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Nasir A, Afridi M, Afridi OK, Khan MA, Khan A, Zhang J, Qian B. The persistent pain enigma: Molecular drivers behind acute-to-chronic transition. Neurosci Biobehav Rev 2025; 173:106162. [PMID: 40239909 DOI: 10.1016/j.neubiorev.2025.106162] [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: 02/26/2025] [Revised: 03/20/2025] [Accepted: 04/14/2025] [Indexed: 04/18/2025]
Abstract
The transition from acute to chronic pain is a complex and multifactorial process that presents significant challenges in both diagnosis and treatment. Key mechanisms of peripheral and central sensitization, neuroinflammation, and altered synaptic plasticity contribute to the amplification of pain signals and the persistence of pain. Glial cell activation, particularly microglia and astrocytes, is pivotal in developing chronic pain by releasing pro-inflammatory cytokines that enhance pain sensitivity. This review explores the molecular, cellular, and systemic mechanisms underlying the transition from acute to chronic pain, offering new insights into the molecular and neurobiological mechanisms involved, which are often underexplored in existing literature. It also addresses emerging therapeutic strategies beyond traditional pain management, offering valuable perspectives for future research and clinical applications.
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Affiliation(s)
- Abdul Nasir
- Department of Anesthesiology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, China; Medical Research Center, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, China.
| | - Maryam Afridi
- Department of Pharmacy, Qurtuba University, Peshawar, KP, Pakistan
| | | | | | - Amir Khan
- Icahn School of Medicine at Mount Sinai, New York, USA
| | - Jun Zhang
- Department of Pain, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, China
| | - Bai Qian
- Department of Anesthesiology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, China; Medical Research Center, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, China.
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2
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Barnet M, Descheemaeker A, Favier L, Moisset X, Schopp J, Dallel R, Artola A, Monconduit L, Antri M. Estrous cycle regulates cephalic mechanical sensitivity and sensitization of the trigemino-cervical complex in a female rat model of chronic migraine. Pain 2025; 166:e83-e96. [PMID: 39480245 DOI: 10.1097/j.pain.0000000000003459] [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: 07/27/2024] [Accepted: 09/22/2024] [Indexed: 11/02/2024]
Abstract
ABSTRACT The higher incidence of migraines in women compared with men has led to the inclusion of female animals in pain research models. However, the critical role of the hormonal cycle is frequently overlooked, despite its clear correlation with migraine occurrences. In this study, we show in a rat model of migraine induced by repeated dural infusions of an inflammatory soup (IS) that a second IS (IS2) injection performed in proestrus/estrus (PE, high estrogen) female rats evokes higher cephalic mechanical hypersensitivities than when performed in metestrus/diestrus (MD, low estrogen) or ovariectomized (OV) rats. This hypersensitivity induced by IS2 correlates with increased c-Fos expression in outer lamina II (IIo) neurons located in the periorbital projection area of the trigemino-cervical complex (TCC), in PE only. Four IS (IS4) repetition induced an enlargement of c-Fos expression in adjacent territories areas in PE, but not MD or OV animals. Unexpectedly, c-Fos expression in locus coeruleus neurons does not potentiate after IS2 or IS4 injections. To examine the impacts of the hormonal cycle on the physiology of lamina II o TCC neurons, we performed whole-cell patch-clamp recordings. Second inflammatory soup depolarizes neurons in PE and MD but not in OV rats and enhances excitatory synaptic inputs in PE animals to a greater extent compared with MD and OV rats. These findings show that central TCC sensitization triggered by meningeal nociceptor activation and the resulting cephalic hypersensitivity are modulated by the estrous cycle. This highlights the crucial need to account for not just sex, but also the female estrous cycle in pain research.
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Affiliation(s)
- Maxime Barnet
- Université Clermont Auvergne, CHU Clermont-Ferrand, Inserm/UCA U1107, Neuro-Dol: Trigeminal Pain and Migraine, Faculté de Chirurgie Dentaire, Clermont-Ferrand, France
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3
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Shen SY, Wu C, Yang ZQ, Wang KX, Shao ZH, Yan W. Advances in cannabinoid receptors pharmacology: from receptor structural insights to ligand discovery. Acta Pharmacol Sin 2025; 46:1495-1510. [PMID: 39910211 PMCID: PMC12098862 DOI: 10.1038/s41401-024-01472-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Accepted: 12/26/2024] [Indexed: 02/07/2025]
Abstract
The medicinal and recreational uses of Cannabis sativa have been recognized for thousands of years. Today, cannabis-derived medicines are used to treat a variety of conditions, including chronic pain, epilepsy, multiple sclerosis, and chemotherapy-induced nausea. However, cannabis use disorder (CUD) has become the third most prevalent substance use disorder globally. Cannabinoid receptors are the primary targets that mediate the effects of cannabis and its analogs. Despite their importance, the mechanisms of modulation and the full therapeutic potential of cannabinoid receptors remain unclear, hindering the development of the next generation of cannabinoid-based drugs. This review summarizes the discovery and medicinal potential of phytocannabinoids and explores the distribution, signaling pathways, and functional roles of cannabinoid receptors. It also discusses classical cannabinoid drugs, as well as agonists, antagonists, and inverse agonists, which serve as key therapeutic agents. Recent advancements in the development of allosteric drugs are highlighted, with a focus on positive and negative allosteric modulators (PAMs and NAMs) that target CB1 and CB2 receptors. The identification of multiple allosteric sites on the CB1 receptor and the structural basis for allosteric modulation are emphasized, along with the structure-based discovery of ago-BAMs for CB1. This review concludes by examining the future potential of allosteric modulators in cannabinoid drug development, noting that ongoing progress in cannabinoid-derived drugs continues to open new avenues for therapeutic use and paves the way for future research into their full medicinal potential.
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Affiliation(s)
- Si-Yuan Shen
- Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Chao Wu
- Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Zhi-Qian Yang
- Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Ke-Xin Wang
- Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Zhen-Hua Shao
- Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
- Tianfu Jincheng Laboratory, Frontier Medical Center, Chengdu, 610212, China.
| | - Wei Yan
- Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
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4
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Chang WJ, Chiang A, Chowdhury N, Adie S, Naylor JM, Finn H, Rizzo RRN, Gorgon E, O'Hagan E, Schabrun SM. Repetitive transcranial magnetic stimulation as an adjunct to quadriceps strengthening exercise in knee osteoarthritis: a pilot randomised controlled trial. BMJ Open 2025; 15:e097293. [PMID: 40409966 PMCID: PMC12104922 DOI: 10.1136/bmjopen-2024-097293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Accepted: 04/17/2025] [Indexed: 05/25/2025] Open
Abstract
OBJECTIVE To examine the feasibility, safety and perceived patient response of a combined repetitive transcranial magnetic stimulation (rTMS) and quadriceps strengthening exercise intervention for knee osteoarthritis. METHODS A two-arm, participant-blinded, therapist-blinded and assessor-blinded, randomised controlled trial with additional follow-up of pain and function at 3 months. Participants were randomised to receive active rTMS+exercise (AR+EX) or sham rTMS+exercise (SR+EX) twice weekly for 6 weeks while completing home exercises twice a week. Primary outcomes included recruitment rate, treatment attendance, dropouts, willingness to undergo therapy (11-point Numeric Rating Scale, 'not at all willing'=0 and 'very willing'=10), success of participant, therapist and outcome assessor blinding, adverse events and Global Perceived Effect Scale. Secondary outcomes were pain, function and measures of physiological mechanisms. RESULTS 86 people were screened, 31 (36%) were randomised, 28 (90%) completed the treatments and 3 (10%) dropouts at 3-month follow-up. Both groups had high treatment attendance (98.4% and 100%). All participants scored at least 7 on the willingness to undergo therapy scale. Blinding was successful. No adverse events were reported. At the postintervention assessment, 80% in the AR+EX group and 75% in the SR+EX group reported an improvement on the Global Perceived Effect Scale. Both groups demonstrated within-group improvements in pain at the postintervention assessment but not at the 3-month follow-up. Function improved only in the AR+EX group at the postintervention assessment. CONCLUSIONS Combined rTMS and quadriceps strengthening exercise intervention for knee osteoarthritis is feasible, safe and well-received. A full-scale trial is justified to assess the clinical benefits of this novel treatment. TRIAL REGISTRATION NUMBER ACTRN12621001712897.
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Affiliation(s)
- Wei-Ju Chang
- School of Health Sciences, University of New South Wales Medicine & Health, Sydney, New South Wales, Australia
- School of Health Sciences, The University of Newcastle, Newcastle, New South Wales, Australia
- Centre for Pain IMPACT, Neuroscience Research Australia, Randwick, New South Wales, Australia
| | - Alan Chiang
- Centre for Pain IMPACT, Neuroscience Research Australia, Randwick, New South Wales, Australia
- School of Clinical Medicine, University of New South Wales Medicine & Health, Sydney, New South Wales, Australia
| | - Nahian Chowdhury
- Centre for Pain IMPACT, Neuroscience Research Australia, Randwick, New South Wales, Australia
| | - Sam Adie
- School of Clinical Medicine, University of New South Wales Medicine & Health, Sydney, New South Wales, Australia
- St George and Sutherland Centre for Clinical Orthopaedic Research Limited, Kogarah, New South Wales, Australia
| | - Justine M Naylor
- School of Clinical Medicine, University of New South Wales Faculty of Medicine, Sydney, New South Wales, Australia
- Ingham Institute for Applied Medical Research, Liverppol, New South Wales, Australia
| | - Harrison Finn
- Neuroscience Research Australia, Randwick, New South Wales, Australia
| | - Rodrigo R N Rizzo
- School of Health Sciences, University of New South Wales Medicine & Health, Sydney, New South Wales, Australia
- Centre for Pain IMPACT, Neuroscience Research Australia, Randwick, New South Wales, Australia
| | - Edward Gorgon
- Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
| | - Edel O'Hagan
- Centre for Pain IMPACT, Neuroscience Research Australia, Randwick, New South Wales, Australia
- Westmead Applied Research Centre, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
| | - Siobhan M Schabrun
- School of Physical Therapy, University of Western Ontario, London, Ontario, Canada
- The Gray Centre for Mobility and Activity, Parkwood Institute, London, Ontario, Canada
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Adamczyk WM, Berendt N, Trillenberg P, Hanssen J, Poehlmann J, Kapitza C, Luebke L, Luedtke K, Brüggemann N, Szikszay TM. Disrupted spatial but not temporal aspects of nociceptive processing determine painful polyneuropathies. Pain 2025:00006396-990000000-00923. [PMID: 40408232 DOI: 10.1097/j.pain.0000000000003666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2025] [Accepted: 04/17/2025] [Indexed: 05/25/2025]
Abstract
ABSTRACT Polyneuropathy remains a diagnostic and clinical challenge, with limited understanding of the mechanisms underlying painful and nonpainful phenotypes. While previous studies have examined various characteristics of these patients, the temporal and spatial dynamics of endogenous pain modulation remains not fully elucidated. In this study, offset analgesia (OA) and spatial summation of pain (SSp) were used as measures of pain modulation in individuals with distal symmetric polyneuropathy, stratified by the presence (n = 30) or absence of pain (n = 30), and compared with healthy controls (n = 30). All participants underwent quantitative sensory testing and assessments of OA and SSp using a thermal stimulator applied to the dorsum of the foot. Patients with painful polyneuropathy exhibited enhanced SSp compared with the pain-free polyneuropathy group and healthy controls (P < 0.05), and impaired OA compared with healthy controls (P < 0.05). The pain-free neuropathy group showed less efficient OA and a slightly enhanced SSp, but this finding did not reach significance. The data suggest that changes in spatial summation were primarily driven by heightened pain responses to nociceptive input from smaller areas, rather than larger ones. Notably, spatial summation and the effects of OA were found to be correlated, irrespective of pain diagnosis. These findings underscore specific impairments in endogenous pain modulation in individuals with painful neuropathy, thus advancing our understanding of its pathophysiological mechanisms. They further highlight the differential roles of spatial and temporal dynamics in pain modulation across various neuropathic populations, offering promising avenues for improved diagnostics and prognostics related to polyneuropathy-associated pain.
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Affiliation(s)
- Wacław M Adamczyk
- Department of Physiotherapy, Pain and Exercise Research Luebeck (P.E.R.L.), Institute of Health Sciences, University of Luebeck, Lübeck, Germany
- Center of Brain, Behavior and Metabolism (CBBM), University of Luebeck, Lübeck, Germany
- Laboratory of Pain Research, Institute of Physiotherapy and Health Sciences, The Jerzy Kukuczka Academy of Physical Education, Katowice, Poland
| | - Nick Berendt
- Department of Physiotherapy, Pain and Exercise Research Luebeck (P.E.R.L.), Institute of Health Sciences, University of Luebeck, Lübeck, Germany
| | - Peter Trillenberg
- Department of Neurology, University Hospital of Schleswig-Holstein, Campus Lübeck, Lübeck, Germany
| | - Janina Hanssen
- School of Human and Life Sciences, Canterbury Christ Church University, Canterbury, United Kingdom
| | - Jakob Poehlmann
- Department of Physiotherapy, Pain and Exercise Research Luebeck (P.E.R.L.), Institute of Health Sciences, University of Luebeck, Lübeck, Germany
| | - Camilla Kapitza
- Department of Physiotherapy, Pain and Exercise Research Luebeck (P.E.R.L.), Institute of Health Sciences, University of Luebeck, Lübeck, Germany
- Faculty of Business, Management and Social Sciences, Department Movement and Rehabilitation Science, Hochschule Osnabrueck, University of Applied Sciences, Osnabrueck, Germany
| | - Luisa Luebke
- Department of Physiotherapy, Pain and Exercise Research Luebeck (P.E.R.L.), Institute of Health Sciences, University of Luebeck, Lübeck, Germany
| | - Kerstin Luedtke
- Department of Physiotherapy, Pain and Exercise Research Luebeck (P.E.R.L.), Institute of Health Sciences, University of Luebeck, Lübeck, Germany
- Center of Brain, Behavior and Metabolism (CBBM), University of Luebeck, Lübeck, Germany
| | - Norbert Brüggemann
- Center of Brain, Behavior and Metabolism (CBBM), University of Luebeck, Lübeck, Germany
- Department of Neurology, University Hospital of Schleswig-Holstein, Campus Lübeck, Lübeck, Germany
| | - Tibor M Szikszay
- Department of Physiotherapy, Pain and Exercise Research Luebeck (P.E.R.L.), Institute of Health Sciences, University of Luebeck, Lübeck, Germany
- Center of Brain, Behavior and Metabolism (CBBM), University of Luebeck, Lübeck, Germany
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de Souza Santana GC, de Jesus MVAC, Cruz ABO, de Lima AA, Lauria PSS, de Souza TA, da Silva MS, Viana MDM, Villarreal CF. Schinus terebinthifolius essential oil and its major component delta-3-carene induce antinociception mediated by serotonergic receptors. JOURNAL OF ETHNOPHARMACOLOGY 2025:120021. [PMID: 40414579 DOI: 10.1016/j.jep.2025.120021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/11/2025] [Revised: 05/17/2025] [Accepted: 05/21/2025] [Indexed: 05/27/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Schinus terebinthifolius Raddi. (Anacardiaceae) is a South American species that widely occurs in Brazil, where it is popularly known as "pimenta rosa". S. terebinthifolius essential oil (STEO) is traditionally used for pain management. AIM OF THE STUDY To investigate the antinociceptive effects of inhaled STEO and its mechanisms of action. MATERIALS AND METHODS Male Swiss mice were exposed to STEO (150-600 μL) via inhalation and assessed for thermal nociception (tail flick test) and motor integrity (rota-rod test). Functional antagonism assays were performed to investigate mechanisms of action. STEO was chemically characterized by GC/MS, and its major component, delta-3-carene (D3C), was tested for antinociceptive activity. SwissADME was used to predict D3C druggability. RESULTS Inhalation of STEO (300-600 μL) significantly elevated thermal nociceptive thresholds without impairing motor performance. Methysergide, but not naloxone or yohimbine, reversed STEO-induced antinociception, implying serotonergic receptor involvement. D3C was identified as the major constituent of STEO and, when administered orally (1.5-25 mg/kg), also promoted antinociceptive effects reversed by methysergide. In silico pharmacokinetics predicted favorable drug-like properties for D3C, supporting its role in STEO's antinociceptive effects. CONCLUSIONS STEO inhalation promoted antinociception mediated by serotonergic receptors, corroborating its traditional use. D3C was likely a significant contributor to STEO's antinociceptive properties.
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Affiliation(s)
| | | | | | - Alyne Almeida de Lima
- School of Pharmacy, Federal University of Bahia, 40.170-115, Salvador, BA, Brazil; Gonçalo Moniz Institute, Oswaldo Cruz Foundation - FIOCRUZ, 40.296-710, Salvador, BA, Brazil.
| | - Pedro Santana Sales Lauria
- School of Pharmacy, Federal University of Bahia, 40.170-115, Salvador, BA, Brazil; Department of Anesthesiology, University of California San Diego, 92037, San Diego, CA, United States.
| | - Thalisson Amorim de Souza
- Institute for Research on Drugs and Medicines, Federal University of Paraíba, 58.059-900, João Pessoa, PB, Brazil.
| | - Marcelo Sobral da Silva
- Institute for Research on Drugs and Medicines, Federal University of Paraíba, 58.059-900, João Pessoa, PB, Brazil.
| | | | - Cristiane Flora Villarreal
- School of Pharmacy, Federal University of Bahia, 40.170-115, Salvador, BA, Brazil; Gonçalo Moniz Institute, Oswaldo Cruz Foundation - FIOCRUZ, 40.296-710, Salvador, BA, Brazil.
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Chu WG, Zhang R, Li HT, Li YC, Ding H, Li ZZ, Han WJ, Wang F, Zheng XX, Mao HH, Yuan H, Wu SX, Xie RG, Luo C. Locus Coeruleus Noradrenergic-Spinal Projections Contribute to Electroacupuncture-Mediated Antinociception in Postoperative Pain in Mice. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025:e01182. [PMID: 40387368 DOI: 10.1002/advs.202501182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/18/2025] [Revised: 04/16/2025] [Indexed: 05/20/2025]
Abstract
Postoperative pain remains a significant challenge in healthcare. Electroacupuncture (EA) has gained polarity in helping manage surgical pain and showed beneficial effects on enhancing postoperative analgesia, decreasing opioid requirement. Despite this, the precise mechanisms underlying these actions are poorly understood. Evidence shows the involvement of noradrenaline (NE) in the action of EA. However, the precise identity of the NE source after EA treatment, its mechanisms of action, and the circuitry locus in the pain-regulating pathway remain elusive. It is shown that plantar incision (PI) leads to hypoactivity of noradrenergic neurons in the locus coeruleus (LC), which brings about impaired NE release in the spinal dorsal horn (SDH). EA treatment normalizes the abnormal hypoexcitability of LC noradrenergic neurons after PI and thus triggers enhanced NE release in the SDH. Optogenetic inhibition of LC noradrenergic neurons eliminates EA-induced NE release and antinociceptive effects after PI, while activation of these neurons mimics EA-induced NE release and antinociception. The resultant increased NE release after EA activates spinal α2A-adrenoceptor and inhibits CaMKII signaling, which in turn depresses spinal excitatory neuronal hyperexcitability and eventually relieves postoperative pain. It is concluded that LC noradrenergic-spinal projections and subsequent α2A-adrenoceptor-CaMKII signaling cascades in the SDH contribute to EA-induced antinociception in postoperative pain.
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Affiliation(s)
- Wen-Guang Chu
- Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China
| | - Ru Zhang
- Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China
- Department of Anesthesiology, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710016, China
- School of Medicine, Yanan University, Yan'an, 716000, China
| | - Hai-Tao Li
- Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China
- The Fourteenth Squadron of the Fourth Regiment, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China
| | - Ying-Chun Li
- Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China
- College of Life Sciences, Northwest University, Xi'an, 710069, China
| | - Hui Ding
- Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China
| | - Zhen-Zhen Li
- Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China
| | - Wen-Juan Han
- Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China
| | - Fei Wang
- Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China
| | - Xing-Xing Zheng
- Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China
- College of Life Sciences, Northwest University, Xi'an, 710069, China
| | - Hong-Hui Mao
- Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China
| | - Hua Yuan
- Department of Rehabilitation Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Sheng-Xi Wu
- Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China
| | - Rou-Gang Xie
- Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China
| | - Ceng Luo
- Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China
- Innovation Research Institute, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
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8
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Yoo JJ, Serafin EK, Baccei ML. Effects of perinatal iron deficiency on spinal dorsal horn circuits. THE JOURNAL OF PAIN 2025; 32:105434. [PMID: 40379071 DOI: 10.1016/j.jpain.2025.105434] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Revised: 04/21/2025] [Accepted: 05/05/2025] [Indexed: 05/19/2025]
Abstract
Clinical association studies have identified early life iron deficiency (ID) as a risk factor for the development of chronic pain. ID during the perinatal period has long-term consequences for the developing nervous system. Mounting evidence from both clinical and preclinical studies suggests that ID alters pain perception. However, nothing is yet known about how perinatal ID impacts nociceptive circuitry. The present study sought to characterize the effects of ID on the spinal superficial dorsal horn (SDH). Using ex vivo patch clamp electrophysiology in a mouse model of perinatal ID, the excitability of inhibitory and putative excitatory interneurons in the SDH was measured. It was found that early life ID did not significantly change the intrinsic excitability of either interneuron cell type in adolescence or adulthood. The investigation of synaptic inputs onto these two populations revealed that ID modulates spontaneous glutamatergic transmission within the SDH, but did not affect the excitatory drive or balance of synaptic excitation and inhibition. Interestingly, while ID altered the pattern of primary afferent inputs onto presumed glutamatergic interneurons in the mature SDH, the overall efficacy of these synapses was not affected by ID. Collectively, these results suggest that spinal nociceptive circuits are resilient to change following perinatal ID. PERSPECTIVE: This study demonstrates that perinatal iron deficiency (ID) elicits few changes to the intrinsic membrane excitability of superficial dorsal horn neurons or the efficacy of their synaptic inputs. These findings represent a critical first step towards elucidating the effects of ID on nociceptive processing in the central nervous system.
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Affiliation(s)
- Judy J Yoo
- Medical Scientist Training Program and Neuroscience Graduate Program, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267, USA; Pain Research Center, Department of Anesthesiology, University of Cincinnati Medical Center, 231 Albert Sabin Way, Cincinnati, OH 45267, USA
| | - Elizabeth K Serafin
- Pain Research Center, Department of Anesthesiology, University of Cincinnati Medical Center, 231 Albert Sabin Way, Cincinnati, OH 45267, USA
| | - Mark L Baccei
- Medical Scientist Training Program and Neuroscience Graduate Program, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267, USA; Pain Research Center, Department of Anesthesiology, University of Cincinnati Medical Center, 231 Albert Sabin Way, Cincinnati, OH 45267, USA.
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9
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Gonçalves WA, de Sousa CDF, Teixeira MM, Souza DG. A brief overview of chikungunya-related pain. Eur J Pharmacol 2025; 994:177322. [PMID: 39892450 DOI: 10.1016/j.ejphar.2025.177322] [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: 07/28/2024] [Revised: 01/15/2025] [Accepted: 01/29/2025] [Indexed: 02/03/2025]
Abstract
Pain is an important symptom associated with the arboviral disease caused by the Chikungunya virus (CHIKV). For a significant number of patients, this symptom can persist for months or even years, negatively affecting their quality of life. Unfortunately, pharmacological options for this condition are limited and only partially effective, as the underlying mechanisms associated with CHIKV-induced pain are still poorly understood. The re-emergence of CHIKV has led to new outbreaks, and the expected high prevalence of pain in these global events requires new scientific advances to find more effective solutions. Here we review the main aspects of pain caused by CHIKV infection, such as the anatomy of the affected sites, the prevalence and management of this symptom, the diversity of possible cellular and molecular mechanisms, and finally highlight a promising meningeal pathway to elucidate the mechanisms involved in the unsolved problem of CHIKV-associated pain.
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Affiliation(s)
- William Antonio Gonçalves
- Departamento de Morfologia, Instituto de Ciências Biológicas (ICB), Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil.
| | - Carla Daiane Ferreira de Sousa
- Department of Neurology with Institute of Translational Neurology, University Hospital Münster, University of Münster, Münster, Germany.
| | - Mauro Martins Teixeira
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas (ICB), Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil.
| | - Daniele G Souza
- Laboratório Interação Microrganismo Hospedeiro, Departamento de Microbiologia, Instituto de Ciências Biológicas (ICB), Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil.
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10
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Ashida M, Murayama N, Kamio Y, Yozaki M, Kuwatsuka Y, Nakahara T, Murota H. Blood levels of neurotransmitters in Yusho patients: An approach via the descending pain inhibitory pathway for persistent sensory disturbance. J Dermatol 2025; 52:934-938. [PMID: 40028778 PMCID: PMC12056279 DOI: 10.1111/1346-8138.17689] [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: 12/17/2024] [Revised: 02/04/2025] [Accepted: 02/17/2025] [Indexed: 03/05/2025]
Abstract
Yusho, a dioxin poisoning incident in Japan, has resulted in patients experiencing persistent symptoms, including sensory disturbances, decades after the initial exposure. This study investigated the potential involvement of the descending pain inhibitory system in Yusho patients. Serum serotonin, dopamine, and norepinephrine levels were measured in 29 Yusho patients and 29 age-matched healthy controls. No significant differences in these neurotransmitters were observed between the two groups. However, weak correlations were found between polychlorinated biphenyl levels and dopamine (r = 0.4310, p = 0.0315) in Yusho patients. This study provides new insights into the pathophysiology of cutaneous sensory disorders and highlights the need for further research to clarify the long-term effects of dioxin exposure on Yusho patients.
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Affiliation(s)
- Miwa Ashida
- Department of DermatologyNagasaki University Graduate School of Biomedical SciencesNagasakiJapan
- Research and Clinical Center for Yusho and DioxinKyushu University HospitalFukuokaJapan
| | | | | | - Mariko Yozaki
- Department of DermatologyNagasaki University Graduate School of Biomedical SciencesNagasakiJapan
| | - Yutaka Kuwatsuka
- Department of DermatologyNagasaki University Graduate School of Biomedical SciencesNagasakiJapan
| | - Takeshi Nakahara
- Research and Clinical Center for Yusho and DioxinKyushu University HospitalFukuokaJapan
| | - Hiroyuki Murota
- Department of DermatologyNagasaki University Graduate School of Biomedical SciencesNagasakiJapan
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11
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Zhang M, Ni Z, Ma J, Liu A, Liu Y, Lou Q, Dong WY, Zhang Z, Li J, Cao P. A neural circuit for sex-dependent conditioned pain hypersensitivity in mice. Nat Commun 2025; 16:3639. [PMID: 40240334 PMCID: PMC12003881 DOI: 10.1038/s41467-025-58851-x] [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: 11/21/2024] [Accepted: 04/01/2025] [Indexed: 04/18/2025] Open
Abstract
The neural mechanisms underlying sex-specific pain, in which males and females exhibit distinct responses to pain, remain poorly understood. Here we show that in a mouse model of male-specific pain hypersensitivity response to pain conditioning environments (contextual pain hypersensitivity model), elevated free-testosterone leads to hyperactivity of glutamatergic neurons in the medial preoptic area (GlumPOA) through activation of androgen receptor signaling, which in turn induces contextual pain hypersensitivity in male mice. Although not observed in naïve female mice, this pain phenotype could be induced in females via chronic administration of testosterone propionate. In addition, GlumPOA neurons send excitatory inputs to GABAergic neurons in the ventrolateral periaqueductal gray (GABAvlPAG) that are required for contextual pain hypersensitivity. Our study thus demonstrates that testosterone/androgen receptor signaling enhances GlumPOA → GABAvlPAG pathway activity, which drives a male-specific contextual pain hypersensitivity, providing insight into the basis of sexually dimorphic pain response.
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Affiliation(s)
- Mingjun Zhang
- Department of Anesthesiology, The First Affiliated Hospital of USTC, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Hefei National Laboratory for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China
| | - Ziyun Ni
- Department of Anesthesiology, The First Affiliated Hospital of USTC, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Hefei National Laboratory for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China
| | - Jun Ma
- Department of Anesthesiology, The First Affiliated Hospital of USTC, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Hefei National Laboratory for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China
| | - An Liu
- Department of Physiology, School of Basic Medical Sciences, Anhui Medical University, Hefei, 230022, China
| | - Ying Liu
- Department of Anesthesiology, The First Affiliated Hospital of USTC, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Hefei National Laboratory for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China
| | - Qianqian Lou
- Department of Anesthesiology, The First Affiliated Hospital of USTC, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Hefei National Laboratory for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China
| | - Wan-Ying Dong
- Department of Anesthesiology, The First Affiliated Hospital of USTC, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Hefei National Laboratory for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China
| | - Zhi Zhang
- Department of Anesthesiology, The First Affiliated Hospital of USTC, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Hefei National Laboratory for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China.
- Department of Physiology, School of Basic Medical Sciences, Anhui Medical University, Hefei, 230022, China.
- Department of Biophysics and Neurobiology, CAS Key laboratory of Brain Function and Disease, University of Science and Technology of China, Hefei, 230026, China.
| | - Juan Li
- Department of Anesthesiology, The First Affiliated Hospital of USTC, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Hefei National Laboratory for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China.
| | - Peng Cao
- Department of Anesthesiology, The First Affiliated Hospital of USTC, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Hefei National Laboratory for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China.
- Department of Biophysics and Neurobiology, CAS Key laboratory of Brain Function and Disease, University of Science and Technology of China, Hefei, 230026, China.
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12
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Wang F, Tian ZC, Ding H, Yang XJ, Wang FD, Ji RX, Xu L, Cao ZX, Ma SB, Zhang M, Cui YT, Cong XY, Chu WG, Li ZZ, Han WJ, Gao YH, Yu YW, Zhao XH, Wang WT, Xie RG, Wu SX, Luo C. A sensory-motor-sensory circuit underlies antinociception ignited by primary motor cortex in mice. Neuron 2025:S0896-6273(25)00246-6. [PMID: 40239652 DOI: 10.1016/j.neuron.2025.03.027] [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: 12/06/2023] [Revised: 02/05/2025] [Accepted: 03/21/2025] [Indexed: 04/18/2025]
Abstract
Sensory-motor integration is crucial in the processing of chronic pain. The primary motor cortex (M1) is emerging as a promising target for chronic pain treatment. However, it remains elusive how nociceptive sensory inputs influence M1 activity and how rectifying M1 defects, in turn, regulates pain processing at cellular and network levels. We show that injury/inflammation leads to hypoactivity of M1Glu pyramidal neurons by excitation-inhibition imbalance between the primary somatosensory cortex (S1) and the M1. The impaired M1 output further weakens inputs to excitatory parvalbumin neurons of the lateral hypothalamus (LHPV) and impairs the descending inhibitory system, hence exacerbating spinal nociceptive sensitivity. When rectifying M1 defects with repetitive transcranial magnetic stimulation (rTMS), the imbalance of the S1-M1 microcircuitry can be effectively reversed, which aids in restoring the ability of the M1 to trigger the descending inhibitory system, thereby alleviating nociceptive hypersensitivity. Thus, a sensory-motor-sensory loop is identified for pain-related interactions between the sensory and motor systems and can be potentially exploited for treating chronic pain.
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Affiliation(s)
- Fei Wang
- Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China; Medical Experiment Center, Shaanxi University of Chinese Medicine, Xianyang 712046, China; Shaanxi Province Key Laboratory of Integrated Traditional Chinese and Western Medicine for the Prevention and Treatment of Cardiovascular Diseases, Shaanxi University of Chinese Medicine, Xianyang 712046, China
| | - Zhi-Cheng Tian
- Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Hui Ding
- Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China
| | - Xin-Jiang Yang
- Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China; Department of Rehabilitation and Physical Therapy, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Fu-Dong Wang
- Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China
| | - Ruo-Xin Ji
- Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China
| | - Lei Xu
- The Sixteenth Squadron of Fourth Regiment, School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China
| | - Zi-Xuan Cao
- The Twenty-Second Squadron of Sixth Regiment, School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China
| | - Sui-Bin Ma
- Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China
| | - Ming Zhang
- Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China
| | - Ya-Ting Cui
- Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China
| | - Xiang-Yu Cong
- Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China
| | - Wen-Guang Chu
- Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China
| | - Zhen-Zhen Li
- Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China
| | - Wen-Juan Han
- Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China
| | - Yong-Heng Gao
- Department of Respiration, Tangdu Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Yuan-Wang Yu
- Shaanxi Province Key Laboratory of Integrated Traditional Chinese and Western Medicine for the Prevention and Treatment of Cardiovascular Diseases, Shaanxi University of Chinese Medicine, Xianyang 712046, China
| | - Xiang-Hui Zhao
- Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China
| | - Wen-Ting Wang
- Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China
| | - Rou-Gang Xie
- Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China
| | - Sheng-Xi Wu
- Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China.
| | - Ceng Luo
- Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China; Innovation Research Institute, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
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13
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Liu Z, Liu A, Chen J, Chai JR, Liu P, Ye RF, Liu JG, Wang YJ. Dezocine Exerts Analgesic Effects in Chronic Pain by Activation of κ- and μ-Opioid Receptors and Inhibition of Norepinephrine and Serotonin Reuptake. Pain Res Manag 2025; 2025:5656675. [PMID: 40224348 PMCID: PMC11991863 DOI: 10.1155/prm/5656675] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2024] [Accepted: 03/06/2025] [Indexed: 04/15/2025]
Abstract
Background: Dezocine is a leading analgesic in China used for relieving moderate to severe pain. Previous studies have characterized its pharmacological properties, demonstrating its role as a partial agonist at both the κ-opioid receptor (KOR) and the μ-opioid receptor (MOR), thereby producing potent antinociceptive effects in acute pain models. However, its efficacy and mechanisms in chronic pain management remained unclear. Methods: Chronic pain models, including chronic neuropathic pain and cancer pain, were employed using chronic constriction injury (CCI) of the sciatic nerve and bone cancer pain (BCP) methodologies, respectively. The assessment of the mechanical allodynia was conducted using a von Frey filament. Results: Dezocine, administered via the intraperitoneal route, alleviated both neuropathic pain and cancer pain in a dose-dependent manner, with ED50 of 1.3 mg/kg and 1.6 mg/kg, respectively. In the CCI model, the analgesic effect of dezocine was significantly inhibited by pretreating with KOR antagonist nor-BNI, MOR antagonist β-FNA, α2-adrenoceptor antagonist yohimbine, and 5-HT2A receptor antagonist altanserin. In the BCP model, dezocine-induced analgesia was markedly suppressed by nor-BNI, β-FNA, and yohimbine but not altanserin. Conclusion: These results suggest that, in neuropathic pain, the analgesic effects of dezocine are mediated through KOR and MOR activation, together with norepinephrine reuptake inhibition (NRI) and serotonin reuptake inhibition. In contrast, in cancer pain, KOR and MOR activation and NRI are involved in mediating the analgesic effect of dezocine. This study, along with previous data, enhances our understanding of the potential clinical utility of dezocine and elucidates its mechanisms of action in chronic pain management.
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MESH Headings
- Animals
- Receptors, Opioid, kappa/metabolism
- Receptors, Opioid, kappa/agonists
- Receptors, Opioid, mu/metabolism
- Receptors, Opioid, mu/agonists
- Male
- Chronic Pain/drug therapy
- Chronic Pain/metabolism
- Chronic Pain/etiology
- Tetrahydronaphthalenes/therapeutic use
- Tetrahydronaphthalenes/pharmacology
- Bridged Bicyclo Compounds, Heterocyclic/therapeutic use
- Bridged Bicyclo Compounds, Heterocyclic/pharmacology
- Analgesics, Opioid/pharmacology
- Analgesics, Opioid/therapeutic use
- Disease Models, Animal
- Neuralgia/drug therapy
- Rats, Sprague-Dawley
- Rats
- Mice
- Hyperalgesia/drug therapy
- Analgesics/therapeutic use
- Analgesics/pharmacology
- Cancer Pain/drug therapy
- Serotonin and Noradrenaline Reuptake Inhibitors/pharmacology
- Serotonin and Noradrenaline Reuptake Inhibitors/therapeutic use
- Norepinephrine/metabolism
- Pain Measurement
- Dose-Response Relationship, Drug
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Affiliation(s)
- Zihan Liu
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, China
| | - Anan Liu
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, China
| | - Jing Chen
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Jing-Rui Chai
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Panwen Liu
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, China
| | - Ru-Feng Ye
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Jing-Gen Liu
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
| | - Yu-Jun Wang
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, China
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14
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Fiúza-Fernandes J, Pereira-Mendes J, Esteves M, Radua J, Picó-Pérez M, Leite-Almeida H. Common neural correlates of chronic pain - A systematic review and meta-analysis of resting-state fMRI studies. Prog Neuropsychopharmacol Biol Psychiatry 2025; 138:111326. [PMID: 40086716 DOI: 10.1016/j.pnpbp.2025.111326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 02/20/2025] [Accepted: 03/05/2025] [Indexed: 03/16/2025]
Abstract
Maladaptive brain plasticity has been reported in chronic pain (CP) conditions, though it remains unclear if there are common alterations across pathologies. Therefore, we systematically synthesized literature comparing resting-state functional magnetic resonance imaging (rs-fMRI) in CP patients and healthy controls (HC), and meta-analyzed data whenever applicable. Separate meta-analyses were performed for each method - (fractional) amplitude of low-frequency fluctuations (fALFF, ALFF), regional homogeneity (ReHo), seed-based connectivity (according to the seed) and independent component analysis (according to the network). In qualitative synthesis, sensory-discriminative pain processing - thalamus, insula, temporal and sensory cortices - and cognitive and emotional processing - cingulate, prefrontal and parietal cortices and precuneus - regions concentrated CP/HC differences. Meta-analyses revealed decreased ALFF and increased ReHo in the precuneus, increased fALFF in the left posterior insula and disrupted within- and cross-network connectivity of default mode network (DMN) nodes, as well as altered connectivity in top-down pain modulation pathways. Specifically, it showed decreased anterior and increased posterior components' representation within DMN, enhanced connectivity between the medial prefrontal cortex (mPFC, part of the DMN) and anterior insula (part of the salience network), and decreased mPFC connectivity with the periaqueductal gray matter (PAG). Collectively, results suggest that CP disrupts the natural functional organization of the brain, particularly impacting DMN nodes (mPFC and precuneus), insula and top-town pain modulation circuits.
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Affiliation(s)
- Juliana Fiúza-Fernandes
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Joana Pereira-Mendes
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Madalena Esteves
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal; Clinical Academic Center, Braga, Portugal
| | - Joaquim Radua
- Imaging of Mood- and Anxiety-Related Disorders (IMARD) Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBERSAM, Barcelona, Spain; Department of Clinical Neuroscience, Centre for Psychiatric Research and Education, Karolinska Institutet, Stockholm, Sweden; Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
| | - Maria Picó-Pérez
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal; Departamento de Psicología Básica, Clínica y Psicobiología, Universitat Jaume I, Castellón de la Plana, Spain
| | - Hugo Leite-Almeida
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal; Clinical Academic Center, Braga, Portugal.
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15
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Luo J, Xu Q, Xu S, Zhai L, Yuan CS, Bian Z. Decoding Abdominal Pain in Constipation-predominant Irritable Bowel Syndrome and Functional Constipation: Mechanisms and Managements. Curr Gastroenterol Rep 2025; 27:22. [PMID: 40095229 PMCID: PMC11914341 DOI: 10.1007/s11894-025-00967-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/12/2025] [Indexed: 03/19/2025]
Abstract
PURPOSE OF REVIEW Abdominal pain in constipation-predominant irritable bowel syndrome (IBS-C) and functional constipation (FC) remains a difficult clinical challenge due to unclear pathophysiological mechanisms and limited pain-targeted treatments. This review critically evaluates the evidence on the underlying pain mechanisms in IBS-C and/or FC and explores management strategies, their limitations, and future directions. RECENT FINDINGS Most research on constipation-related pain is based on IBS-C patients or animal models, with limited studies focusing on FC. Visceral hypersensitivity, serotonin dysregulation, gut-brain axis dysfunction, and central/peripheral nervous system alterations are implicated in IBS-C pain, while FC pain is less studied and may be primarily linked to colonic distension and motility dysfunction. Management strategies include 5-HT4 agonists, GC-C agonists, chloride channel activators, psychological therapies, probiotics and complementary medicine. Despite available treatment options, managing abdominal pain in IBS-C and FC remains challenging due to heterogeneous pathophysiology and limited targeted therapies. While some interventions provide symptomatic relief, there is no universally effective treatment for abdominal pain across all patients. Future research should focus on identifying pain-specific biomarkers, refining diagnostic criteria, and integrating multi-omics data and neuroimaging techniques to better distinguish pain mechanisms in IBS-C versus FC and develop more precise, patient-centered interventions.
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Affiliation(s)
- Jingyuan Luo
- Vincent V.C. Woo Chinese Medicine Clinical Research Institute, School of Chinese Medicine, Hong Kong Baptist University, 3/F, Jockey Club School of Chinese Medicine Building, 7 Baptist University Road, Kowloon Tong, Hong Kong, SAR, China
- Center for Chinese Herbal Medicine Drug Development and School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, SAR, China
| | - Qianqian Xu
- Vincent V.C. Woo Chinese Medicine Clinical Research Institute, School of Chinese Medicine, Hong Kong Baptist University, 3/F, Jockey Club School of Chinese Medicine Building, 7 Baptist University Road, Kowloon Tong, Hong Kong, SAR, China
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY, 14214-8033, USA
| | - Shujun Xu
- Center for Chinese Herbal Medicine Drug Development and School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, SAR, China
| | - Lixiang Zhai
- Center for Chinese Herbal Medicine Drug Development and School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, SAR, China.
| | - Chun-Su Yuan
- Tang Center for Herbal Medicine Research and Department of Anesthesia and Critical Care, Pritzker School of Medicine, University of Chicago, 5841 South Maryland Avenue, MC 4028, Chicago, IL, 60637, USA.
- Department of Anesthesia and Critical Care, Pritzker School of Medicine, University of Chicago, Chicago, IL, 60637, USA.
| | - Zhaoxiang Bian
- Vincent V.C. Woo Chinese Medicine Clinical Research Institute, School of Chinese Medicine, Hong Kong Baptist University, 3/F, Jockey Club School of Chinese Medicine Building, 7 Baptist University Road, Kowloon Tong, Hong Kong, SAR, China.
- Center for Chinese Herbal Medicine Drug Development and School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, SAR, China.
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16
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Gao T, Wang C, Yang X, He Z, Wang Y, Mi W. Hyperoside ameliorates neuropathic pain by modulating the astroglial reactivity in the vlPAG. Neuropharmacology 2025; 266:110276. [PMID: 39716641 DOI: 10.1016/j.neuropharm.2024.110276] [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: 09/21/2024] [Revised: 12/06/2024] [Accepted: 12/18/2024] [Indexed: 12/25/2024]
Abstract
Hyperoside, a natural flavonoid, exhibits a wide range of biological activities, including analgesic effects on acute and chronic inflammatory pain. This study illustrates that repeated intraperitoneal administration or microinjection of hyperoside into the ventrolateral periaqueductal grey (vlPAG) alleviated mechanical allodynia, cold allodynia, and abnormal gait induced by spared nerve injury (SNI) in male mice. Furthermore, repeated hyperoside administration suppressed SNI-induced astrocyte reactivity in the vlPAG. Moreover, hyperoside alleviated the pain behaviors resulting from the pharmacogenetic activation of vlPAG astrocytes. These results suggest that hyperoside may effectively mitigate neuropathic pain and inhibit astroglial reactivity in the vlPAG, highlighting its potential as a viable therapeutic intervention for chronic neuropathic pain.
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Affiliation(s)
- Tianchi Gao
- Department of Integrative Medicine and Neurobiology, School of Basic Medical Science, Institutes of Integrative Medicine, Shanghai Key Laboratory of Acupuncture Mechanism and Acupoint Function, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Chenghao Wang
- Department of Integrative Medicine and Neurobiology, School of Basic Medical Science, Institutes of Integrative Medicine, Shanghai Key Laboratory of Acupuncture Mechanism and Acupoint Function, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai, 200032, China; College of Sports Medicine and Rehabilitation, Shandong First Medical University & Shandong Academy of Medical Sciences, Tai'an, 271016, China
| | - Xiaotong Yang
- Department of Integrative Medicine and Neurobiology, School of Basic Medical Science, Institutes of Integrative Medicine, Shanghai Key Laboratory of Acupuncture Mechanism and Acupoint Function, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Zhiwei He
- Department of Integrative Medicine and Neurobiology, School of Basic Medical Science, Institutes of Integrative Medicine, Shanghai Key Laboratory of Acupuncture Mechanism and Acupoint Function, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Yanqing Wang
- Department of Integrative Medicine and Neurobiology, School of Basic Medical Science, Institutes of Integrative Medicine, Shanghai Key Laboratory of Acupuncture Mechanism and Acupoint Function, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Wenli Mi
- Department of Integrative Medicine and Neurobiology, School of Basic Medical Science, Institutes of Integrative Medicine, Shanghai Key Laboratory of Acupuncture Mechanism and Acupoint Function, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
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17
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Attias S, Ramon-Gonen R, Erez Y, Bosak N, Granovsky Y, Shelly S. Deep learning modelling of structural brain MRI in chronic head and neck pain after mild TBI. Pain 2025:00006396-990000000-00850. [PMID: 40084983 DOI: 10.1097/j.pain.0000000000003587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Accepted: 01/23/2025] [Indexed: 03/16/2025]
Abstract
ABSTRACT Chronic headache is a common complication after mild traumatic brain injury (mTBI), which affects close to 70 million individuals annually worldwide. This study aims to test the utility of a unique, early predictive magnetic resonance imaging (MRI)-based classification model using structural brain MRI scans, a rarely used approach to identify high-risk individuals for post-mTBI chronic pain. We recruited 227 patients with mTBI after a vehicle collision, between March 30, 2016 and December 30, 2019. T1-weighted brain MRI scans from 128 patients within 72 hours postinjury were included and served as input for a pretrained 3D ResNet-18 deep learning model. All patients had initial assessments within the first 72 hours after the injury and performed follow-ups for 1 year. Chronic pain was reported in 43% at 12 months postinjury; remaining 57% were assigned to the recovery group. The best results were achieved for the axial plane with an average accuracy of 0.59 and an average area under the curve (AUC) of 0.56. Across the model's 8 folds. The highest performance across folds reached an AUC of 0.78, accuracy of 0.69, and recall of 0.83. Saliency maps highlighted the right insula, bilateral ventromedial prefrontal cortex, and periaqueductal gray matter as key regions. Our study provides insights at the intersection of neurology, neuroimaging, and predictive modeling, demonstrating that early T1-weighted MRI scans may offer useful information for predicting chronic head and neck pain. Saliency maps may help identify brain regions linked to chronic pain, representing an initial step toward targeted rehabilitation and early intervention for patients with mTBI to enhance clinical outcomes.
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Affiliation(s)
- Sivan Attias
- The Graduate School of Business Administration, Bar-Ilan University, Ramat-Gan, Israel
- Faculty of Engineering, Bar-Ilan University, Ramat-Gan, Israel
| | - Roni Ramon-Gonen
- The Graduate School of Business Administration, Bar-Ilan University, Ramat-Gan, Israel
- Data Science Institute, Bar-Ilan University, Ramat-Gan, Israel
| | - Yaara Erez
- Faculty of Engineering, Bar-Ilan University, Ramat-Gan, Israel
- Data Science Institute, Bar-Ilan University, Ramat-Gan, Israel
- Gonda Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat-Gan, Israel
| | - Noam Bosak
- Department of Neurology, Rambam Health Care Campus, Haifa, Israel
- Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
| | - Yelena Granovsky
- Department of Neurology, Rambam Health Care Campus, Haifa, Israel
- Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
| | - Shahar Shelly
- Department of Neurology, Rambam Health Care Campus, Haifa, Israel
- Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
- Department of Neurology, Mayo Clinic, Rochester, MN, United States
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18
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Hunt JR, Knazovicky D, Harris J, Kelly S, Knowles TG, Murrell JC, Lascelles BDX. Ice water immersion does not activate diffuse noxious inhibitory controls of spinal reflexes in sedated or anaesthetised dogs ( Canis familiaris): a pilot study. FRONTIERS IN PAIN RESEARCH 2025; 6:1505064. [PMID: 40129491 PMCID: PMC11931054 DOI: 10.3389/fpain.2025.1505064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Accepted: 02/19/2025] [Indexed: 03/26/2025] Open
Abstract
Introduction Diffuse noxious inhibitory controls (DNIC) may be impaired in human subjects with osteoarthritis (OA) pain. Spontaneously occurring OA in dogs is considered a valuable model of human OA; however, methodology for assessing DNIC in dogs has not been fully developed. The aim of this study was to develop a suitable DNIC protocol using ice water immersion, similar to protocols used in humans. Objective This study objective was to create an experimental protocol for inducing DNIC in sedated or anesthetized dogs, ensuring it has face validity for future assessments of DNIC in studies involving the spontaneous canine OA model. We hypothesized that inducing DNIC in healthy dogs would result in a reduced electromyographic (EMG) response to a specific nociceptive stimulus. Methods Electromyographic (EMG) responses of the cranial tibial muscle to test electrical stimuli and interdigital skin temperature were recorded in seven healthy dogs before and during a 20-min duration conditioning ice water immersion of the distal forelimb. The protocol was repeated for each dog using three different states: sedation with acepromazine or alfaxalone or anaesthesia with alfaxalone. Results Ice water immersion caused a decrease of interdigital skin temperature in dogs in all three groups with the nadir (4.9-13.6°C) at 10 min following immersion. Skin temperatures remained significantly higher (p = 0.018) in alfaxalone sedated compared to acepromazine sedated dogs and returned to baseline more quickly than in acepromazine sedated dogs. Magnitudes of EMG responses were significantly larger in acepromazine sedated dogs compared to alfaxalone treated dogs (p < 0.001). DNIC was not induced, as the EMG magnitude did not significantly change over time for either the early (p = 0.07) or late responses (p = 0.27), and no significant interactions were observed between time and anaesthetic state in relation to EMG magnitude. Conclusion Our data suggest that a cold conditioning stimulus failed to elicit DNIC. It is possible that the magnitude of the conditioning stimulus was not sufficient to recruit DNIC in dogs.
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Affiliation(s)
- J. R. Hunt
- School of Veterinary Sciences, University of Bristol, Bristol, United Kingdom
| | - D. Knazovicky
- Comparative Pain Research Laboratory, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States
- Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States
| | - J. Harris
- Division of Animal Sciences, School of Biosciences, University of Nottingham, Sutton Bonington Campus, Loughborough, United Kingdom
| | - S. Kelly
- Division of Animal Sciences, School of Biosciences, University of Nottingham, Sutton Bonington Campus, Loughborough, United Kingdom
| | - T. G. Knowles
- School of Veterinary Sciences, University of Bristol, Bristol, United Kingdom
| | | | - B. D. X. Lascelles
- Comparative Pain Research Laboratory, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States
- Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States
- Translational Research in Pain Program, Comparative Pain Research and Education Centre, Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States
- Center for Translational Pain Research, Department of Anesthesiology, Duke University, Durham, NC, United States
- Thurston Arthritis Center, UNC, Chapel Hill, NC, United States
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19
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Antal M. Molecular Anatomy of Synaptic and Extrasynaptic Neurotransmission Between Nociceptive Primary Afferents and Spinal Dorsal Horn Neurons. Int J Mol Sci 2025; 26:2356. [PMID: 40076973 PMCID: PMC11900602 DOI: 10.3390/ijms26052356] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 02/26/2025] [Accepted: 03/04/2025] [Indexed: 03/14/2025] Open
Abstract
Sensory signals generated by peripheral nociceptors are transmitted by peptidergic and nonpeptidergic nociceptive primary afferents to the superficial spinal dorsal horn, where their central axon terminals establish synaptic contacts with secondary sensory spinal neurons. In the case of suprathreshold activation, the axon terminals release glutamate into the synaptic cleft and stimulate postsynaptic spinal neurons by activating glutamate receptors located on the postsynaptic membrane. When overexcitation is evoked by peripheral inflammation, neuropathy or pruritogens, peptidergic nociceptive axon terminals may corelease various neuropeptides, neurotrophins and endomorphin, together with glutamate. However, in contrast to glutamate, neuropeptides, neurotrophins and endomorphin are released extrasynaptically. They diffuse from the site of release and modulate the function of spinal neurons via volume transmission, activating specific extrasynaptic receptors. Thus, the released neuropeptides, neurotrophins and endomorphin may evoke excitation, disinhibition or inhibition in various spinal neuronal populations, and together with glutamate, induce overall overexcitation, called central sensitization. In addition, the synaptic and extrasynaptic release of neurotransmitters is subjected to strong retrograde control mediated by various retrogradely acting transmitters, messengers, and their presynaptic receptors. Moreover, the composition of this complex chemical apparatus is heavily dependent on the actual patterns of nociceptive primary afferent activation in the periphery. This review provides an overview of the complexity of this signaling apparatus, how nociceptive primary afferents can activate secondary sensory spinal neurons via synaptic and volume transmission in the superficial spinal dorsal horn, and how these events can be controlled by presynaptic mechanisms.
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Affiliation(s)
- Miklós Antal
- Department of Anatomy, Histology and Embryology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary
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20
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Camacho-Cruz R, Alcalá-Hernández DF, Huerta-Cruz JC, Arrieta-Valencia J, Sánchez-Mendoza ME, Flores-Murrieta FJ, Navarrete A, Reyes-García JG, Rocha-González HI. Evaluation of the Antinociceptive Effect of Sesamin: Role of 5HT 1A Serotonergic Receptors. Pharmaceutics 2025; 17:330. [PMID: 40142993 PMCID: PMC11944384 DOI: 10.3390/pharmaceutics17030330] [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: 01/21/2025] [Revised: 02/18/2025] [Accepted: 02/28/2025] [Indexed: 03/28/2025] Open
Abstract
Background/Objectives: Sesame (Sesamum indicum L.) is used in folk medicine to treat painful disorders. Sesamin is the main lignan found in this plant; however, its antinociceptive potential has scarcely been studied. The aim was to investigate the antinociceptive effect of sesamin on inflammatory and neuropathic pain models, as well as the possible mechanism of action through which sesamin mediates its own antinociceptive effect. Methods: Formalin and carrageenan animal models were used to assess inflammatory pain, whereas an L5/L6-spinal-nerve-ligated rat model was employed to evaluate neuropathic pain. Results: Oral sesamin significantly reduced carrageenan-induced hyperalgesia and inflammation, formalin-induced nociception, and L5/L6-spinal-nerve-ligation-induced allodynia. Sesamin was more effective than diclofenac in the inflammatory pain models, but it was less effective than pregabalin in the neuropathic pain model. The antinociceptive effect of sesamin, in the formalin test, was prevented by the intraperitoneal administration of methiothepin (5-HT1/5 antagonist), but not by naltrexone (an opioid antagonist) or L-NAME (an NOS inhibitor). In addition, WAY-100635 (5-HT1A antagonist), but not SB-224289 (5-HT1B antagonist), BRL-15542 (5-HT1D antagonist), and SB-699551 (5-HT5A antagonist), impeded sesamin-induced antinociception. Conclusions: This study's results support the use of sesamin to treat inflammatory pain disorders and suggest that 5-HT1A receptors influence the antinociceptive effect of this drug.
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Affiliation(s)
- Roberto Camacho-Cruz
- Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City 11340, Mexico; (R.C.-C.); (J.A.-V.); (M.E.S.-M.); (F.J.F.-M.); (J.G.R.-G.)
| | | | - Juan Carlos Huerta-Cruz
- Instituto Nacional de Enfermedades Respiratorias, Ismael Cosío Villegas, Mexico City 14080, Mexico;
| | - Jesús Arrieta-Valencia
- Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City 11340, Mexico; (R.C.-C.); (J.A.-V.); (M.E.S.-M.); (F.J.F.-M.); (J.G.R.-G.)
| | - María Elena Sánchez-Mendoza
- Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City 11340, Mexico; (R.C.-C.); (J.A.-V.); (M.E.S.-M.); (F.J.F.-M.); (J.G.R.-G.)
| | - Francisco Javier Flores-Murrieta
- Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City 11340, Mexico; (R.C.-C.); (J.A.-V.); (M.E.S.-M.); (F.J.F.-M.); (J.G.R.-G.)
- Instituto Nacional de Enfermedades Respiratorias, Ismael Cosío Villegas, Mexico City 14080, Mexico;
| | - Andrés Navarrete
- Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico;
| | - Juan Gerardo Reyes-García
- Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City 11340, Mexico; (R.C.-C.); (J.A.-V.); (M.E.S.-M.); (F.J.F.-M.); (J.G.R.-G.)
| | - Héctor Isaac Rocha-González
- Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City 11340, Mexico; (R.C.-C.); (J.A.-V.); (M.E.S.-M.); (F.J.F.-M.); (J.G.R.-G.)
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21
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Jayathilake NJ, Phan TT, Kim J, Lee KP, Park JM. Modulating neuroplasticity for chronic pain relief: noninvasive neuromodulation as a promising approach. Exp Mol Med 2025; 57:501-514. [PMID: 40025172 PMCID: PMC11958754 DOI: 10.1038/s12276-025-01409-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Revised: 11/20/2024] [Accepted: 12/01/2024] [Indexed: 03/04/2025] Open
Abstract
Chronic neuropathic pain is a debilitating neuroplastic disorder that notably impacts the quality of life of millions of people worldwide. This complex condition, encompassing various manifestations, such as sciatica, diabetic neuropathy and postherpetic neuralgia, arises from nerve damage or malfunctions in pain processing pathways and involves various biological, physiological and psychological processes. Maladaptive neuroplasticity, known as central sensitization, plays a critical role in the persistence of chronic neuropathic pain. Current treatments for neuropathic pain include pharmacological interventions (for example, antidepressants and anticonvulsants), invasive procedures (for example, deep brain stimulation) and physical therapies. However, these approaches often have limitations and potential side effects. In light of these challenges, interest in noninvasive neuromodulation techniques as alternatives or complementary treatments for neuropathic pain is increasing. These methods aim to induce analgesia while reversing maladaptive plastic changes, offering potential advantages over conventional pharmacological practices and invasive methods. Recent technological advancements have spurred the exploration of noninvasive neuromodulation therapies, such as repetitive transcranial magnetic stimulation, transcranial direct current stimulation and transcranial ultrasound stimulation, as well as innovative transformations of invasive techniques into noninvasive methods at both the preclinical and clinical levels. Here this review aims to critically examine the mechanisms of maladaptive neuroplasticity in chronic neuropathic pain and evaluate the efficacy of noninvasive neuromodulation techniques in pain relief. By focusing on optimizing these techniques, we can better assess their short-term and long-term effects, refine treatment variables and ultimately improve the quality of neuropathic pain management.
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Affiliation(s)
- Nishani Jayanika Jayathilake
- Department of Physiology, College of Veterinary Medicine, Chungnam National University, Daejeon, Republic of Korea
- Center for Cognition and Sociality, Institute for Basic Science, Daejeon, Republic of Korea
| | - Tien Thuy Phan
- Center for Cognition and Sociality, Institute for Basic Science, Daejeon, Republic of Korea
| | - Jeongsook Kim
- Department of Physiology, College of Veterinary Medicine, Chungnam National University, Daejeon, Republic of Korea
| | - Kyu Pil Lee
- Department of Physiology, College of Veterinary Medicine, Chungnam National University, Daejeon, Republic of Korea.
| | - Joo Min Park
- Center for Cognition and Sociality, Institute for Basic Science, Daejeon, Republic of Korea.
- Sungkyunkwan University, Suwon, Republic of Korea.
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22
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Ten Barge JA, van den Bosch GE, Slater R, van den Hoogen NJ, Reiss IKM, Simons SHP. Visceral Pain in Preterm Infants with Necrotizing Enterocolitis: Underlying Mechanisms and Implications for Treatment. Paediatr Drugs 2025; 27:201-220. [PMID: 39752054 PMCID: PMC11829917 DOI: 10.1007/s40272-024-00676-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/03/2024] [Indexed: 01/04/2025]
Abstract
Necrotizing enterocolitis (NEC) is a relatively rare but very severe gastrointestinal disease primarily affecting very preterm infants. NEC is characterized by excessive inflammation and ischemia in the intestines, and is associated with prolonged, severe visceral pain. Despite its recognition as a highly painful disease, current pain management for NEC is often inadequate, and research on optimal analgesic therapy for these patients is lacking. Insight into the mechanisms underlying intestinal pain in infants with NEC-visceral pain-could help identify the most effective analgesics for these vulnerable patients. Therefore, this comprehensive review aims to provide an overview of visceral nociception, including transduction, transmission, modulation, and experience, and discuss the implications for analgesic therapy in preterm infants with NEC. The transmission of visceral pain differs from that of somatic pain, contributing to the diffuse nature of visceral pain. Studies evaluating the effectiveness of analgesics for treating visceral pain in infants are scarce. However, research in visceral pain models highlights agents that may be particularly effective for treating visceral pain based on their mechanisms of action. Further research is necessary to determine whether agents that have shown promise for treating visceral pain in preclinical studies and adults are effective in infants with NEC as well.
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Affiliation(s)
- Judith A Ten Barge
- Department of Neonatal and Pediatric Intensive Care, Division of Neonatology, Erasmus MC - Sophia Children's Hospital, Rotterdam, The Netherlands.
| | - Gerbrich E van den Bosch
- Department of Neonatal and Pediatric Intensive Care, Division of Neonatology, Erasmus MC - Sophia Children's Hospital, Rotterdam, The Netherlands
| | | | | | - Irwin K M Reiss
- Department of Neonatal and Pediatric Intensive Care, Division of Neonatology, Erasmus MC - Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Sinno H P Simons
- Department of Neonatal and Pediatric Intensive Care, Division of Neonatology, Erasmus MC - Sophia Children's Hospital, Rotterdam, The Netherlands
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23
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Islam J, Rahman MT, Ali M, Kim HK, Kc E, Park YS. Optogenetic inhibition of ventrolateral orbitofrontal cortex astrocytes facilitates ventrolateral periaqueductal gray glutamatergic activity to reduce hypersensitivity in infraorbital nerve injury rat model. J Headache Pain 2025; 26:41. [PMID: 39994518 PMCID: PMC11854010 DOI: 10.1186/s10194-025-01977-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Accepted: 02/10/2025] [Indexed: 02/26/2025] Open
Abstract
BACKGROUND Trigeminal neuropathic pain (TNP) is a chronic condition characterized by heightened nociceptive responses and neuroinflammatory changes. While astrocytes are recognized as critical players in pain modulation, their specific role in influencing descending trigeminal pain pathways via ventrolateral orbitofrontal cortex (vlOFC) activity modulation remains underexplored. Therefore, we investigated the impact of optogenetic modulation of astrocytes in the vlOFC on pain hypersensitivity in a rat model of chronic constriction injury of the infraorbital nerve (CCI-ION). METHOD Adult female Sprague Dawley rats underwent ION constriction to mimic TNP symptoms, with naive and sham animals serving as controls. AAV8-GFAP-hChR2-mCherry, AAV8-GFAP-eNpHR3.0-mCherry, or AAV8-GFAP-mCherry were delivered to the vlOFC for in vivo optogenetic manipulation. Pain behaviors were assessed using acetone, von Frey, and elevated plus maze tests, while electrophysiological recordings from the ventrolateral periaqueductal gray (vlPAG) and ventral posteromedial (VPM) thalamus were obtained. RESULTS Orofacial hyperalgesia, reduced vlPAG activity, and thalamic hyperexcitability were associated with vlOFC astrocytic hyperactivity in the TNP animals. In contrast, optogenetic inhibition of vlOFC astrocytes restored vlOFC glutamatergic signaling, increased vlPAG glutamatergic neuronal activity, and reduced hyperactivity in the VPM thalamus. Behavioral assessments also revealed alleviation of hyperalgesia, allodynia, and anxiety-like behaviors during the stimulation-ON phase, alongside reduced neuroinflammatory markers, including P2 × 3 and Iba-1. However, astrocytic excitation and null virus controls did not alter TNP responses, underscoring the specificity of astrocytic inhibition. CONCLUSION These findings suggest that the astrocytic subpopulation in the vlOFC and its robust influence on vlPAG glutamatergic neurons play a crucial role in restoring descending pain processing pathways, potentially contributing to the development of novel therapeutic approaches for TNP management.
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Affiliation(s)
- Jaisan Islam
- Program in Neuroscience, College of Medicine, Chungbuk National University, Cheongju, 28644, Republic of Korea
| | - Md Taufiqur Rahman
- Program in Neuroscience, College of Medicine, Chungbuk National University, Cheongju, 28644, Republic of Korea
| | - Muhammad Ali
- Program in Neuroscience, College of Medicine, Chungbuk National University, Cheongju, 28644, Republic of Korea
| | - Hyong Kyu Kim
- Department of Medicine and Microbiology, College of Medicine, Chungbuk National University, Cheongju, 28644, Republic of Korea
| | - Elina Kc
- Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Young Seok Park
- Program in Neuroscience, College of Medicine, Chungbuk National University, Cheongju, 28644, Republic of Korea.
- Department of Neurosurgery, Chungbuk National University Hospital, Cheongju, 28644, Republic of Korea.
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24
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Ghanbari A. Beneficial Effects of Exercise in Neuropathic Pain: An Overview of the Mechanisms Involved. Pain Res Manag 2025; 2025:3432659. [PMID: 40040749 PMCID: PMC11879594 DOI: 10.1155/prm/3432659] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2024] [Accepted: 02/08/2025] [Indexed: 03/06/2025]
Abstract
Neuropathic pain is a prevalent issue that often arises following injuries to the peripheral or central nervous system. Unfortunately, there is currently no definitive and flawless treatment available to alleviate this type of pain. However, exercise has emerged as a promising nonpharmacological and adjunctive approach, demonstrating a significant impact in reducing pain intensity. This is why physical therapy is considered a beneficial approach for diminishing pain and promoting functional recovery following nerve injuries. Regular physical activity exerts its hypoalgesic effects through a diverse array of mechanisms. These include inhibiting oxidative stress, suppressing inflammation, and modulating neurotransmitter levels, among others. It is possible that multiple activated mechanisms may coexist within an individual. However, the priming mechanism does not need to be the same across all subjects. Each person's response to physical activity and pain modulation may vary depending on their unique physiological and genetic factors. In this review, we aimed to provide a concise overview of the mechanisms underlying the beneficial effects of regular exercise on neuropathic pain. We have discussed several key mechanisms that contribute to the improvement of neuropathic pain through exercise. However, it is important to note that this is not an exhaustive analysis, and there may be other mechanisms at play. Our goal was to provide a brief yet informative exploration of the topic.
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Affiliation(s)
- Ali Ghanbari
- Research Center of Physiology, Semnan University of Medical Sciences, Semnan, Iran
- Department of Physiology, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
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25
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Tassou A, Richebe P, Rivat C. Mechanisms of chronic postsurgical pain. Reg Anesth Pain Med 2025; 50:77-85. [PMID: 39909543 DOI: 10.1136/rapm-2024-105964] [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: 08/14/2024] [Accepted: 10/25/2024] [Indexed: 02/07/2025]
Abstract
Chronic pain after surgery, also known as chronic postsurgical pain (CPSP), is recognized as a significant public health issue with serious medical and economic consequences. Current research on CPSP underscores the significant roles of both peripheral and central sensitization in pain development and maintenance. Peripheral sensitization occurs at the site of injury, through the hyperexcitability of nerve fibers due to surgical damage and the release of inflammatory mediators. This leads to increased expression of pronociceptive ion channels and receptors, such as transient receptor potential and acid-sensing ion channels (ASIC), enhancing pain signal transmission. Central sensitization involves long-term changes in the central nervous system, particularly in the spinal cord. In this context, sensitized spinal neurons become more responsive to pain signals, driven by continuous nociceptive input from the periphery, which results in an enhanced pain response characterized by hyperalgesia and/or allodynia. Key players in this process include N-methyl-D-aspartate receptor and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, along with proinflammatory cytokines and chemokines released by activated glia. These glial cells release substances that further increase neuronal excitability, maintaining the sensitized state and contributing to persistent pain. The activation of antinociceptive systems is required for the resolution of pain after surgery, and default in these systems may also be considered as an important component of CPSP. In this review, we will examine the clinical factors underlying CPSP in patients and the mechanisms previously established in preclinical models of CPSP that may explain how acute postoperative pain may transform into chronic pain in patients.
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Affiliation(s)
- Adrien Tassou
- Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
- UNC Neuroscience Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Philippe Richebe
- Department of Anesthesiology and Pain Medicine, Polyclinique Bordeaux Nord Aquitaine (PBNA), Bordeaux, France
- Anesthesiology and Pain Medicine, Maisonneuve Rosemont Hospital, University of Montreal, Montreal, Quebec, Canada
| | - Cyril Rivat
- University of Montpellier, Montpellier, France
- Institut des Neurosciences de Montpellier INSERM U1298, Montpellier, France
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26
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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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Du Y, Li Y, Hu J, Fang R, Liu Y, Cai L, Song Y, Ma S, Gao J, Zhang H, Li B, Xiong H, Yu H, Yang S, Zhu S, Zheng H. Repetitive Transcranial Magnetic Stimulation: Is it an Effective Treatment for Cancer Pain? Pain Ther 2025; 14:47-66. [PMID: 39551863 PMCID: PMC11751341 DOI: 10.1007/s40122-024-00679-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Accepted: 10/25/2024] [Indexed: 11/19/2024] Open
Abstract
Cancer is a major public health issue, with an estimated 20 million new cases and 9.7 million cancer-related deaths worldwide in 2022. Approximately 44.5% of patients experience cancer pain, significantly impacting their quality of life and causing physical and psychological burdens. Repetitive transcranial magnetic stimulation (rTMS), a non-invasive neuromodulation technique, shows potential in managing cancer pain. This review summarizes current research on rTMS for cancer pain, focusing on pain directly caused by tumors, pain from cancer treatments, postoperative pain, and cancer-related symptoms. Additionally, rTMS shows promise in improving cancer-related fatigue, anxiety, depression, and cognitive dysfunction, which can indirectly reduce cancer pain. The analgesic mechanisms of rTMS include inhibiting nociceptive signal transmission in the spinal cord, modulating hemodynamic changes in brain regions, and promoting endogenous opioid release. High-frequency stimulation of the primary motor cortex (M1) has shown significant analgesic effects, improving patients' emotional and cognitive functions and overall quality of life. rTMS has a favorable safety profile, with most studies reporting no severe adverse events. In conclusion, rTMS holds substantial potential for cancer pain management, offering a non-invasive and multifaceted therapeutic approach. Continued research and clinical application are expected to establish rTMS as an essential component of comprehensive cancer pain treatment strategies, significantly enhancing the overall well-being of patients with cancer.
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Affiliation(s)
- Yanyuan Du
- Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, No. 5, Beixiange, Xicheng District, Beijing, 100053, China
| | - Yaoyuan Li
- Department of Rehabilitation Medicine, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China
| | - Jieqing Hu
- Fengtai Community Health Service Center, Beijing, 100071, China
| | - Ruiying Fang
- Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, No. 5, Beixiange, Xicheng District, Beijing, 100053, China
| | - Yuming Liu
- Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, No. 5, Beixiange, Xicheng District, Beijing, 100053, China
| | - Liu Cai
- Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, No. 5, Beixiange, Xicheng District, Beijing, 100053, China
| | - Ying Song
- Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, No. 5, Beixiange, Xicheng District, Beijing, 100053, China
| | - Susu Ma
- Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, No. 5, Beixiange, Xicheng District, Beijing, 100053, China
| | - Jin Gao
- Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, No. 5, Beixiange, Xicheng District, Beijing, 100053, China
| | - Hanyue Zhang
- Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, No. 5, Beixiange, Xicheng District, Beijing, 100053, China
| | - Baihui Li
- Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, No. 5, Beixiange, Xicheng District, Beijing, 100053, China
| | - Hongtai Xiong
- Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, No. 5, Beixiange, Xicheng District, Beijing, 100053, China
| | - Huibo Yu
- Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, No. 5, Beixiange, Xicheng District, Beijing, 100053, China
| | - Shenglei Yang
- School of Sports Medicine and Rehabilitation, Beijing Sport University, Beijing, 100084, China
| | - Shuduo Zhu
- Binzhou People's Hospital, Binzhou, 256610, China
| | - Honggang Zheng
- Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, No. 5, Beixiange, Xicheng District, Beijing, 100053, China.
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Wani P, Anand R. Neuroplasticity and Pain Perception: Exploring the Complexities of Temporomandibular Disorders. Cureus 2025; 17:e79098. [PMID: 40104480 PMCID: PMC11918487 DOI: 10.7759/cureus.79098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/16/2025] [Indexed: 03/20/2025] Open
Abstract
Temporomandibular disorders (TMDs) are prevalent conditions affecting the temporomandibular joint (TMJ), masticatory muscles, and associated structures, leading to pain, restricted movement, and joint noises. These disorders are multifactorial in origin, involving structural, functional, and psychological components. This review delves into the neurophysiological mechanisms of pain perception in TMDs, focusing on peripheral and central processes, including the role of neural plasticity in chronic pain. Peripheral mechanisms involve nociceptors in the TMJ, activated by inflammatory mediators, mechanical stress, and tissue damage, leading to pain. Peripheral sensitization, driven by factors such as cytokines and neuropeptides, enhances nociceptor sensitivity, contributing to chronic pain states. The trigeminal nerve is pivotal in transmitting nociceptive information to the central nervous system (CNS), with C-fibers and A-delta fibers involved in pain perception. Central sensitization, a hallmark of chronic pain in TMDs, involves neuroplastic changes in the CNS, including wind-up and long-term potentiation (LTP), enhancing pain perception and facilitating pain persistence. Neuroplasticity, both central and peripheral, plays a critical role in the development of chronic pain. Central plasticity includes synaptic changes and alterations in brain connectivity, which were observed in functional imaging studies of TMD patients. Peripheral plasticity involves the upregulation of ion channels and neurotransmitters, sustaining pain signals. Additionally, neuroimmune interactions between microglia, astrocytes, and pain pathways are integral to central sensitization. Understanding these mechanisms is crucial for developing effective treatments targeting both peripheral and central pain processes. Emerging therapies, including transient receptor potential (TRP) channel blockers and neuroimmune modulators, offer new avenues for managing TMD pain, emphasizing the need for a multifaceted treatment approach.
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Affiliation(s)
- Pinaki Wani
- Physiology, All India Institute of Medical Sciences, Raebareli, Raebareli, IND
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Antoniazzi E, Cavigioli C, Tang V, Zoccola C, Todisco M, Tassorelli C, Cosentino G. Effects of Repetitive Transcranial Magnetic Stimulation Applied over the Primary Motor Cortex on the Offset Analgesia Phenomenon. Life (Basel) 2025; 15:182. [PMID: 40003592 PMCID: PMC11856385 DOI: 10.3390/life15020182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Revised: 01/17/2025] [Accepted: 01/23/2025] [Indexed: 02/27/2025] Open
Abstract
In this study, we investigate the effects of high-frequency repetitive transcranial magnetic stimulation (rTMS) applied over the left upper limb primary motor cortex (M1) on the offset analgesia (OA) phenomenon, a measure of endogenous pain modulation. In particular, we aim to determine whether rTMS influences OA differently in the forearm region, corresponding to the stimulated cortical area, compared to the trigeminal region. Twenty-two healthy volunteers underwent three experimental sessions: a baseline session without stimulation, an active rTMS session, and a sham rTMS session. Quantitative sensory testing (QST) paradigms, including warm and cold detection thresholds, heat pain threshold corresponding to a visual analogue scale (VAS) score of approximately 50-60 out of 100 (Pain50-60), and constant and offset trials, were assessed in both the forearm and trigeminal regions. The results revealed that active rTMS significantly enhanced the OA phenomenon in the forearm during the late phase, while no significant effects were observed in the trigeminal region. These findings suggest that rTMS may modulate central pain mechanisms in a body region-specific manner, potentially linked to the somatotopic organization of M1. This study points to possible mechanisms of action of rTMS for pain relief, highlighting the importance of region-specific effects in chronic pain treatment. Further research is needed to investigate the underlying mechanisms and clinical applicability of rTMS in patients with chronic pain conditions, especially when OA is compromised.
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Affiliation(s)
- Elisa Antoniazzi
- Translational Neurophysiology Research Section, IRCCS Mondino Foundation, 27100 Pavia, Italy; (E.A.); (C.C.); (V.T.); (C.Z.); (M.T.)
| | - Camilla Cavigioli
- Translational Neurophysiology Research Section, IRCCS Mondino Foundation, 27100 Pavia, Italy; (E.A.); (C.C.); (V.T.); (C.Z.); (M.T.)
| | - Vanessa Tang
- Translational Neurophysiology Research Section, IRCCS Mondino Foundation, 27100 Pavia, Italy; (E.A.); (C.C.); (V.T.); (C.Z.); (M.T.)
| | - Clara Zoccola
- Translational Neurophysiology Research Section, IRCCS Mondino Foundation, 27100 Pavia, Italy; (E.A.); (C.C.); (V.T.); (C.Z.); (M.T.)
| | - Massimiliano Todisco
- Translational Neurophysiology Research Section, IRCCS Mondino Foundation, 27100 Pavia, Italy; (E.A.); (C.C.); (V.T.); (C.Z.); (M.T.)
| | - Cristina Tassorelli
- Department of Brain and Behavioral Sciences, University of Pavia, 27100 Pavia, Italy
- Headache Science and Neurorehabilitation Center, IRCCS Mondino Foundation, 27100 Pavia, Italy
| | - Giuseppe Cosentino
- Translational Neurophysiology Research Section, IRCCS Mondino Foundation, 27100 Pavia, Italy; (E.A.); (C.C.); (V.T.); (C.Z.); (M.T.)
- Department of Brain and Behavioral Sciences, University of Pavia, 27100 Pavia, Italy
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Stroman PW, Staud R, Pukall CF. Evidence of a persistent altered neural state in people with fibromyalgia syndrome during functional MRI studies and its relationship with pain and anxiety. PLoS One 2025; 20:e0316672. [PMID: 39854440 PMCID: PMC11759356 DOI: 10.1371/journal.pone.0316672] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Accepted: 12/14/2024] [Indexed: 01/26/2025] Open
Abstract
Altered neural signaling in fibromyalgia syndrome (FM) was investigated with functional magnetic resonance imaging (fMRI). We employed a novel fMRI network analysis method, Structural and Physiological Modeling (SAPM), which provides more detailed information than previous methods. The study involved brain fMRI data from participants with FM (N = 22) and a control group (HC, N = 18), acquired during a noxious stimulation paradigm. The analyses were supported by fMRI data from the brainstem and spinal cord in FM and HC, brain fMRI data from participants with provoked vestibulodynia (PVD), and eye-tracking data from an fMRI study of FM. The results demonstrate differences in connectivity, and in blood oxygenation-level dependent (BOLD) responses, between FM and HC. In the FM group, BOLD signals underwent a large increase during the first 40 seconds of each fMRI run, prior to the application of any stimuli, compared to much smaller increases in HC. This indicates a heightened state of neural activity in FM that is sustained during fMRI runs, and dissipates between runs. The exaggerated initial rise was not observed in PVD. Autonomic functioning differed between groups. Pupil sizes were larger in FM than in HC, and the groups exhibited pupil dilation to the same levels during noxious stimulation. The initial BOLD increase varied in relation to state and trait anxiety scores. The results indicate that people with FM enter a heightened state of neural activity associated with anxiety and autonomic functioning, during every fMRI run, concurrent with increased pupil sizes, and heightened pain sensitivity. These findings may relate to the well-known hypervigilance and global hypersensitivity of FM participants.
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Affiliation(s)
- Patrick W. Stroman
- Centre for Neuroscience Studies, Queen’s University, Kingston, Ontario, Canada
- Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, Ontario, Canada
- Department of Physics, Queen’s University, Kingston, Ontario, Canada
| | - Roland Staud
- Division of Rheumatology, Department of Medicine, University of Florida, Gainesville, Florida, United States of America
| | - Caroline F. Pukall
- Centre for Neuroscience Studies, Queen’s University, Kingston, Ontario, Canada
- Department of Psychology, Queen’s University, Kingston, Ontario, Canada
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Grivet Z, Aby F, Verboven A, Bouali-Benazzouz R, Sueur B, Maingret F, Naudet F, Dhellemmes T, De Deurwaerdere P, Benazzouz A, Fossat P. Brainstem serotonin amplifies nociceptive transmission in a mouse model of Parkinson's disease. NPJ Parkinsons Dis 2025; 11:11. [PMID: 39774033 PMCID: PMC11706991 DOI: 10.1038/s41531-024-00857-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Accepted: 11/22/2024] [Indexed: 01/11/2025] Open
Abstract
Parkinson's disease arises from the degeneration of dopaminergic neurons in the substantia nigra pars compacta, leading to motor symptoms such as akinesia, rigidity, and tremor at rest. The non-motor component of Parkinson's disease includes increased neuropathic pain, the prevalence of which is 4 to 5 times higher than the general rate. By studying a mouse model of Parkinson's disease induced by 6-hydroxydopamine, we assessed the impact of dopamine depletion on pain modulation. Mice exhibited mechanical hypersensitivity associated with hyperexcitability of neurons in the dorsal horn of the spinal cord (DHSC). Serotonin (5-HT) levels increased in the spinal cord, correlating with reduced tyrosine hydroxylase (TH) immunoreactivity in the nucleus raphe magnus (NRM) and increased excitability of 5-HT neurons. Selective optogenetic inhibition of 5-HT neurons attenuated mechanical hypersensitivity and reduced DHSC hyperexcitability. In addition, the blockade of 5-HT2A and 5-HT3 receptors reduced mechanical hypersensitivity. These results reveal, for the first time, that PD-like dopamine depletion triggers spinal-mediated mechanical hypersensitivity, associated with serotonergic hyperactivity in the NRM, opening up new therapeutic avenues for Parkinson's disease-associated pain targeting the serotonergic systems.
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Affiliation(s)
- Zoé Grivet
- Université de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France
- CNRS, Institut des Maladies Neurodégénératives, Bordeaux, France
| | - Franck Aby
- Université de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France
- CNRS, Institut des Maladies Neurodégénératives, Bordeaux, France
| | - Aude Verboven
- Université de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France
- CNRS, Institut des Maladies Neurodégénératives, Bordeaux, France
| | - Rabia Bouali-Benazzouz
- Université de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France
- CNRS, Institut des Maladies Neurodégénératives, Bordeaux, France
| | - Benjamin Sueur
- Université de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France
- CNRS, Institut des Maladies Neurodégénératives, Bordeaux, France
| | - François Maingret
- Université de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France
- CNRS, Institut des Maladies Neurodégénératives, Bordeaux, France
| | - Frédéric Naudet
- Université de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France
- CNRS, Institut des Maladies Neurodégénératives, Bordeaux, France
| | - Thibault Dhellemmes
- Université de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France
- CNRS, Institut des Maladies Neurodégénératives, Bordeaux, France
| | - Philippe De Deurwaerdere
- Université de Bordeaux, Institut des neurosciences cognitives et intégratives d'aquitaine, Bordeaux, France
- CNRS, Institut des neurosciences cognitives et intégratives d'aquitaine, Bordeaux, France
| | - Abdelhamid Benazzouz
- Université de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France
- CNRS, Institut des Maladies Neurodégénératives, Bordeaux, France
| | - Pascal Fossat
- Université de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France.
- CNRS, Institut des Maladies Neurodégénératives, Bordeaux, France.
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Pereira-Silva R, Neto FL, Martins I. Diffuse Noxious Inhibitory Controls in Chronic Pain States: Insights from Pre-Clinical Studies. Int J Mol Sci 2025; 26:402. [PMID: 39796255 PMCID: PMC11722076 DOI: 10.3390/ijms26010402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Revised: 12/19/2024] [Accepted: 12/22/2024] [Indexed: 01/13/2025] Open
Abstract
Diffuse noxious inhibitory control (DNIC), also known as conditioned pain modulation (CPM) in humans, is a paradigm wherein the heterotopic application of a noxious stimulus results in the attenuation of another spatially distant noxious input. The pre-clinical and clinical studies show the involvement of several neurochemical systems in DNIC/CPM and point to a major contribution of the noradrenergic, serotonergic, and opioidergic systems. Here, we thoroughly review the latest data on the monoaminergic and opioidergic studies, focusing particularly on pre-clinical models of chronic pain. We also conduct an in-depth analysis of these systems by integrating the available data with the descending pain modulatory circuits and the neurochemical systems therein to bring light to the mechanisms involved in the regulation of DNIC. The most recent data suggest that DNIC may have a dual outcome encompassing not only analgesic effects but also hyperalgesic effects. This duality might be explained by the underlying circuitry and the receptor subtypes involved therein. Acknowledging this duality might contribute to validating the prognostic nature of the paradigm. Additionally, DNIC/CPM may serve as a robust paradigm with predictive value for guiding pain treatment through more effective targeting of descending pain modulation.
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Affiliation(s)
- Raquel Pereira-Silva
- Instituto de Investigação e Inovação em Saúde da Universidade do Porto–i3S, R. Alfredo Allen 208, 4200-135 Porto, Portugal;
- Instituto de Biologia Molecular e Celular (IMBC), Universidade do Porto, R. Alfredo Allen 208, 4200-135 Porto, Portugal
- Departamento de Biomedicina, Unidade de Biologia Experimental, Faculdade de Medicina, Universidade do Porto, Al. Prof Hernâni Monteiro, 4200-319 Porto, Portugal
| | - Fani L. Neto
- Instituto de Investigação e Inovação em Saúde da Universidade do Porto–i3S, R. Alfredo Allen 208, 4200-135 Porto, Portugal;
- Instituto de Biologia Molecular e Celular (IMBC), Universidade do Porto, R. Alfredo Allen 208, 4200-135 Porto, Portugal
- Departamento de Biomedicina, Unidade de Biologia Experimental, Faculdade de Medicina, Universidade do Porto, Al. Prof Hernâni Monteiro, 4200-319 Porto, Portugal
| | - Isabel Martins
- Instituto de Investigação e Inovação em Saúde da Universidade do Porto–i3S, R. Alfredo Allen 208, 4200-135 Porto, Portugal;
- Instituto de Biologia Molecular e Celular (IMBC), Universidade do Porto, R. Alfredo Allen 208, 4200-135 Porto, Portugal
- Departamento de Biomedicina, Unidade de Biologia Experimental, Faculdade de Medicina, Universidade do Porto, Al. Prof Hernâni Monteiro, 4200-319 Porto, Portugal
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Manengu C, Zhu CH, Zhang GD, Tian MM, Lan XB, Tao LJ, Ma L, Liu Y, Yu JQ, Liu N. Metabotropic Glutamate Receptor 5: A Potential Target for Neuropathic Pain Treatment. Curr Neuropharmacol 2025; 23:276-294. [PMID: 39411936 PMCID: PMC11808587 DOI: 10.2174/1570159x23666241011163035] [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: 02/24/2024] [Revised: 06/13/2024] [Accepted: 06/20/2024] [Indexed: 02/12/2025] Open
Abstract
Neuropathic pain, a multifaceted and incapacitating disorder, impacts a significant number of individuals globally. Despite thorough investigation, the development of efficacious remedies for neuropathic pain continues to be a formidable task. Recent research has revealed the potential of metabotropic glutamate receptor 5 (mGlu5) as a target for managing neuropathic pain. mGlu5 is a receptor present in the central nervous system that has a vital function in regulating synaptic transmission and the excitability of neurons. This article seeks to investigate the importance of mGlu5 in neuropathic pain pathways, analyze the pharmacological approach of targeting mGlu5 for neuropathic pain treatment, and review the negative allosteric mGlu5 modulators used to target mGlu5. By comprehending the role of mGlu5 in neuropathic pain, we can discover innovative treatment approaches to ease the distress endured by persons afflicted with this incapacitating ailment.
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Affiliation(s)
- Chalton Manengu
- College of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan, 750004, Ningxia Hui Autonomous Region, China
- School of International Education, Ningxia Medical University, 1160 Shengli Street, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Chun-Hao Zhu
- College of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan, 750004, Ningxia Hui Autonomous Region, China
| | - Guo-Dong Zhang
- College of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan, 750004, Ningxia Hui Autonomous Region, China
| | - Miao-Miao Tian
- College of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan, 750004, Ningxia Hui Autonomous Region, China
| | - Xiao-Bing Lan
- College of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan, 750004, Ningxia Hui Autonomous Region, China
| | - Li-Jun Tao
- Department of Pharmacy, People’s Hospital of Ningxia Hui Autonomous Region, Yinchuan, 750004, China
| | - Lin Ma
- College of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan, 750004, Ningxia Hui Autonomous Region, China
| | - Yue Liu
- College of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan, 750004, Ningxia Hui Autonomous Region, China
| | - Jian-Qiang Yu
- College of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan, 750004, Ningxia Hui Autonomous Region, China
| | - Ning Liu
- College of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan, 750004, Ningxia Hui Autonomous Region, China
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Ansari S, Khahpay R, Khakpai F, Heidarzadeh Z, Khojasteh SMB. Comparison of pain modulatory effect of the LPGi estragon receptor on inflammatory pain between pro-estrus and estrus phases and OVX rats. Psychopharmacology (Berl) 2025; 242:129-147. [PMID: 39180591 DOI: 10.1007/s00213-024-06653-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Accepted: 07/12/2024] [Indexed: 08/26/2024]
Abstract
The present study has investigated whether circulating estrogen level variations in the pro-estrus and estrus phases of the intact rats and estrogen depletion in the ovariectomized animals (OVX) adjust the formalin-induced nociceptive behaviors. During the pro-estrus and estrus phases of rats' estrus cycle and in the OVX rats, 17β-estradiol and ICI 182,780 (estrogen receptor antagonist) were administered into the right paragigantocellularis lateralis (LPGi) nucleus. Then, the formalin-induced flexing and licking responses were recorded for 60 min. The findings of this study revealed that intra-LPGi administration of 17β-estradiol (0.8 μmol) reduced the formalin-induced flexing and licking duration in pro-estrus and estrus rats (P < 0.001), suggesting an analgesic effect. 17β-Estradiol injection into the LPGi nucleus of OVX rats increased the flexing duration (P < 0.05) while decreasing the licking duration (P < 0.05) of the formalin test. The pain modulatory effect of 17β-estradiol on the flexing response was reversed by ICI 182,780 (15 nmol) in the pro-estrus (P < 0.001) and estrus rats (P < 0.001) but not in the OVX rats. Also, pretreatment of LPGi nucleus with ICI 182,780 reversed the analgesic effect of 17β-estradiol on the licking response in the pro-estrus (P < 0.05), estrus (P < 0.001), and OVX rats (P < 0.001). These results suggest that the pain threshold in intact female rats is modulated independently of the estrus state. Still, the basal level of plasma estrogen and the activation of its receptors are necessary for pain modulation.
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Affiliation(s)
- Sanam Ansari
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Roghaieh Khahpay
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran.
| | - Fatemeh Khakpai
- Department of Physiology, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Zahra Heidarzadeh
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
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Martínez-Magaña CJ, Murbartián J. Estrogen receptor α regulates the IKKs/NF-kB activity involved in the development of mechanical allodynia induced by REM sleep deprivation in rats. Brain Res 2024; 1845:149269. [PMID: 39384127 DOI: 10.1016/j.brainres.2024.149269] [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: 07/04/2024] [Revised: 09/11/2024] [Accepted: 10/06/2024] [Indexed: 10/11/2024]
Abstract
Several signaling pathways that converge in NF-kB activation have been linked to developing and maintaining different types of pathological pain. In addition, some mechanisms implied in the establishment of chronic pain have been demonstrated to have a sex-dependent correlation. This study aimed to determine if the IKKs/NF-kB signaling pathway is involved in establishing REM sleep deprivation (REMSD) induced mechanical allodynia in rats and its possible regulation depending on estradiol and estrogen receptors. Intrathecal administration of BMS-345541 or minocycline, two drugs that reduce the IKKs/NF-kB activity, avoided the development of mechanical allodynia in female but not in male rats subjected to 48 h of REMSD. Ovariectomy in female rats abolished the effect of BMS-345541 and minocycline. Meanwhile, the 17-β-estradiol restitution restored it. Intrathecal administration of MPP, a selective ERα antagonist, but not PHTPP, a selective ERβ antagonist, avoided the effect of BMS-345541 in female rats without hormonal manipulation. In addition, the transient run-down of ERα in female rats abolished the effect of BMS-345541. All data suggest an important role of ERα as a regulator of the IKKs/NF-kB activity. REMSD increased the ERα protein expression in the dorsal root ganglia and the dorsal spinal cord in females but not in male rats. Interestingly, ERα activation or ERα overexpression allowed the effect of BMS-345541 in male rats. Data suggest an important regulatory role of ERα in the IKKs/NF-kB activity on establishing mechanical allodynia induced by REMSD in female rats.
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Affiliation(s)
| | - Janet Murbartián
- Pharmacobiology Department, Cinvestav, South Campus, Mexico City, Mexico.
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Powers JM, Koning E, Ioachim G, Stroman PW. Pain is what you think: functional magnetic resonance imaging evidence toward a cognitive and affective approach for pain research. FRONTIERS IN PAIN RESEARCH 2024; 5:1388460. [PMID: 39720318 PMCID: PMC11666527 DOI: 10.3389/fpain.2024.1388460] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Accepted: 11/22/2024] [Indexed: 12/26/2024] Open
Abstract
The sensory/discriminative domain of pain is often given more consideration than the cognitive and affective influences that ultimately make pain what it is: a highly subjective experience that is based on an individual's life history and experiences. While many investigations of the underlying mechanisms of pain have focused on solely noxious stimuli, few have compared somatosensory stimuli that cross the boundary from innocuous to noxious. Of those that have, there is little consensus on the similarities and differences in neural signaling across these sensory domains. The purpose of this study was to apply our established network connectivity analyses toward the goal of understanding the neural mechanisms behind sensory, cognitive, and affective responses to noxious and innocuous stimuli. Functional MRI data were collected from 19 healthy women and men that experienced warm and hot thermal stimuli across multiple trials. This is a within-subjects cross-sectional experimental study with repeated measures. Ratings of stimulus intensity and unpleasantness that were collected during each run confirmed significant perceptual differences between the two types of stimuli. Despite this finding, no group differences in network connectivity were found across conditions. When individual differences related to pain ratings were investigated, subtle differences were found in connectivity that could be attributed to sensory and association regions in the innocuous condition, and cognitive, affective, and autonomic regions in the pain condition. These results were reflected in the time-course data for each condition. Overall, signaling mechanisms for innocuous and noxious somatosensation are intricately linked, but pain-specific perception appears to be driven by our psychological and autonomic states.
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Affiliation(s)
- Jocelyn M. Powers
- Centre for Neuroscience Studies, Queen’s University, Kingston, ON, Canada
| | - Elena Koning
- Centre for Neuroscience Studies, Queen’s University, Kingston, ON, Canada
| | - Gabriela Ioachim
- Centre for Neuroscience Studies, Queen’s University, Kingston, ON, Canada
| | - Patrick W. Stroman
- Centre for Neuroscience Studies, Queen’s University, Kingston, ON, Canada
- Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, Canada
- Department of Physics, Queen’s University, Kingston, ON, Canada
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37
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Islam J, Rahman MT, Ali M, Kc E, Park YS. Potential hypothalamic mechanisms in trigeminal neuropathic pain: a comparative analysis with migraine and cluster headache. J Headache Pain 2024; 25:205. [PMID: 39587517 PMCID: PMC11587712 DOI: 10.1186/s10194-024-01914-z] [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: 09/26/2024] [Accepted: 11/15/2024] [Indexed: 11/27/2024] Open
Abstract
Trigeminal neuropathic pain (TNP), migraine, and cluster headache (CH) profoundly impact the quality of life and present significant clinical challenges due to their complex neurobiological underpinnings. This review delves into the pivotal role of the hypothalamus in the pathophysiology of these facial pain syndromes, highlighting its distinctive functions and potential as a primary target for research, diagnosis, and therapy. While the involvement of the hypothalamus in migraine and CH has been increasingly supported by imaging and clinical studies, the precise mechanisms of its role remain under active investigation. The role of the hypothalamus in TNP, in contrast, is less explored and represents a critical gap in our understanding. The hypothalamus's involvement varies significantly across these conditions, orchestrating a unique interplay of neural circuits and neurotransmitter systems that underlie the distinct characteristics of each pain type. We have explored advanced neuromodulation techniques, such as deep brain stimulation (DBS) and optogenetics, which show promise in targeting hypothalamic dysfunction to alleviate pain symptoms. Furthermore, we discuss the neuroplastic changes within the hypothalamus that contribute to the chronicity of these pains and the implications of these findings for developing targeted therapies. By offering a comprehensive examination of the hypothalamus's roles, this paper aims to bridge existing knowledge gaps and propel forward the understanding and management of facial neuralgias, underscoring the hypothalamus's critical position in future neurological research.
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Affiliation(s)
- Jaisan Islam
- Department of Medical Neuroscience, College of Medicine, Chungbuk National University, Cheongju, Republic of Korea
| | - Md Taufiqur Rahman
- Department of Medical Neuroscience, College of Medicine, Chungbuk National University, Cheongju, Republic of Korea
- Department of Neurosurgery, Chungbuk National University Hospital, Cheongju, Republic of Korea
| | - Muhammad Ali
- Department of Medical Neuroscience, College of Medicine, Chungbuk National University, Cheongju, Republic of Korea
| | - Elina Kc
- Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Young Seok Park
- Department of Medical Neuroscience, College of Medicine, Chungbuk National University, Cheongju, Republic of Korea.
- Department of Neurosurgery, Chungbuk National University Hospital, Cheongju, Republic of Korea.
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Li JL, Zhu CH, Tian MM, Liu Y, Ma L, Tao LJ, Zheng P, Yu JQ, Liu N. Negative allosteric modulator of Group Ⅰ mGluRs: Recent advances and therapeutic perspective for neuropathic pain. Neuroscience 2024; 560:406-421. [PMID: 39368605 DOI: 10.1016/j.neuroscience.2024.10.004] [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: 07/13/2024] [Revised: 09/26/2024] [Accepted: 10/01/2024] [Indexed: 10/07/2024]
Abstract
Neuropathic pain (NP) is a widespread public health problem that existing therapeutic treatments cannot manage adequately; therefore, novel treatment strategies are urgently required. G-protein-coupled receptors are important for intracellular signal transduction, and widely participate in physiological and pathological processes, including pain perception. Group I metabotropic glutamate receptors (mGluRs), including mGluR1 and mGluR5, are predominantly implicated in central sensitization, which can lead to hyperalgesia and allodynia. Many orthosteric site antagonists targeting Group I mGluRs have been found to alleviate NP, but their poor efficacy, low selectivity, and numerous side effects limit their development in NP treatment. Here we reviewed the advantages of Group I mGluRs negative allosteric modulators (NAMs) over orthosteric site antagonists based on allosteric modulation mechanism, and the challenges and opportunities of Group I mGluRs NAMs in NP treatment. This article aims to elucidate the advantages and future development potential of Group I mGluRs NAMs in the treatment of NP.
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Affiliation(s)
- Jia-Ling Li
- School of Pharmacy, Ningxia Medical University, Yinchuan 750000, China
| | - Chun-Hao Zhu
- School of Pharmacy, Ningxia Medical University, Yinchuan 750000, China
| | - Miao-Miao Tian
- School of Pharmacy, Ningxia Medical University, Yinchuan 750000, China
| | - Yue Liu
- School of Pharmacy, Ningxia Medical University, Yinchuan 750000, China
| | - Lin Ma
- School of Pharmacy, Ningxia Medical University, Yinchuan 750000, China
| | - Li-Jun Tao
- Department of Pharmacy, People's Hospital of Ningxia Hui Autonomous Region, Yinchuan 750000, China
| | - Ping Zheng
- School of Pharmacy, Ningxia Medical University, Yinchuan 750000, China.
| | - Jian-Qiang Yu
- School of Pharmacy, Ningxia Medical University, Yinchuan 750000, China.
| | - Ning Liu
- School of Pharmacy, Ningxia Medical University, Yinchuan 750000, China; School of Basic Medical Science, Ningxia Medical University, Yinchuan 750000, China.
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39
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Baudat M, Joosten EAJ, Simons SHP. Repetitive daily oxytocin treatment reduces weight gain but not acute neonatal procedural pain. Pediatr Res 2024:10.1038/s41390-024-03680-9. [PMID: 39523390 DOI: 10.1038/s41390-024-03680-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 09/09/2024] [Accepted: 10/08/2024] [Indexed: 11/16/2024]
Abstract
BACKGROUND While the incidence of neonatal intensive care unit (NICU) admission steadily increases, neonatology lacks evidence of a safe, effective, and preventive analgesic for treating procedural pain. Given its role in nociception and promoting healthy neurodevelopment, the endogenous neuropeptide oxytocin (OT) emerges as a promising candidate. METHODS This study investigates the use of daily repeated subcutaneous OT (1 mg/kg) treatment in an established model of neonatal repetitive procedural pain and assesses the effectivity of OT treatment on mechanical sensitivity and body weight. RESULTS Contrary to our hypothesis repeated daily OT treatment did not prevent the development of mechanical hypersensitivity following needle pricks. Furthermore, treatment with OT diminished body weight gain in neonatal pups, a major side effect observed throughout the neonatal week. These results highlight the unique nature of the maturing nociceptive system that makes the identification and selection of analgesic options for the treatment of acute neonatal procedural pain a major challenge. CONCLUSION In conclusion, our preclinical results do not support the use of repeated OT for acute pain relief in the NICU, and the side effects on body weight gain raise concerns about the use of OT in the NICU. IMPACT Repeated daily OT treatment inhibits weight gain in neonatal rat pus. Repetitive daily OT administration does not prevent the development of mechanical hypersensitivity in a model of neonatal procedural pain. Future research must focus on the unique physiology of the developing nociceptive system to establish safe, effective and protective treatment of neonatal procedural pain.
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Affiliation(s)
- Mathilde Baudat
- Department of Anesthesiology and Pain Management, Maastricht University Medical Centre+, Maastricht, the Netherlands.
- Department of Translational Neuroscience, Institute of Mental Health and Neuroscience Research, Maastricht University, Maastricht, the Netherlands.
| | - Elbert A J Joosten
- Department of Anesthesiology and Pain Management, Maastricht University Medical Centre+, Maastricht, the Netherlands
- Department of Translational Neuroscience, Institute of Mental Health and Neuroscience Research, Maastricht University, Maastricht, the Netherlands
| | - Sinno H P Simons
- Department of Neonatal and Pediatric Intensive Care, Division of Neonatology, Erasmus University Medical Centre Rotterdam- Sophia Children Hospital, Rotterdam, the Netherlands
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40
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Raffa RB, Fink W, Tripathi AD. On Including Pain as an Integral Part of the Fight-or-Flight Response. J Pain Res 2024; 17:3667-3668. [PMID: 39540034 PMCID: PMC11559197 DOI: 10.2147/jpr.s500847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Accepted: 11/06/2024] [Indexed: 11/16/2024] Open
Affiliation(s)
- Robert B Raffa
- Temple University (Emeritus), Philadelphia, PA, USA
- University of Arizona (Adjunct), Tucson, AZ, USA
| | - Wolfgang Fink
- Visual and Autonomous Exploration Systems Research Laboratory, University of Arizona, Tucson, AZ, USA
| | - Anuj D Tripathi
- Visual and Autonomous Exploration Systems Research Laboratory, University of Arizona, Tucson, AZ, USA
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41
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Hubli M, Leone C. Clinical neurophysiology of neuropathic pain. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2024; 179:125-154. [PMID: 39580211 DOI: 10.1016/bs.irn.2024.10.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/25/2024]
Abstract
Timely and accurate diagnosis of neuropathic pain is critical for optimizing therapeutic outcomes and minimizing treatment delays. According to current standards, the diagnosis of definite neuropathic pain requires objective confirmation of a lesion or disease affecting the somatosensory nervous system. This can be provided by specialized neurophysiological techniques as conventional methods like nerve conduction studies and somatosensory evoked potentials may not be sufficient as they do not assess pain pathways. These specialized techniques apply various stimuli, such as thermal, electrical, or mechanical, alongside assessments of spinal/cortical potential or electromyographic reflex recordings. The selection of techniques is guided by the patient's clinical history and examination. The most common neurophysiological tests used in clinical practice are pain-related evoked potentials (PREPs) providing an objective evaluation of nociceptive pathways. Four types of PREPs are employed: laser evoked potentials, contact-heat evoked potentials, intra-epidermal electrical stimulation evoked potentials, and pinprick evoked potentials, with the two former ones being the most robust and reliable ones. These techniques investigate small-diameter fibers, primarily Aδ-fibers, and spinothalamic tracts allowing the identification of peripheral or central nervous system lesions. Yet, they are limited in capturing neuronal mechanisms underlying neuropathic pain or in providing objective quantification of pain sensation. Two neurophysiological measures which investigate the pain system beyond its integrity are the nociceptive withdrawal reflex and the N13 component of somatosensory evoked potentials. Both of these methods are more commonly used in research than clinical practice, but they pose interesting approaches to quantify central sensitization, a key underlying mechanism of neuropathic pain. Future investigations in neuropathic pain are therefore warranted.
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Affiliation(s)
- Michèle Hubli
- Spinal Cord Injury Center, Balgrist University Hospital, University of Zurich, Zurich, Switzerland
| | - Caterina Leone
- Department of Human Neuroscience, Sapienza University, Rome, Italy.
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42
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Franciosa F, Acuña MA, Nevian NE, Nevian T. A cellular mechanism contributing to pain-induced analgesia. Pain 2024; 165:2517-2529. [PMID: 38968393 PMCID: PMC11474934 DOI: 10.1097/j.pain.0000000000003315] [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: 09/29/2023] [Revised: 03/25/2024] [Accepted: 03/27/2024] [Indexed: 07/07/2024]
Abstract
ABSTRACT The anterior cingulate cortex (ACC) plays a crucial role in the perception of pain. It is consistently activated by noxious stimuli and its hyperactivity in chronic pain indicates plasticity in the local neuronal network. However, the way persistent pain effects and modifies different neuronal cell types in the ACC and how this contributes to sensory sensitization is not completely understood. This study confirms the existence of 2 primary subtypes of pyramidal neurons in layer 5 of the rostral, agranular ACC, which we could classify as intratelencephalic (IT) and cortico-subcortical (SC) projecting neurons, similar to other cortical brain areas. Through retrograde labeling, whole-cell patch-clamp recording, and morphological analysis, we thoroughly characterized their different electrophysiological and morphological properties. When examining the effects of peripheral inflammatory pain on these neuronal subtypes, we observed time-dependent plastic changes in excitability. During the acute phase, both subtypes exhibited reduced excitability, which normalized to pre-inflammatory levels after day 7. Daily conditioning with nociceptive stimuli during this period induced an increase in excitability specifically in SC neurons, which was correlated with a decrease in mechanical sensitization. Subsequent inhibition of the activity of SC neurons projecting to the periaqueductal gray with in vivo chemogenetics, resulted in reinstatement of the hypersensitivity. Accordingly, it was sufficient to enhance the excitability of these neurons chemogenetically in the inflammatory pain condition to induce hypoalgesia. These findings suggest a cell type-specific effect on the descending control of nociception and a cellular mechanism for pain-induced analgesia. Furthermore, increased excitability in this neuronal population is hypoalgesic rather than hyperalgesic.
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Affiliation(s)
| | - Mario A. Acuña
- Department of Physiology, University of Bern, Bern, Switzerland
| | | | - Thomas Nevian
- Department of Physiology, University of Bern, Bern, Switzerland
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43
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Lambert J, Petrovitch D, Himes KP, Freiermuth CE, Braun RS, Brown JL, Bischof JJ, Lyons MS, Punches BE, Littlefield AK, Kisor DF, Sprague JE. Association of genetic variants in CYP3A5, DRD2 and NK1R with opioid overdose. Chem Biol Interact 2024; 403:111242. [PMID: 39265714 DOI: 10.1016/j.cbi.2024.111242] [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: 05/22/2024] [Revised: 08/29/2024] [Accepted: 09/10/2024] [Indexed: 09/14/2024]
Abstract
In 2023, 3651 Ohioans died because of an opioid overdose. Of those opioid overdoses, 3579 (98%) of which were attributed to fentanyl. We evaluated the association between 180 candidate single nucleotide polymorphisms (SNPs) and self-reported, nonfatal opioid overdose history from a prospective sample of 1301 adult patients (≥18 years of age) seen in three urban emergency departments in Ohio. Candidate SNPs included 120 related to the dopamine reward pathway and 60 related to pharmacokinetics. Of the 821 patients who reported having been exposed to opioids in their lifetime, 95 (11.6%) also reported having experienced an opioid-related overdose. Logistic regression, adjusting for age and biologic sex, was used to characterize the association between each SNP and opioid overdose, correcting for multiple comparisons. Three SNPs, located in three different genes were associated with opioid overdose: increased odds with CYP3A5 (rs776746) and DRD2 (rs4436578), and decreased odds with NKIR (rs6715729). Homozygotic CYP3A5 (rs776746) had the highest adjusted odds ratio (OR) of 6.96 (95% CI [2.45, 29.23]) and homozygotic NK1R (rs6715729) had the lowest OR of 0.28 (95% CI [0.14, 0.54). Given that CYP3A5 (rs776746) has been associated with increased plasma concentrations of fentanyl, rs776746 could potentially be utilized as a prognostic risk indicator for the potential of an opioid overdose. NK1R regulates the expression of the neurokinin-1 receptor, a regulator of respiration and NK1R (rs6715729) represents a novel genetic marker for a decreased risk of opioid overdose risk.
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Affiliation(s)
- Joshua Lambert
- College of Nursing, University of Cincinnati, Cincinnati, OH, USA
| | - Dan Petrovitch
- Department of Psychological Sciences, Texas Tech University, Lubbock, TX, USA
| | - Katie P Himes
- Department of Psychological Sciences, Texas Tech University, Lubbock, TX, USA
| | - Caroline E Freiermuth
- Department of Emergency Medicine, University of Cincinnati, Cincinnati, OH, USA; Center for Addiction Research, University of Cincinnati, Cincinnati, OH, USA
| | - Robert S Braun
- Department of Emergency Medicine, University of Cincinnati, Cincinnati, OH, USA
| | - Jennifer L Brown
- Department of Psychological Sciences, Purdue University, West Lafayette, IN, USA
| | - Jason J Bischof
- Department of Emergency Medicine, The Ohio State University, Columbus, OH, USA
| | - Michael S Lyons
- Department of Emergency Medicine, The Ohio State University, Columbus, OH, USA
| | - Brittany E Punches
- Department of Emergency Medicine, The Ohio State University, Columbus, OH, USA; College of Nursing, The Ohio State University, Columbus, OH, USA
| | | | - David F Kisor
- Department of Pharmaceutical Sciences and Pharmacogenomics, College of Pharmacy, Natural and Health Sciences, Manchester University, Fort Wayne, Indiana, USA
| | - Jon E Sprague
- The Ohio Attorney General's Center for the Future of Forensic Science, Bowling Green State University, Bowling Green, OH, USA.
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44
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Li J, Bai Y, Ge J, Zhang Y, Zhao Q, Li D, Guo B, Gao S, Zhu Y, Cai G, Wan X, Huang J, Wu S. Cell Type-Specific Modulation of Acute Itch Processing in the Anterior Cingulate Cortex. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2403445. [PMID: 39316379 DOI: 10.1002/advs.202403445] [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: 04/07/2024] [Revised: 07/24/2024] [Indexed: 09/25/2024]
Abstract
Despite remarkable progress in understanding the fundamental bases of itching, its cortical mechanisms remain poorly understood. Herein, the causal contributions of defined anterior cingulate cortex (ACC) neuronal populations to acute itch modulation in mice are established. Using cell type-specific manipulations, the opposing functions of ACC glutamatergic and GABAergic neurons in regulating acute itching are demonstrated. Photometry studies indicated that ACC glutamatergic neurons are activated during scratching induced by both histamine and chloroquine, whereas the activation pattern of GABAergic neurons is complicated by GABAergic subpopulations and acute itch modalities. By combining cell type- and projection-specific techniques, a thalamocortical circuit is further identified from the mediodorsal thalamus driving the itch-scratching cycle related to histaminergic and non-histaminergic itching, which is contingent on the activation of postsynaptic parvalbumin-expressing neurons in the ACC. These findings reveal a cellular and circuit signature of ACC neurons orchestrating behavioral responses to itching and may provide insights into therapies for itch-related diseases.
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Affiliation(s)
- Jiaqi Li
- Department of Neurobiology, Basic Medical Science Academy, Fourth Military Medical University, Xi'an, 710032, China
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
| | - Yang Bai
- Department of Neurosurgery, General Hospital of Northern Theater Command, Shenyang, 110015, China
| | - Junye Ge
- Department of Neurobiology, Basic Medical Science Academy, Fourth Military Medical University, Xi'an, 710032, China
| | - Yiwen Zhang
- Department of Neurobiology, Basic Medical Science Academy, Fourth Military Medical University, Xi'an, 710032, China
| | - Qiuying Zhao
- Department of Neurobiology, Basic Medical Science Academy, Fourth Military Medical University, Xi'an, 710032, China
| | - Dangchao Li
- Department of Neurobiology, Basic Medical Science Academy, Fourth Military Medical University, Xi'an, 710032, China
| | - Baolin Guo
- Department of Neurobiology, Basic Medical Science Academy, Fourth Military Medical University, Xi'an, 710032, China
| | - Shasha Gao
- Department of Neurobiology, Basic Medical Science Academy, Fourth Military Medical University, Xi'an, 710032, China
| | - Yuanyuan Zhu
- Department of Neurobiology, Basic Medical Science Academy, Fourth Military Medical University, Xi'an, 710032, China
| | - Guohong Cai
- Department of Neurobiology, Basic Medical Science Academy, Fourth Military Medical University, Xi'an, 710032, China
| | - Xiangdong Wan
- Department of Neurobiology, Basic Medical Science Academy, Fourth Military Medical University, Xi'an, 710032, China
| | - Jing Huang
- Department of Neurobiology, Basic Medical Science Academy, Fourth Military Medical University, Xi'an, 710032, China
| | - Shengxi Wu
- Department of Neurobiology, Basic Medical Science Academy, Fourth Military Medical University, Xi'an, 710032, China
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Mitchell JR, Vincelette L, Tuberman S, Sheppard V, Bergeron E, Calitri R, Clark R, Cody C, Kannan A, Keith J, Parakoyi A, Pikus M, Vance V, Ziane L, Brenhouse H, Laine MA, Shansky RM. Behavioral and neural correlates of diverse conditioned fear responses in male and female rats. Neurobiol Stress 2024; 33:100675. [PMID: 39391589 PMCID: PMC11465128 DOI: 10.1016/j.ynstr.2024.100675] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 09/10/2024] [Accepted: 09/19/2024] [Indexed: 10/12/2024] Open
Abstract
Pavlovian fear conditioning is a widely used tool that models associative learning in rodents. For decades the field has used predominantly male rodents and focused on a sole conditioned fear response: freezing. However, recent work from our lab and others has identified darting as a female-biased conditioned response, characterized by an escape-like movement across a fear conditioning chamber. It is also accompanied by a behavioral phenotype: Darters reliably show decreased freezing compared to Non-darters and males and reach higher velocities in response to the foot shock ("shock response"). However, the relationship between shock response and conditioned darting is not known. This study investigated if this link is due to differences in general processing of aversive stimuli between Darters, Non-darters and males. Across a variety of modalities, including corticosterone measures, the acoustic startle test, and sensitivity to thermal pain, Darters were found not to be more reactive or sensitive to aversive stimuli, and, in some cases, they appear less reactive to Non-darters and males. Analyses of cFos activity in regions involved in pain and fear processing following fear conditioning identified discrete patterns of expression among Darters, Non-darters, and males exposed to low and high intensity foot shocks. The results from these studies further our understanding of the differences between Darters, Non-darters and males and highlight the importance of studying individual differences in fear conditioning as indicators of fear state.
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Affiliation(s)
| | | | | | | | | | | | - Rose Clark
- Northeastern University, Boston, MA, USA
| | | | | | - Jack Keith
- Northeastern University, Boston, MA, USA
| | | | | | | | | | | | - Mikaela A. Laine
- Northeastern University, Boston, MA, USA
- Smith College, Northampton, MA, USA
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46
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Stamp GE, Wadley AL, Iacovides S. Could Relationship-Based Learnt Beliefs and Expectations Contribute to Physiological Vulnerability of Chronic Pain? Making a Case to Consider Attachment in Pain Research. THE JOURNAL OF PAIN 2024; 25:104619. [PMID: 38945383 DOI: 10.1016/j.jpain.2024.104619] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 04/10/2024] [Accepted: 06/22/2024] [Indexed: 07/02/2024]
Abstract
Pain is an interpersonal and inherently social experience. Pain perception and administration of medical treatment all occur in a particular environmental and social context. Early environmental influences and early learning experiences and interactions condition the body's response to different threats (like pain), ultimately shaping the underlying neurophysiology. These early interactions and experiences also determine what situations are perceived as threatening, as well as our belief in our own ability to self-manage, and our belief in others to offer support, during perceived threats. These beliefs intrinsically drive the combination of behaviors that emerge in response to perceived threats, including pain. Such behaviors can be categorized into attachment styles. In this interdisciplinary review, we synthesize and summarize evidence from the neurobiological, psychobiological, psychosocial, and psychobehavioral fields, to describe how these beliefs are embedded in the brain's prediction models to generate a series of expectations/perceptions around the level of safety/threat in different contexts. As such, these beliefs may predict how one experiences and responds to pain, with potentially significant implications for the development and management of chronic pain. Little attention has been directed to the effect of adult attachment style on pain in research studies and in the clinical setting. Using interdisciplinary evidence, we argue why we think this interaction merits further consideration and research. PERSPECTIVE: This review explores the influence of attachment styles on pain perception, suggesting a link between social connections and chronic pain development. It aligns with recent calls to emphasize the social context in pain research and advocates for increased focus on adult attachment styles in research and clinical practice.
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Affiliation(s)
- Gabriella Elisabeth Stamp
- Brain Function Research Group, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
| | - Antonia Louise Wadley
- Brain Function Research Group, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Stella Iacovides
- Brain Function Research Group, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
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47
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Terlouw EMC, Paulmier V, Andanson S, Picgirard L, Aleyrangues X, Durand D. Slaughter of cattle without stunning: Questions related to pain, stress and endorphins. Meat Sci 2024; 219:109686. [PMID: 39490250 DOI: 10.1016/j.meatsci.2024.109686] [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: 07/11/2024] [Revised: 09/27/2024] [Accepted: 10/10/2024] [Indexed: 11/05/2024]
Abstract
EEG studies have suggested that cattle perceive pain when bled without stunning. The present study on bleeding without stunning, compared cows that had received a local anaesthetic on the site of the bleeding cut (Lurocaine; Luro cows) one hour before bleeding with a 35 cm knife, with cows that had not (saline: Placebo cows). Various physiological indicators potentially related to pain or stress were evaluated. Increases in heart rate (P < 0.02) and cortisol levels (P < 0.001) during slaughter, compared to control levels are indicative of slaughter stress in both groups. GSH/GSSG ratio, plasma PGE2, TNFα, and NO levels and blood haematocrit levels at slaughter were not influenced by slaughter or treatment. At bleeding, excluding two out of the 15 cows with non-missing data, Placebo cows presented a longer delay between the loss of the corneal reflex and respiratory arrest. Post-mortem, Longissimus muscle of Placebo cows had a faster pH decline and remained warmer. Overall, results suggest greater stress levels in this group, probably due to pain. Plasma or brain β-endorphin contents in relevant brain structures did not increase following bleeding in either group, thus not supporting the hypothesis that stress or pain-induced release of endorphins reduces pain perceived following the cut. Furthermore, according to existing knowledge, plasma β-endorphins do not reduce pain perceived. Thus, both our study and previous research do not provide evidence that slaughter without stunning does not cause pain or other forms of stress in at least part of the animals.
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Affiliation(s)
- E M Claudia Terlouw
- Université Clermont Auvergne, INRAE, VetAgro Sup, UMR Herbivores, Saint-Genès-Champanelle, France.
| | - Valérie Paulmier
- Association pour le Développement de Institut de la Viande, Clermont-Ferrand, France; Present address: Cap Emploi 63 - 19 Boulevard Berthelot, 62400 Chamalieres, France
| | - Stéphane Andanson
- Université Clermont Auvergne, INRAE, VetAgro Sup, UMR Herbivores, Saint-Genès-Champanelle, France; Université Clermont Auvergne, INRAE, PIAF, F-63000 Clermont-Ferrand, France
| | - Laurent Picgirard
- Association pour le Développement de Institut de la Viande, Clermont-Ferrand, France
| | - Xavier Aleyrangues
- Association pour le Développement de Institut de la Viande, Clermont-Ferrand, France
| | - Denis Durand
- Université Clermont Auvergne, INRAE, VetAgro Sup, UMR Herbivores, Saint-Genès-Champanelle, France
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Rezende RM, Coimbra RS, Kohlhoff M, Favarato LSC, Martino HSD, Leite LB, Soares LL, Encarnação S, Forte P, de Barros Monteiro AM, Peluzio MDCG, José Natali A. Effects of Tryptophan and Physical Exercise on the Modulation of Mechanical Hypersensitivity in a Fibromyalgia-like Model in Female Rats. Cells 2024; 13:1647. [PMID: 39404410 PMCID: PMC11475953 DOI: 10.3390/cells13191647] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Revised: 09/25/2024] [Accepted: 10/01/2024] [Indexed: 10/19/2024] Open
Abstract
Though the mechanisms are not fully understood, tryptophan (Trp) and physical exercise seem to regulate mechanical hypersensitivity in fibromyalgia. Here, we tested the impact of Trp supplementation and continuous low-intensity aerobic exercise on the modulation of mechanical hypersensitivity in a fibromyalgia-like model induced by acid saline in female rats. Twelve-month-old female Wistar rats were randomly divided into groups: [control (n = 6); acid saline (n = 6); acid saline + exercise (n = 6); acid saline + Trp (n = 6); and acid saline + exercise + Trp (n = 6)]. Hypersensitivity was caused using two intramuscular jabs of acid saline (20 μL; pH 4.0; right gastrocnemius), 3 days apart. The tryptophan-supplemented diet contained 7.6 g/hg of Trp. The three-week exercise consisted of progressive (30-45 min) treadmill running at 50 to 60% intensity, five times (Monday to Friday) per week. We found that acid saline induced contralateral mechanical hypersensitivity without changing the levels of Trp, serotonin (5-HT), and kynurenine (KYN) in the brain. Hypersensitivity was reduced by exercise (~150%), Trp (~67%), and its combination (~160%). The Trp supplementation increased the levels of Trp and KYN in the brain, and the activity of indoleamine 2,3-dioxygenase (IDO), and decreased the ratio 5-HT:KYN. Exercise did not impact the assessed metabolites. Combining the treatments reduced neither hypersensitivity nor the levels of serotonin and Trp in the brain. In conclusion, mechanical hypersensitivity induced by acid saline in a fibromyalgia-like model in female rats is modulated by Trp supplementation, which increases IDO activity and leads to improved Trp metabolism via the KYN pathway. In contrast, physical exercise does not affect mechanical hypersensitivity through brain Trp metabolism via either the KYN or serotonin pathways. Because this is a short study, generalizing its findings warrants caution.
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Affiliation(s)
- Rafael Marins Rezende
- Department of Physiotherapy, Universidade Federal de Juiz de Fora, Governador Valadares 35020-360, MG, Brazil;
| | - Roney Santos Coimbra
- Instituto Rene Rachou–Fiocurz Minas, Belo Horizonte 30190-009, MG, Brazil; (R.S.C.); (M.K.)
| | - Markus Kohlhoff
- Instituto Rene Rachou–Fiocurz Minas, Belo Horizonte 30190-009, MG, Brazil; (R.S.C.); (M.K.)
| | | | - Hércia Stampini Duarte Martino
- Department of Nutrition and Health, Universidade Federal de Viçosa, Viçosa 36570-900, MG, Brazil; (H.S.D.M.); (M.d.C.G.P.)
| | - Luciano Bernardes Leite
- Exercise Biology Laboratory, Department of Physical Education, Universidade Federal de Viçosa, Viçosa 36570-900, MG, Brazil; (L.B.L.); (L.L.S.)
- Department of Sports Sciences, Instituto Politécnico de Bragança, 5300-253 Bragança, Portugal; (P.F.); (A.M.d.B.M.)
| | - Leoncio Lopes Soares
- Exercise Biology Laboratory, Department of Physical Education, Universidade Federal de Viçosa, Viçosa 36570-900, MG, Brazil; (L.B.L.); (L.L.S.)
| | - Samuel Encarnação
- Instituto Politécnico de Bragança, Campus de Santa Apolónia, 5300-253 Bragança, Portugal;
- Department of Physical Education, Sport and Human Movement, Universidad Autónoma de Madrid, 28049 Madrid, Spain
- Research Centre for Active Living and Wellbeing (Livewell), Instituto Politécnico de Bragança, 5300-253 Bragança, Portugal
| | - Pedro Forte
- Department of Sports Sciences, Instituto Politécnico de Bragança, 5300-253 Bragança, Portugal; (P.F.); (A.M.d.B.M.)
- Research Centre for Active Living and Wellbeing (Livewell), Instituto Politécnico de Bragança, 5300-253 Bragança, Portugal
- CI-ISCE, Instituto Superior de Ciências Educativas do Douro (ISCE Douro), 4560-547 Penafiel, Portugal
- Research Centre in Sports Sciences, Health Sciences and Human Development, 5001-801 Vila Real, Portugal
| | - António Miguel de Barros Monteiro
- Department of Sports Sciences, Instituto Politécnico de Bragança, 5300-253 Bragança, Portugal; (P.F.); (A.M.d.B.M.)
- Research Centre for Active Living and Wellbeing (Livewell), Instituto Politécnico de Bragança, 5300-253 Bragança, Portugal
| | - Maria do Carmo Gouveia Peluzio
- Department of Nutrition and Health, Universidade Federal de Viçosa, Viçosa 36570-900, MG, Brazil; (H.S.D.M.); (M.d.C.G.P.)
| | - Antônio José Natali
- Exercise Biology Laboratory, Department of Physical Education, Universidade Federal de Viçosa, Viçosa 36570-900, MG, Brazil; (L.B.L.); (L.L.S.)
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49
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Cawley DR, Seton B, Logullo D, Pandey R, Tickal A, Onyeke A, Jones C, Saliba N, Moralejo L, Pearson WG. Autonomic recalibration: A pilot study documenting mechanistic evidence for a trauma-informed manual therapy for chronic pain. J Bodyw Mov Ther 2024; 40:1985-1993. [PMID: 39593555 DOI: 10.1016/j.jbmt.2024.10.061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Revised: 10/06/2024] [Accepted: 10/20/2024] [Indexed: 11/28/2024]
Affiliation(s)
- Daniel R Cawley
- Edward Via College of Osteopathic Medicine Auburn Campus, USA.
| | - Bob Seton
- Edward Via College of Osteopathic Medicine Auburn Campus, USA; Hope Institute for Human Performance, USA.
| | - Drew Logullo
- Edward Via College of Osteopathic Medicine Auburn Campus, USA.
| | - Rishika Pandey
- Edward Via College of Osteopathic Medicine Auburn Campus, USA.
| | - Adam Tickal
- Edward Via College of Osteopathic Medicine Auburn Campus, USA.
| | - Amanda Onyeke
- Edward Via College of Osteopathic Medicine Auburn Campus, USA.
| | - Cody Jones
- Edward Via College of Osteopathic Medicine Auburn Campus, USA.
| | - Natalie Saliba
- Edward Via College of Osteopathic Medicine Auburn Campus, USA.
| | - Laura Moralejo
- Edward Via College of Osteopathic Medicine Auburn Campus, USA.
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50
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Nazir MM, Inam S, Ijaz MU, Zafar N, Yeni DK, Asad F, Farzeen I, Ashraf A. In vivo and in silico elucidation of possible potential and mechanisms involved in the analgesic action of ethanolic extract of Lavandula Stoechas. J Pharm Pharmacol 2024; 76:1178-1198. [PMID: 38984979 DOI: 10.1093/jpp/rgae072] [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: 03/02/2024] [Accepted: 05/29/2024] [Indexed: 07/11/2024]
Abstract
OBJECTIVES Our research focused on plant's ethanolic extract Lavandula stoechas flower part to investigate the potential analgesic effects and possible pathways involvements. METHODS Four experimental tests were performed on Swiss albino mice with five animals in each group at different doses (50, 100, and 200mg/kg); formalin test, tail-flick test, acetic acid-induced writhing, and hot-plate test. The opioidergic, noradrenergic, cholinergic, and K channel blockers in the analgesic actions were also carried out for the potential route involvement. KEY FINDING The percentage inhibition for abdominal writhing's and formalin activity showed a dose-dependent manner for early and late phases reducing abdominal writhing's and time period of licking, respectively. Tail immersion and hot-plate test demonstrated a substantial and dose-dependent increase in the latency time and time period of paw liking and jumping response respectively. GC-MS showed the abundantly present compounds were octadecatrienoic acid (34.35%), n-hexadecanoic acid (12.98%). In silico analyses have revealed three compounds that had good interactions with 6y3c receptor proteins, demonstrating strong binding affinities and satisfying docking parameters. CONCLUSIONS Overall, these studies showed that ethanolic extract of L. stoechas is an important medicinal plant, with both central and peripheral antinociceptive and analgesic activities supporting its traditional use for therapeutic purposes.
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Affiliation(s)
| | - Sana Inam
- Department of Pharmaceutics, Government College University, Faisalabad 38000, Pakistan
| | - Muhammad Umar Ijaz
- Department of Zoology, Wildlife and Fisheries, University of Agriculture, Faisalabad 38040, Pakistan
| | - Nimrah Zafar
- Department of Zoology, Government College University, Faisalabad 38000, Pakistan
| | - Derya Karatas Yeni
- Department of Microbiology, University of Necmettin Erbakan, Konya, Turkey
| | - Farkhanda Asad
- Department of Zoology, Government College University, Faisalabad 38000, Pakistan
| | - Iqra Farzeen
- Department of Zoology, Government College University, Faisalabad 38000, Pakistan
| | - Asma Ashraf
- Department of Zoology, Government College University, Faisalabad 38000, Pakistan
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