100A8, and MMP8 genes can provide new therapeutic targets for arthritis pain and affect the signaling pathway to play an anti-inflammatory role after the treatment of BoNT/A.
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Affiliation(s)
- Xinhe Li
- Department of Rehabilitation Medicine, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yinshuang Ye
- Department of Rehabilitation Medicine, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Wenwen Zhou
- Department of Rehabilitation Medicine, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Qilin Shi
- Department of Rehabilitation Medicine, Qingdao West Coast New District People's Hospital, Qingdao, China
| | - Lin Wang
- Department of Rehabilitation Medicine, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Tieshan Li
- Department of Rehabilitation Medicine, The Affiliated Hospital of Qingdao University, Qingdao, China
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Galiazzo G, De Silva M, Giancola F, Rinnovati R, Peli A, Chiocchetti R. Cellular distribution of cannabinoid-related receptors TRPV1, PPAR-gamma, GPR55 and GPR3 in the equine cervical dorsal root ganglia. Equine Vet J 2021; 54:788-798. [PMID: 34418142 PMCID: PMC9293124 DOI: 10.1111/evj.13499] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 06/18/2021] [Accepted: 08/19/2021] [Indexed: 11/26/2022]
Abstract
BACKGROUND The activation of cannabinoid and cannabinoid-related receptors by endogenous, plant-derived or synthetic cannabinoids may exert beneficial effects on pain perception. Of the cannabinoids contained in Cannabis sativa, cannabidiol (CBD) does not produce psychotropic effects and seems to represent a molecule having great therapeutic potential. Cannabidiol acts on a great number of cannabinoid and cannabinoid-related G-protein-coupled receptors and ionotropic receptors which have, to date, been understudied in veterinary medicine particularly in equine medicine. OBJECTIVES To localise the cellular distribution of four putative cannabinoid-related receptors in the equine cervical dorsal root ganglia (DRG). STUDY DESIGN A qualitative and quantitative immunohistochemical study. METHODS The cervical (C6-C8) DRG of six slaughtered horses were obtained from a local slaughterhouse. The tissues were fixed and processed for immunohistochemistry, and the resulting cryosections were used to investigate immunoreactivity for the following putative CBD receptors: Transient receptor potential vanilloid type 1 (TRPV1), nuclear peroxisome proliferator-activated receptor gamma (PPARγ), and G protein-coupled receptors 55 (GPR55) and 3 (GPR3). RESULTS Large percentages of neuronal cell bodies showed immunoreactivity for TRPV1 (80 ± 20%), PPARγ (100%), GPR55 (64 ± 15%) and GPR3 (63 ± 11%). The satellite glial cells (SGCs) were immunoreactive for TRPV1, PPARγ and GPR55. In addition, GPR55 immunoreactivity was expressed by DRG interneuronal macrophages. In addition, microglia cells were observed surrounding the neuron-SGC complex. MAIN LIMITATIONS The limited number of horses included in the study. CONCLUSIONS Cannabinoid-related receptors were distributed in the sensory neurons (TRPV1, PPARγ, GPR55 and GPR3), SGCs (TRPV1, PPARγ and GPR55), macrophages (GPR55) and other interneuronal cells (PPARγ and GPR55) of the equine DRG. Given the key role of DRG cellular elements and cannabinoid receptors in the pathophysiology of pain, the present findings provided an anatomical basis for additional studies aimed at exploring the therapeutic uses of non-psychotropic cannabinoid agonists for the management of pain in horses.
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Affiliation(s)
- Giorgia Galiazzo
- Department of Veterinary Medical Sciences (UNI EN ISO 9001:2008)University of BolognaBolognaItaly
| | - Margherita De Silva
- Department of Veterinary Medical Sciences (UNI EN ISO 9001:2008)University of BolognaBolognaItaly
| | - Fiorella Giancola
- Department of Veterinary Medical Sciences (UNI EN ISO 9001:2008)University of BolognaBolognaItaly
| | - Riccardo Rinnovati
- Department of Veterinary Medical Sciences (UNI EN ISO 9001:2008)University of BolognaBolognaItaly
| | - Angelo Peli
- Department of Veterinary Medical Sciences (UNI EN ISO 9001:2008)University of BolognaBolognaItaly
| | - Roberto Chiocchetti
- Department of Veterinary Medical Sciences (UNI EN ISO 9001:2008)University of BolognaBolognaItaly
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34
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Noopept Attenuates Diabetes-Mediated Neuropathic Pain and Oxidative Hippocampal Neurotoxicity via Inhibition of TRPV1 Channel in Rats. Mol Neurobiol 2021; 58:5031-5051. [PMID: 34241806 DOI: 10.1007/s12035-021-02478-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Accepted: 06/27/2021] [Indexed: 10/20/2022]
Abstract
Neuropathic pain and oxidative neurotoxicity are two adverse main actions of diabetes mellitus (DM). The expression levels of calcium ion (Ca2+) permeable TRPV1 channels are high in the dorsal root ganglion (DRGs) and hippocampus (HIPPO). TRPV1 is activated by capsaicin and reactive free oxygen radicals (fROS) to mediate peripheral neuropathy and neurotoxicity. Noopept (NP) acted several protective antioxidant actions against oxidative neurotoxicity. As DM is known to increase the levels of fROS, the protective roles of antioxidant NP were evaluated on the DM-mediated neurotoxicity and neuropathic pain via the modulation of TRPV1 in rats. Thirty-six rats were equally divided into control, NP, DM (streptozotocin, STZ), and STZ + NP groups. A decrease on the STZ-mediated increase of neuropathic pain (via the analyses of Von Frey and hot plate) and blood glucose level was observed by the treatment of NP. A protective role of NP via downregulation of TRPV1 activity on the STZ-induced increase of apoptosis, mitochondrial fROS, lipid peroxidation, caspase -3 (CASP-3), caspase -9 (CASP-9), TRPV1 current density, glutathione (GSH), cytosolic free Zn2+, and Ca2+ concentrations in the DRGs and HIPPO was also observed. The STZ-mediated decrease of glutathione peroxidase, GSH, vitamin E, and β-carotene concentrations in the brain cortex, erythrocyte, liver, kidney, and plasma was also attenuated by the treatment of NP. The STZ-mediated increase of TRPV1, CASP-3, and CASP-9 expressions was decreased in the DRGs and HIPPO by the treatment of NP. In conclusion, the treatment of NP induced protective effects against STZ-induced adverse peripheral pain and HIPPO oxidative neurotoxicity. These effects might attribute to the potent antioxidant property of NP.
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35
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Liao HY, Lin YW. Electroacupuncture reduces cold stress-induced pain through microglial inactivation and transient receptor potential V1 in mice. Chin Med 2021; 16:43. [PMID: 34082798 PMCID: PMC8173787 DOI: 10.1186/s13020-021-00451-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 05/24/2021] [Indexed: 11/16/2022] Open
Abstract
Background The treatment, and efficacy thereof, is considered to be inadequate with specificity to alleviation of Fibromyalgia and its associated pain. Fibromyalgia patients suffer from chronic and persistent widespread pain and generalized tenderness. Transient receptor potential V1 (TRPV1), which is reported as a Ca2+ permeable ion channel that can be activated by inflammation, is reported to be involved in the development of fibromyalgia pain. Methods The current study explored the TRPV1 channel functions as a noxious sensory input in mice cold stress model. It remains unknown whether electroacupuncture (EA) attenuates fibromyalgia pain or affects the TRPV1 pathway. Results We show that cold stress increases mechanical and thermal pain (day 7: mechanical: 1.69 ± 0.41 g; thermal: 4.68 ± 0.56 s), and that EA and Trpv1 deletion counter this increase. EA and Trpv1 deletion reduced the cold stress-induced increase in inflammatory mediators and TRPV1-related molecules in the hypothalamus, periaqueductal gray (PAG), and cerebellum of mice. Conclusions Our results imply that EA has an analgesic effect associated with TRPV1 downregulation. We provide novel evidence that these inflammatory mediators can modulate the TRPV1 signaling pathway and suggest new potential therapeutic targets for fibromyalgia pain.
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Affiliation(s)
- Hsien-Yin Liao
- College of Chinese Medicine, School of Post-Baccalaureate Chinese Medicine, China Medical University, Taichung, 40402, Taiwan
| | - Yi-Wen Lin
- College of Chinese Medicine, Graduate Institute of Acupuncture Science, China Medical University, 91 Hsueh-Shih Road, Taichung, 40402, Taiwan. .,Chinese Medicine Research Center, China Medical University, Taichung, 40402, Taiwan.
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36
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Tian L, Chen Y, Chang S, Xu L, Zhou X, Mao Q, Liang L. Antisense oligonucleotides targeting alternative splicing of Nrcam exon 10 suppress neurite outgrowth of ganglion sensory neurons in vitro. Neuroreport 2021; 32:548-554. [PMID: 33850082 DOI: 10.1097/wnr.0000000000001625] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Neuron-glial-related cell adhesion molecule (NrCAM) is a neuronal cell adhesion molecule that has been shown to be involved in several cellular processes in the peripheral nervous system, including neurite outgrowth. We recently reported that alternative splicing of Nrcam mRNA at exon 10 in the dorsal root ganglion (DRG) contributes to the peripheral mechanism of neuropathic pain. Specially, Nrcam antisense oligonucleotides (ASO) targeting Nrcam exon 10, attenuated neuropathic pain hypersensitivities in mice. Here, we investigated the effect of Nrcam ASO on neurite outgrowth of DRG neurons in vitro. By immunostaining DRG neurons with different DRG markers, Nrcam ASO significantly reduced neurite lengths in neurofilament 200-, calcitonin gene-related peptide and isolectin B4-positive neurons in primary DRG neuronal culture. Moreover, Nrcam ASO activates epidermal growth factor receptor, which may mediate the effect of Nrcam ASO on neurite outgrowth of cultured DRG neurons. These results provide evidence that Nrcam ASO suppresses neurite outgrowth in DRG neurons by regulating alternative splicing of Nrcam gene at exon 10 and activation of epidermal growth factor receptor signaling, indicating the differential roles of NrCAM variants/isoforms in neurite outgrowth.
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Affiliation(s)
- Lixia Tian
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences
- Institute of Neuroscience, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi
| | - Yu Chen
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences
| | - Shuyang Chang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences
- Institute of Neuroscience, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi
| | - Linping Xu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences
- Institute of Neuroscience, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi
| | - Xiaoqiong Zhou
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences
- Institute of Neuroscience, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi
| | - Qingxiang Mao
- Department of Anesthesiology, Daping Hospital, Army Medical University, Chongqing
| | - Lingli Liang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences
- Institute of Neuroscience, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi
- Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Beijing, PR China
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37
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Liang L, Zhang J, Tian L, Wang S, Xu L, Wang Y, Guo-Shuai Q, Dong Y, Chen Y, Jia H, Yang X, Yuan C. AXL signaling in primary sensory neurons contributes to chronic compression of dorsal root ganglion-induced neuropathic pain in rats. Mol Pain 2021; 16:1744806919900814. [PMID: 31884887 PMCID: PMC6970473 DOI: 10.1177/1744806919900814] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Low back pain is a chronic, highly prevalent, and hard-to-treat condition in the elderly. Clinical studies indicate that AXL, which belongs to the tyrosine kinase receptor subfamily, mediates pathological pain. However, it is not clear exactly how AXL regulates pain behaviors. In this study, we used a model of chronic compression of dorsal root ganglion-induced neuropathic pain to recreate clinical intervertebral foramen stenosis and related lumbocrural pain to explore whether AXL in primary sensory neurons contributes to this neuropathic pain in rats. Using double-labeling immunofluorescence, we observed that both phosphorylated AXL and AXL were localized primarily on isolectin B4-positive and calcitonin gene-related peptide-positive neurons, while AXL was also localized in neurofilament-200-positive neurons. Chronic compression of dorsal root ganglion-induced pain was associated with the upregulation of AXL mRNA and protein in injured dorsal root ganglia. Repeated intrathecal administration of the AXL inhibitor, TP0903, or the AXL small interfering RNA effectively alleviated chronic compression of dorsal root ganglion-induced pain hypersensitivities. Moreover, repeated intrathecal administration of either TP0903 or AXL small interfering RNA reduced the expression of mammalian target of rapamycin in injured dorsal root ganglia, suggesting that mammalian target of rapamycin may mediate AXL’s actions. These results indicate that the upregulation of dorsal root ganglion AXL may be part of a peripheral mechanism of neuropathic pain via an intracellular mammalian target of rapamycin-signaling pathway. Thus, while AXL inhibitors have so far primarily shown clinical efficacy in tumor treatment, AXL intervention could also serve as a potential target for the treatment of neuropathic pain.
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Affiliation(s)
- Lingli Liang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, PR China.,Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Beijing, PR China
| | - Jun Zhang
- Department of Pain Medicine, Tianjin Union Medical Center, Nankai University, Tianjin, PR China
| | - Lixia Tian
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, PR China.,Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Beijing, PR China
| | - Shuo Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, PR China.,Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Beijing, PR China
| | - Linping Xu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, PR China.,Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Beijing, PR China
| | - Yingxuan Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, PR China
| | - Qingying Guo-Shuai
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, PR China
| | - Yue Dong
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, PR China
| | - Yu Chen
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, PR China
| | - Hong Jia
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, PR China.,Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Beijing, PR China
| | - Xuewei Yang
- Department of Pain Medicine, Tianjin Union Medical Center, Nankai University, Tianjin, PR China
| | - Chunmei Yuan
- Department of Pain Medicine, Tianjin Union Medical Center, Nankai University, Tianjin, PR China
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38
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Chen Y, Cheng J, Zhang Y, Chen JDZ, Seralu FM. Electroacupuncture at ST36 Relieves Visceral Hypersensitivity via the NGF/TrkA/TRPV1 Peripheral Afferent Pathway in a Rodent Model of Post-Inflammation Rectal Hypersensitivity. J Inflamm Res 2021; 14:325-339. [PMID: 33584100 PMCID: PMC7875081 DOI: 10.2147/jir.s285146] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Accepted: 12/31/2020] [Indexed: 12/25/2022] Open
Abstract
Purpose The aim of the study was to investigate the effects of electroacupuncture (EA) at ST36 on rectal hypersensitivity and compliance in DSS-treated post-inflammation rats. In addition, we explored the involvement of mast cells-triggered NGF/TrkA/TRPV1 peripheral afferent pathway. Methods Rats were provided water with 5% dextran sulphate sodium (DSS) for 7 days. Two weeks after the DSS treatment they were subjected to initial and repetitive EA. Different sets of parameters were compared in the initial test and then EA with the selected parameters were performed for 2 weeks. Rectal compliance was assessed by colorectal distension while visceral sensitivity was evaluated by abdominal withdraw reflexes (AWR) and electromyogram (EMG). Masson's trichrome staining was performed to stain collagen and toluidine blue staining was applied to assess the degranulation of mast cells. Nerve growth factor (NGF), tryptase, TrkA and TRPV1 were measured by Western blot or immunofluorescence staining. Results EA at 100 Hz was more effective in improving rectal compliance and visceral hypersensitivity. Daily EA improved visceral hypersensitivity but not rectal compliance. Five weeks after DSS treatment, fibrosis was noted in both sham-EA and EA groups. The expression and activation of mast cells were significantly reduced after the 2-week EA treatment with a concurrent decrease in the expression of colonic NGF/TrkA and TRPV1 in both colon and dorsal root ganglions. Conclusion EA at ST36 with a special set of parameters has no effect on reduced rectal compliance but relieves visceral hypersensitivity via the mast cells-triggered NGF/TrkA/TRPV1 peripheral afferent pathway in DSS-treated post-inflammation rats.
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Affiliation(s)
- Yan Chen
- Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.,Division of Gastroenterology, Binzhou Medical University Hospital, Binzhou, Shandong, People's Republic of China
| | - Jiafei Cheng
- Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Yiling Zhang
- Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Jiande D Z Chen
- Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.,Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA
| | - Florin M Seralu
- Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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39
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Spinal PAR2 Activation Contributes to Hypersensitivity Induced by Peripheral Inflammation in Rats. Int J Mol Sci 2021; 22:ijms22030991. [PMID: 33498178 PMCID: PMC7863954 DOI: 10.3390/ijms22030991] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 01/16/2021] [Accepted: 01/17/2021] [Indexed: 11/17/2022] Open
Abstract
The mechanisms of inflammatory pain need to be identified in order to find new superior treatments. Protease-activated receptors 2 (PAR2) and transient receptor potential vanilloid 1 (TRPV1) are highly co-expressed in dorsal root ganglion neurons and implicated in pain development. Here, we examined the role of spinal PAR2 in hyperalgesia and the modulation of synaptic transmission in carrageenan-induced peripheral inflammation, using intrathecal (i.t.) treatment in the behavioral experiments and recordings of spontaneous, miniature and dorsal root stimulation-evoked excitatory postsynaptic currents (sEPSCs, mEPSCs and eEPSCs) in spinal cord slices. Intrathecal PAR2-activating peptide (AP) administration aggravated the carrageenan-induced thermal hyperalgesia, and this was prevented by a TRPV1 antagonist (SB 366791) and staurosporine i.t. pretreatment. Additionally, the frequency of the mEPSC and sEPSC and the amplitude of the eEPSC recorded from the superficial dorsal horn neurons were enhanced after acute PAR2 AP application, while prevented with SB 366791 or staurosporine pretreatment. PAR2 antagonist application reduced the thermal hyperalgesia and decreased the frequency of mEPSC and sEPSC and the amplitude of eEPSC. Our findings highlight the contribution of spinal PAR2 activation to carrageenan-induced hyperalgesia and the importance of dorsal horn PAR2 and TRPV1 receptor interactions in the modulation of nociceptive synaptic transmission.
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40
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Baba K, Kawasaki M, Nishimura H, Suzuki H, Matsuura T, Fujitani T, Tsukamoto M, Tokuda K, Yamanaka Y, Ohnishi H, Yoshimura M, Maruyama T, Sanada K, Ueno H, Sonoda S, Nishimura K, Tanaka K, Ueta Y, Sakai A. Heat hypersensitivity is attenuated with altered expression level of spinal astrocytes after sciatic nerve injury in TRPV1 knockout mice. Neurosci Res 2021; 170:273-283. [PMID: 33440224 DOI: 10.1016/j.neures.2020.12.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 12/12/2020] [Accepted: 12/24/2020] [Indexed: 12/21/2022]
Abstract
Transient receptor potential vanilloid 1 (TRPV1) modulates pain. Studies have indicated that TRPV1 is upregulated in the spinal dorsal horn in the neuropathic pain model, but its mechanism is unknown. Here, we examined the mechanism by which TRPV1 modulates neuropathic pain by employing partial sciatic nerve ligation (pSNL) in adult male C57BL/6 J (wild-type: WT) and TRPV1 knockout (Trpv1-/-) mice. We analyzed mechanical/heat sensitivities (von Frey test/hot plate test) and glial/neuronal activities (Iba-1/GFAP/FosB by immunofluorescence) in laminae I and II in the L5 ipsilateral dorsal horn of the spinal cord. Mechanical/heat sensitivities, expression levels of microglial Iba-1 and astrocytic GFAP, and the number of FosB-positive neurons were significantly increased on days 7 and 14 in the pSNL group compared with the sham-operated and non-operated groups of both WT and Trpv1-/- mice. While mechanical sensitivity was comparable between WT and Trpv1-/- mice, the threshold against heat sensitivity was markedly prolonged in Trpv1-/- than WT mice on day 14 after pSNL. Conversely, the increment of FosB positive neurons was significantly attenuated in Trpv1-/- than WT mice on days 7 and 14 after pSNL. These results suggest that TRPV1 may modulate thermal perception via increased astrocytes in the dorsal horn of the spinal cord.
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Affiliation(s)
- Kazuhiko Baba
- Department of Orthopaedic Surgery, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Makoto Kawasaki
- Department of Orthopaedic Surgery, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
| | - Haruki Nishimura
- Department of Orthopaedic Surgery, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Hitoshi Suzuki
- Department of Orthopaedic Surgery, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Takanori Matsuura
- Department of Orthopaedic Surgery, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Teruaki Fujitani
- Department of Orthopaedic Surgery, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Manabu Tsukamoto
- Department of Orthopaedic Surgery, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Kotaro Tokuda
- Department of Orthopaedic Surgery, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Yoshiaki Yamanaka
- Department of Orthopaedic Surgery, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Hideo Ohnishi
- Department of Orthopaedic Surgery, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Mitsuhiro Yoshimura
- Department of Physiology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Takashi Maruyama
- Department of Physiology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Kenya Sanada
- Department of Physiology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Hiromichi Ueno
- Department of Physiology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Satomi Sonoda
- Department of Physiology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Kazuaki Nishimura
- Department of Physiology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Kentaro Tanaka
- Department of Physiology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Yoichi Ueta
- Department of Physiology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Akinori Sakai
- Department of Orthopaedic Surgery, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
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Xie D, Xu Y, Yang Y, Hua Z, Li J, Fu G, Wu Q. Sensory denervation increases potential of bisphosphonates to induce osteonecrosis via disproportionate expression of calcitonin gene-related peptide and substance P. Ann N Y Acad Sci 2020; 1487:56-73. [PMID: 33301204 DOI: 10.1111/nyas.14540] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 10/30/2020] [Accepted: 11/03/2020] [Indexed: 12/17/2022]
Abstract
Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a serious side effect of systematic administration of bisphosphonates (BPs). Sensory innervation is crucial for bone healing. We established inferior alveolar nerve injury (IANI) and inferior alveolar nerve transection (IANT) models characterized by disorganized periosteum, increased osteoclasts, and unbalanced neuropeptide expression. Zoledronate injection disrupted neuropeptide expression in the IANI and IANT models by decreasing calcitonin gene-related peptide (CGRP) and increasing substance P (SP); associated with this, BRONJ prevalence was significantly higher in the IANT model, followed by the IANI model and the sham control. CGRP treatment significantly reduced BRONJ occurrence, whereas SP administration had the opposite effect. In vitro, RAW 264.7 cells were treated with BPs and then CGRP and/or SP to study changes in zoledronate toxicity; combined application of CGRP and SP decreased zoledronate toxicity, whereas CGRP or SP applied alone showed no effects. These results demonstrate that sensory denervation facilitates the occurrence of BRONJ and that CGRP used therapeutically may prevent BRONJ progression, provided that SP is also present. Further studies are necessary to determine the optimal ratio of CGRP to SP for promoting bone healing and to uncover the mechanism by which CGRP and SP cooperate.
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Affiliation(s)
- Dongni Xie
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Stomatological Hospital of Chongqing Medical University, Chongqing, China
| | - Yamei Xu
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Stomatological Hospital of Chongqing Medical University, Chongqing, China
| | - Yao Yang
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Stomatological Hospital of Chongqing Medical University, Chongqing, China
| | - Ziyi Hua
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Stomatological Hospital of Chongqing Medical University, Chongqing, China
| | - Jiao Li
- Department of Oral Implantology, Stomatological Hospital of Chongqing Medical University, Chongqing, China
| | - Gang Fu
- Department of Oral Implantology, Stomatological Hospital of Chongqing Medical University, Chongqing, China
| | - Qingqing Wu
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Stomatological Hospital of Chongqing Medical University, Chongqing, China
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Hu S, Huang Y, Chen Y, Zhou R, Yang X, Zou Y, Gao D, Huang H, Yu D. Diosmetin reduces bone loss and osteoclastogenesis by regulating the expression of TRPV1 in osteoporosis rats. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:1312. [PMID: 33209892 PMCID: PMC7661890 DOI: 10.21037/atm-20-6309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Background Osteoporosis is a systemic skeletal disorder and occurs frequently in postmenopausal women and older men. This study aimed to examine whether diosmetin (DIO) can relieve estrogen deficiency—induced osteoporosis and to explore the underlying mechanisms of this potential effect. Methods Forty-nine Sprague-Dawley (SD) rats were divided into seven groups. Six groups underwent bilateral ovariectomy (OVX), while the sham group underwent ovarian exposure surgery. DIO and evodiamine were administered 3 days before surgery, and then subcutaneously every 3 days for 3 months in the following fashion: group I, DIO (100 mg/kg); group II, OVX; group III, OVX + DIO (50 mg/kg); group IV, OVX + DIO (100 mg/kg); group V, OVX + evodiamine (10 mg/kg) group; group VI, OVX + DIO (100 mg/kg) + evodiamine (10 mg/kg) group. Bone histopathological damage, bone loss, osteoclast production, and the expression level of transient receptor potential vanilloid 1 (TRPV1) were detected. Results Compared with the sham group, the expression of bone resorption–related genes, osteoclast-associated receptor (OSCAR) (1.00%±0.16% versus 4.5%±0.28%, **, P<0.01) and tartrate-resistant acid phosphatase (TRAP) (2.0%±0.6% versus 18.00±1.2%, ***, P<0.001), was increased significantly. The protein level of osteogenic marker proteins, osterix (Osx) (1.0%±0.1% versus 0.03%±0.01%, **, P<0.01) and type 1 collagen (COL1A1) (1.0%±0.13% versus 0.13%±0.05%, **, P<0.01) was decreased significantly with the increase of TRPV1 (1.0%±0.15% versus 2.89%±0.28%, **, P<0.01) protein level. Notably, DIO can alleviate some abnormal symptoms related to osteoporosis. Conclusions DIO can relieve typical osteoporosis symptoms in an OVX osteoporosis rat model. The underlying mechanism may be associated with the downregulation of TRPV1.
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Affiliation(s)
- Song Hu
- Department of Orthopedics, West China-Guang'an Hospital, Sichuan University, Guang'an, China
| | - Youyi Huang
- Medical Department of Nanchang University, Nanchang, China
| | - Yong Chen
- Department of Orthopedics, West China-Guang'an Hospital, Sichuan University, Guang'an, China
| | - Renyi Zhou
- Department of Orthopedics, First hospital of China Medical University, Shenyang, China
| | - Xiaozhong Yang
- Department of Orthopedics, West China-Guang'an Hospital, Sichuan University, Guang'an, China
| | - Yi Zou
- Department of Orthopedics, West China-Guang'an Hospital, Sichuan University, Guang'an, China
| | - Daxin Gao
- Department of Orthopedics, West China-Guang'an Hospital, Sichuan University, Guang'an, China
| | - Hua Huang
- Department of Orthopedics, West China-Guang'an Hospital, Sichuan University, Guang'an, China
| | - Dongming Yu
- Department of Orthopedics, West China-Guang'an Hospital, Sichuan University, Guang'an, China
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Poulson SJ, Aldarraji A, Arain II, Dziekonski N, Motlana K, Riley R, Holmes MM, Martin LJ. Naked mole-rats lack cold sensitivity before and after nerve injury. Mol Pain 2020; 16:1744806920955103. [PMID: 32880221 PMCID: PMC7475789 DOI: 10.1177/1744806920955103] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Neuropathic pain is a chronic disease state resulting from injury to the nervous system. This type of pain often responds poorly to standard treatments and occasionally may get worse instead of better over time. Patients who experience neuropathic pain report sensitivity to cold and mechanical stimuli. Since the nociceptive system of African naked mole-rats contains unique adaptations that result in insensitivity to some pain types, we investigated whether naked mole-rats may be resilient to sensitivity following nerve injury. Using the spared nerve injury model of neuropathic pain, we showed that sensitivity to mechanical stimuli developed similarly in mice and naked mole-rats. However, naked mole-rats lacked sensitivity to mild cold stimulation after nerve injury, while mice developed robust cold sensitivity. We pursued this response deficit by testing behavior to activators of transient receptor potential (TRP) receptors involved in detecting cold in naïve animals. Following mustard oil, a TRPA1 activator, naked mole-rats responded similarly to mice. Conversely, icilin, a TRPM8 agonist, did not evoke pain behavior in naked mole-rats when compared with mice. Finally, we used RNAscope to probe for TRPA1 and TRPM8 messenger RNA expression in dorsal root ganglia of both species. We found increased TRPA1 messenger RNA, but decreased TRPM8 punctae in naked mole-rats when compared with mice. Our findings likely reflect species differences due to evolutionary environmental responses that are not easily explained by differences in receptor expression between the species.
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Affiliation(s)
- Sandra J Poulson
- Department of Psychology, University of Toronto Mississauga, Mississauga, ON, Canada
| | - Ahmed Aldarraji
- Department of Psychology, University of Toronto Mississauga, Mississauga, ON, Canada
| | - Iqra I Arain
- Department of Psychology, University of Toronto Mississauga, Mississauga, ON, Canada
| | - Natalia Dziekonski
- Department of Psychology, University of Toronto Mississauga, Mississauga, ON, Canada
| | - Keza Motlana
- Department of Psychology, University of Toronto Mississauga, Mississauga, ON, Canada
| | - Rachel Riley
- Department of Psychology, University of Toronto Mississauga, Mississauga, ON, Canada
| | - Melissa M Holmes
- Department of Psychology, University of Toronto Mississauga, Mississauga, ON, Canada.,Department of Cell and Systems Biology, University of Toronto, Toronto, ON, Canada.,Department of Ecology & Evolutionary Biology, University of Toronto, Toronto, ON, Canada
| | - Loren J Martin
- Department of Psychology, University of Toronto Mississauga, Mississauga, ON, Canada.,Department of Cell and Systems Biology, University of Toronto, Toronto, ON, Canada
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Wei TH, Hsieh CL. Effect of Acupuncture on the p38 Signaling Pathway in Several Nervous System Diseases: A Systematic Review. Int J Mol Sci 2020; 21:E4693. [PMID: 32630156 PMCID: PMC7370084 DOI: 10.3390/ijms21134693] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 06/26/2020] [Accepted: 06/28/2020] [Indexed: 12/16/2022] Open
Abstract
Acupuncture is clinically used to treat various diseases and exerts positive local and systemic effects in several nervous system diseases. Advanced molecular and clinical studies have continually attempted to decipher the mechanisms underlying these effects of acupuncture. While a growing understanding of the pathophysiology underlying several nervous system diseases shows it to be related to inflammation and impair cell regeneration after ischemic events, the relationship between the therapeutic mechanism of acupuncture and the p38 MAPK signal pathway has yet to be elucidated. This review discusses the latest advancements in the identification of the effect of acupuncture on the p38 signaling pathway in several nervous system diseases. We electronically searched databases including PubMed, Embase, and the Cochrane Library from their inception to April 2020, using the following keywords alone or in various combinations: "acupuncture", "p38 MAPK pathway", "signaling", "stress response", "inflammation", "immune", "pain", "analgesic", "cerebral ischemic injury", "epilepsy", "Alzheimer's disease", "Parkinson's disease", "dementia", "degenerative", and "homeostasis". Manual acupuncture and electroacupuncture confer positive therapeutic effects by regulating proinflammatory cytokines, ion channels, scaffold proteins, and transcription factors including TRPV1/4, Nav, BDNF, and NADMR1; consequently, p38 regulates various phenomena including cell communication, remodeling, regeneration, and gene expression. In this review article, we found the most common acupoints for the relief of nervous system disorders including GV20, GV14, ST36, ST37, and LI4. Acupuncture exhibits dual regulatory functions of activating or inhibiting different p38 MAPK pathways, contributing to an overall improvement of clinical symptoms and function in several nervous system diseases.
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Affiliation(s)
- Tzu-Hsuan Wei
- Department of Chinese Medicine, China Medical University Hospital, Taichung 40447, Taiwan;
| | - Ching-Liang Hsieh
- Department of Chinese Medicine, China Medical University Hospital, Taichung 40447, Taiwan;
- Chinese Medicine Research Center, China Medical University, Taichung 40402, Taiwan
- Graduate Institute of Acupuncture Science, College of Chinese Medicine, China Medical University, Taichung 40402, Taiwan
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Paclitaxel Induces Upregulation of Transient Receptor Potential Vanilloid 1 Expression in the Rat Spinal Cord. Int J Mol Sci 2020; 21:ijms21124341. [PMID: 32570786 PMCID: PMC7352737 DOI: 10.3390/ijms21124341] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2020] [Accepted: 06/11/2020] [Indexed: 02/07/2023] Open
Abstract
Painful peripheral neuropathy is a common adverse effect of paclitaxel (PTX) treatment. To analyze the contribution of transient receptor potential vanilloid 1 (TRPV1) in the development of PTX-induced mechanical allodynia/hyperalgesia and thermal hyperalgesia, TRPV1 expression in the rat spinal cord was analyzed after intraperitoneal administration of 2 and 4 mg/kg PTX. PTX treatment increased the expression of TRPV1 protein in the spinal cord. Immunohistochemistry showed that PTX (4 mg/kg) treatment increased TRPV1 protein expression in the superficial layers of the spinal dorsal horn 14 days after treatment. Behavioral assessment using the paw withdrawal response showed that PTX-induced mechanical allodynia/hyperalgesia and thermal hyperalgesia after 14 days was significantly inhibited by oral or intrathecal administration of the TRPV1 antagonist AMG9810. We found that intrathecal administration of small interfering RNA (siRNA) to knock down TRPV1 protein expression in the spinal cord significantly decreased PTX-induced mechanical allodynia/hyperalgesia and thermal hyperalgesia. Together, these results demonstrate that TRPV1 receptor expression in spinal cord contributes, at least in part, to the development of PTX-induced painful peripheral neuropathy. TRPV1 receptor antagonists may be useful in the prevention and treatment of PTX-induced peripheral neuropathic pain.
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Nikbakhtzadeh M, Borzadaran FM, Zamani E, Shabani M. Protagonist Role of Opioidergic System on Post-Traumatic Stress Disorder and Associated Pain. Psychiatry Investig 2020; 17:506-516. [PMID: 32492768 PMCID: PMC7324730 DOI: 10.30773/pi.2020.0002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Revised: 03/19/2020] [Accepted: 03/24/2020] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVE Post-traumatic stress disorder (PTSD) and chronic pain often co-occur. Studies have shown an interaction between pain and PTSD. In this narrative review, we aim to support conducting comprehensive studies by describing PTSD, pain and determining whether opioidergic system, its agonist and antagonist manipulation could positively or negatively affect PTSD symptoms and concurrent pain. METHODS Term searches was done in Google Scholar, Scopus, ScienceDirect, Web of Science and PubMed databases as well as hand searching in key resource journals from 1979-2019. RESULTS There are a lot of contradictions and disputes when endogenous opioidergic system and opioidergic antagonist system are studied in PTSD patients. Exogenous morphine administration in PTSD patients can decrease the symptoms of PTSD but it doesn't have a pain reduction effect to an acceptable level. Beta-endorphin as an endogenous opioid is effective in pain reduction in the moment of events but after minutes to hours, the endorphins withdrawal syndrome leads to exaggerated intrusive thoughts and flashbacks of PTSD, which exacerbate the pain. It has also been shown that naloxone, as an opioidergic antagonist, can reduce or increase the PTSD symptoms and its associated pain. CONCLUSION Data suggest different roles of opioidergic system and their antagonist in pain control and mood in PTSD. However, further investigations need to be done in order to reveal the role of endogenous opioidergic system and opioidergic antagonist system as a mediator in PTSD patients suffering from acute or chronic pain.
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Affiliation(s)
- Marjan Nikbakhtzadeh
- Department of Physiology, School of Medicine, Tehran University of Medical Science, Tehran, Iran
| | - Fatemeh Mohtashami Borzadaran
- Kerman Neuroscience Research Center, Neuropharmacology Institute, Kerman University of Medical Sciences, Kerman, Iran
| | - Elham Zamani
- Department of Physiology, School of Medicine, Tehran University of Medical Science, Tehran, Iran
| | - Mohammad Shabani
- Kerman Neuroscience Research Center, Neuropharmacology Institute, Kerman University of Medical Sciences, Kerman, Iran
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Wang S, Liu S, Xu L, Zhu X, Liu W, Tian L, Chen Y, Wang Y, Nagendra BVP, Jia S, Liang L, Huo FQ. The upregulation of EGFR in the dorsal root ganglion contributes to chronic compression of dorsal root ganglions-induced neuropathic pain in rats. Mol Pain 2020; 15:1744806919857297. [PMID: 31215332 PMCID: PMC6585252 DOI: 10.1177/1744806919857297] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Affiliation(s)
- Shuo Wang
- 1 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.,2 Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Beijing, China
| | - Siyi Liu
- 1 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.,2 Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Beijing, China
| | - Linping Xu
- 1 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.,2 Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Beijing, China
| | - Xuan Zhu
- 1 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.,3 Department of Anesthesiology, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, China
| | - Wanyuan Liu
- 1 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Lixia Tian
- 1 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.,2 Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Beijing, China
| | - Yu Chen
- 1 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Yuying Wang
- 1 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.,2 Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Beijing, China
| | - Borra V Padma Nagendra
- 1 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Shushan Jia
- 3 Department of Anesthesiology, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, China
| | - Lingli Liang
- 1 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.,2 Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Beijing, China
| | - Fu-Quan Huo
- 1 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.,2 Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Beijing, China
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Zhang BY, Zhang YL, Sun Q, Zhang PA, Wang XX, Xu GY, Hu J, Zhang HH. Alpha-lipoic acid downregulates TRPV1 receptor via NF-κB and attenuates neuropathic pain in rats with diabetes. CNS Neurosci Ther 2020; 26:762-772. [PMID: 32175676 PMCID: PMC7298987 DOI: 10.1111/cns.13303] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Revised: 02/17/2020] [Accepted: 03/01/2020] [Indexed: 12/14/2022] Open
Abstract
Aims Painful diabetic neuropathy (PDN) is a refractory complication of diabetes. The study aimed to investigate the role of α‐lipoic acid (ALA) on the regulation of transient receptor potential vanilloid‐1 (TRPV1) in dorsal root ganglion (DRG) neurons of rats with diabetes. Methods Whole‐cell patch‐clamp recordings were employed to measure neuronal excitability in DiI‐labeled DRG neurons of control and streptozotocin (STZ)‐induced diabetic rats. Western blotting and immunofluorescence assays were used to determine the expression and location of NF‐κBp65 and TRPV1. Results STZ‐induced hindpaw pain hypersensitivity and neuronal excitability in L4‐6 DRG neurons were attenuated by intraperitoneal injection with ALA once a day lasted for one week. TRPV1 expression was enhanced in L4‐6 DRGs of diabetic rats compared with age‐matched control rats, which was also suppressed by ALA treatment. In addition, TRPV1 and p65 colocated in the same DRG neurons. The expression of p65 was upregulated in L4‐6 DRGs of diabetic rats. Inhibition of p65 signaling using recombinant lentiviral vectors designated as LV‐NF‐κBp65 siRNA remarkably suppressed TRPV1 expression. Finally, p65 expression was downregulated by ALA treatment. Conclusion Our findings demonstrated that ALA may alleviate neuropathic pain in diabetes by regulating TRPV1 expression via affecting NF‐κB.
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Affiliation(s)
- Bing-Yu Zhang
- Department of Endocrinology, The Second Affiliated Hospital, Soochow University, Suzhou, China
| | - Yi-Lian Zhang
- Department of Endocrinology, The Second Affiliated Hospital, Soochow University, Suzhou, China
| | - Qian Sun
- Center for Translational Pain Medicine, Institute of Neuroscience, Soochow University, Suzhou, China
| | - Ping-An Zhang
- Center for Translational Pain Medicine, Institute of Neuroscience, Soochow University, Suzhou, China
| | - Xi-Xi Wang
- Department of Endocrinology, The Second Affiliated Hospital, Soochow University, Suzhou, China
| | - Guang-Yin Xu
- Center for Translational Pain Medicine, Institute of Neuroscience, Soochow University, Suzhou, China
| | - Ji Hu
- Department of Endocrinology, The Second Affiliated Hospital, Soochow University, Suzhou, China
| | - Hong-Hong Zhang
- Department of Endocrinology, The Second Affiliated Hospital, Soochow University, Suzhou, China
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Tu C, Wu DZ, Huang YS, Zhuang JS, Zeng JH, Xu P, Meng TT, Zhong ZM. Oxidative Stress Contributes to Hyperalgesia in Osteoporotic Mice. J Pain Res 2020; 13:131-142. [PMID: 32021402 PMCID: PMC6970262 DOI: 10.2147/jpr.s234334] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Accepted: 12/24/2019] [Indexed: 11/23/2022] Open
Abstract
Purpose Chronic pain is one of the most common complications of postmenopausal osteoporosis. Since oxidative stress is involved in the pathogenesis of postmenopausal osteoporosis, we explored whether oxidative stress contributes to postmenopausal osteoporotic pain. Methods Osteoporosis was induced in mice by ovariectomy (OVX). Pain-related behaviours were assessed by measuring sensitivity to mechanical, thermal and cold stimulation. The expression of pain-related transcripts, such acid-sensing ion channel 3 (ASIC3), transient receptor potential vanilloid 1 (TRPV1) and calcitonin gene-related peptide (CGRP), was evaluated. Plasma markers of oxidative stress were also measured. In addition, the effects of the reactive oxygen species scavenger phenyl N-tert-butylnitrone (PBN) on these parameters were assessed. Results The OVX mice presented hyperalgesia, as demonstrated by decreased paw withdrawal thresholds to mechanical stimulation and withdrawal latencies to thermal and cold stimulation, along with upregulated expression of ASIC3, TRPV1 and CGRP in the dorsal root ganglia, spinal cord and thalamus tissue. OVX elevated the plasma levels of malondialdehyde (MDA) and advanced oxidation protein products (AOPPs). However, the administration of PBN alleviated these effects. Conclusion Our results indicated that oxidative stress contributes to hyperalgesia in OVX mice. Enhanced oxidative stress may be associated with osteoporotic pain. Antioxidant treatment could help alleviate chronic pain in postmenopausal osteoporotic patients.
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Affiliation(s)
- Chen Tu
- Department of Spinal Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Di-Zheng Wu
- Department of Spinal Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Yu-Sheng Huang
- Department of Spinal Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Jing-Shen Zhuang
- Department of Spinal Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Ji-Huan Zeng
- Department of Orthopaedic Surgery, Jiangxi Province People's Hospital, Nanchang University, Nanchang, People's Republic of China
| | - Ping Xu
- Department of Spinal Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Ting-Ting Meng
- Department of Anaesthesia, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Zhao-Ming Zhong
- Department of Spinal Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
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Ling YH, Chen SP, Fann CSJ, Wang SJ, Wang YF. TRPM8 genetic variant is associated with chronic migraine and allodynia. J Headache Pain 2019; 20:115. [PMID: 31842742 PMCID: PMC6916225 DOI: 10.1186/s10194-019-1064-2] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Accepted: 12/02/2019] [Indexed: 11/25/2022] Open
Abstract
Background Many single nucleotide polymorphisms (SNPs) have been reported to be associated with migraine susceptibility. However, evidences for their associations with migraine endophenotypes or subtypes are scarce. We aimed to investigate the associations of pre-identified migraine susceptibility loci in Taiwanese with migraine endophenotypes or subtypes, including chronic migraine and allodynia. Methods The associations of six SNPs identified from our previous study, including TRPM8 rs10166942, LRP1 rs1172113, DLG2 rs655484, GFRA1 rs3781545, UPP2 rs7565931, and GPR39 rs10803531, and migraine endophenotypes, including chronic migraine and allodynia were tested. Significant associations in the discovery cohort were validated in the replication cohort. The adjusted odds ratios (aOR) were calculated after controlling for confounders. Results In total, 1904 patients (mean age 37.5 ± 12.2 years old, female ratio: 77.7%) including 1077 in the discovery cohort and 827 in the replication cohort were recruited. Of them, 584 (30.7%) had chronic migraine. Of the 6 investigated SNPs, TRPM8 rs10166942 T allele-carrying patients were more likely to have chronic migraine than non-T allele carriers in both discovery and replication cohorts and combined samples (33.7% vs. 25.8%, p = 0.004, aOR = 1.62). In addition, T allele carriers reported more allodynic symptoms than non-T allele carriers (3.5 ± 3.7 vs. 2.6 ± 2.8, p < 0.001). However, allodynia severity did not differ between episodic and chronic migraine patients. No further correlations between genetic variants and endophenotypes were noted for the other SNPs. Conclusions TRPM8 may contribute to the pathogenesis of chronic migraine. However, our study did not support allodynia as a link between them. The underlying mechanisms deserve further investigations.
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Affiliation(s)
- Yu-Hsiang Ling
- Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan.,Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Shih-Pin Chen
- Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan.,Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.,Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.,Brain Research Center, National Yang-Ming University, Taipei, Taiwan.,Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan
| | | | - Shuu-Jiun Wang
- Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan.,Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.,Brain Research Center, National Yang-Ming University, Taipei, Taiwan
| | - Yen-Feng Wang
- Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan. .,Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan. .,Brain Research Center, National Yang-Ming University, Taipei, Taiwan.
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