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de Azambuja G, Moreira Simabuco F, Gonçalves de Oliveira MC. Macrophage-P2X4 receptors pathway is essential to persistent inflammatory muscle hyperalgesia onset, and is prevented by physical exercise. PLoS One 2025; 20:e0318107. [PMID: 39932994 PMCID: PMC11813081 DOI: 10.1371/journal.pone.0318107] [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: 08/25/2024] [Accepted: 01/09/2025] [Indexed: 02/13/2025] Open
Abstract
Peripheral inflammation may lead to severe inflammatory painful conditions. Macrophages are critical for inflammation; modulating related pathways could be an essential therapeutic strategy for chronic pain diseases. Here we hypothesized that 1) Macrophage-P2X4 receptors are involved in the transition from acute to persistent inflammatory muscle hyperalgesia and that 2) P2X4 activation triggers a pro-inflammatory phenotype leading to Interleukin-1β (IL-1β) increase. Once physical exercise prevents exacerbated inflammatory processes related to chronic diseases including chronic muscle pain, we also hypothesized that 3) physical exercise, through PPARγ receptors, prevents P2X4 receptors activation. With pharmacological behaviour, biomolecular analysis and swimming physical exercise in a mouse model of persistent inflammatory muscle hyperalgesia we demonstrated that P2X4 receptors are essential for transitioning from acute to persistent inflammatory muscle hyperalgesia; Phosphorylation of p38MAPK indicated P2X4 signalling activation associated with inflammatory macrophage and an increase of IL-1β expression in skeletal muscle; Exercise-PPARγ receptors prevented phosphorylation of p38MAPK in muscle tissue. Our findings suggest that exercise-PPARγ modulates the acute inflammatory phase of developing persistent muscle hyperalgesia by controlling p38MAPK-related P2X4 signalling. These highlight the great potential of modulating macrophage phenotypes and P2X4 receptors to prevent pain conditions and the ability of physical exercise to prevent inflammatory processes related to chronic muscle pain.
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Affiliation(s)
- Graciana de Azambuja
- Universidade Estadual de Campinas (UNICAMP), Faculdade de Ciências Aplicadas, Laboratório de Estudos em Dor e Inflamação (LABEDI), Limeira, São Paulo, Brasil
| | - Fernando Moreira Simabuco
- Universidade Estadual de Campinas (UNICAMP), Faculdade de Ciências Aplicadas, Multidisciplinary Laboratory in Food and Health, Limeira, São Paulo, Brasil
| | - Maria Cláudia Gonçalves de Oliveira
- Universidade Estadual de Campinas (UNICAMP), Faculdade de Ciências Aplicadas, Laboratório de Estudos em Dor e Inflamação (LABEDI), Limeira, São Paulo, Brasil
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Wang C, He H, Gao T, Sun X, Du L, Yang Y, Zhu J, Yang Y, Wang Y, Mi W. Analgesic Effect of Exercise on Neuropathic Pain via Regulating the Complement Component 3 of Reactive Astrocytes. Anesth Analg 2024; 139:840-850. [PMID: 38294950 PMCID: PMC11379360 DOI: 10.1213/ane.0000000000006884] [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] [Accepted: 11/21/2023] [Indexed: 02/02/2024]
Abstract
BACKGROUND Exercise has been proven to be an efficient intervention in attenuating neuropathic pain. However, the underlying mechanisms that drive exercise analgesia remain unknown. In this study, we aimed to examine the role of complement component 3 (C3) in neuropathic pain and whether antinociceptive effects are produced by exercise via regulating C3 in mice. METHODS In this study, using a spared nerve injury (SNI)-induced neuropathic pain mice model, C57BL/6J mice were divided into 3 groups: Sham mice, SNI mice, and SNI + Exercise (Ex) mice with 30-minute low-intensity aerobic treadmill running (10 m/min, no inclination). Paw withdrawal threshold; thermal withdrawal latency; and glial fibrillary acidic protein, C3, tumor necrosis factor-α, and interlukin-1β expression in the spinal cord were monitored. C3 knockout (KO) mice were further used to verify the role of C3 in neuropathic pain. RESULTS von Frey test, acetone test, and CatWalk gait analysis revealed that treadmill exercise for 4 weeks reversed pain behaviors. In addition, exercise reduced astrocyte reactivity (SNI mean = 14.5, 95% confidence interval [CI], 12.7-16.3; SNI + Ex mean = 10.3, 95% CI, 8.77-11.9, P = .0003 SNI + Ex versus SNI) and inflammatory responses in the spinal cord after SNI. Moreover, it suppressed the SNI-induced upregulation of C3 expression in the spinal cord (SNI mean = 5.46, 95% CI, 3.39-7.53; SNI + Ex mean = 2.41, 95% CI, 1.42-3.41, P = .0054 SNI + Ex versus SNI in Western blot). C3 deficiency reduced SNI-induced pain and spinal astrocyte reactivity (wild type mean = 7.96, 95% CI, 6.80-9.13; C3 KO mean = 5.98, 95% CI, 5.14-6.82, P = .0052 C3 KO versus wild type). Intrathecal injection of recombinant C3 (rC3) was sufficient to produce mechanical (rC3-Ex mean = 0.77, 95% CI, 0.15-1.39; rC3 mean = 0.18, 95% CI, -0.04 to 0.41, P = .0168 rC3-Ex versus rC3) and cold (rC3-Ex mean = 1.08, 95% CI, 0.40-1.77; rC3 mean = 3.46, 95% CI, 1.45-5.47, P = .0025 rC3-Ex versus rC3) allodynia in mice. Importantly, exercise training relieved C3-induced mechanical and cold allodynia, and the analgesic effect of exercise was attenuated by a subeffective dose of intrathecal injection of C3. CONCLUSIONS Overall, these results suggest that exercise suppresses neuropathic pain by regulating astroglial C3 expression and function, thereby providing a rationale for the analgesic effect of exercise as an acceptable alternative approach for treating neuropathic pain.
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Affiliation(s)
- Chenghao Wang
- From the 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, China
- China Institute of Sport and Health Science, Beijing Sport University, Beijing, China
| | - Hui He
- China Institute of Sport and Health Science, Beijing Sport University, Beijing, China
- Key Laboratory of Physical Fitness and Exercise, Ministry of Education, Beijing Sport University, Beijing, China
| | - Tianchi Gao
- From the 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, China
| | - Xinzheng Sun
- China Institute of Sport and Health Science, Beijing Sport University, Beijing, China
| | - Lixia Du
- Department of Biochemistry, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yayue Yang
- From the 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, China
| | - Jianyu Zhu
- From the 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, China
| | - Yachen Yang
- From the 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, China
| | - Yanqing Wang
- From the 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, China
| | - Wenli Mi
- From the 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, China
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Sumizono M, Yoshizato Y, Imai T, Tani A, Nakanishi K, Nojima N, Kakimoto S, Sakakima H. Effects of Pain Relief Through Minimal Exercise Intervention in a Rat Model of Neuropathic Pain. Cureus 2024; 16:e62897. [PMID: 39044893 PMCID: PMC11262913 DOI: 10.7759/cureus.62897] [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] [Accepted: 06/22/2024] [Indexed: 07/25/2024] Open
Abstract
We aimed to minimize the frequency of exercise intervention and test the efficacy of pain relief. We also investigated the mechanism of neuropathic pain to determine the best frequency of pain relief for neuropathic pain. The chronic constriction injury (CCI) rat model was randomly divided into three groups: exercise (Ex), No-Ex, and normal. The treadmill exercise intervention was administered, and the 50% withdrawal threshold was assessed using the Von Frey Test. Ionized calcium-binding adaptor molecule 1 (IBA1), glial fibrillary acidic protein (GFAP), brain-derived neurotrophic factor (BDNF), C-C chemokine receptor type 2 (CCR2), and tumor necrosis factor receptor-associated factor 6 (TRAF6) activation was determined through immunohistochemistry. In the brain, we examined the increased expression of β-endorphin/met-enkephalin in the gray matter of the midbrain aqueduct. Co-expression of CCR2, IBA1, and Neu-N was observed in the spinal cord dorsal horn by immunofluorescence staining. The 50% pain response threshold was significantly lower in the Ex group than in the No-Ex group at five weeks post-CCI, indicating a high analgesic effect. In the dorsal horn of the spinal cord, IBA1 and GFAP were significantly decreased in the Ex group than in the No-Ex group at five weeks post-CCI. However, no significant difference in activation of BDNF, CCR2, and TRAF6 was observed. In the midbrain, the Ex group showed a significant increase compared to the No-Ex group. In summary, our results suggest that in minimal-exercise intervention, neuropathic pain relief is achieved by activation of the descending pain inhibitory system in the midbrain.
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Affiliation(s)
- Megumi Sumizono
- Rehabilitation, Kyushu University of Nursing and Social Welfare, Tamana, JPN
- Physical Therapy, School of Health Sciences, Kagoshima University, Kagoshima, JPN
| | - Yushin Yoshizato
- Rehabilitation, Kyushu University of Nursing and Social Welfare, Tamana, JPN
| | - Takaki Imai
- Rehabilitation, Kyushu University of Nursing and Social Welfare, Tamana, JPN
| | - Akira Tani
- Physical Therapy, School of Health Sciences, Kagoshima University, Kagoshima, JPN
| | - Kazuki Nakanishi
- Physical Therapy, School of Health Sciences, Kagoshima University, Kagoshima, JPN
| | - Nao Nojima
- Physical Therapy, School of Health Sciences, Kagoshima University, Kagoshima, JPN
| | - Shogo Kakimoto
- Physical Therapy, School of Health Sciences, Kagoshima University, Kagoshima, JPN
| | - Harutoshi Sakakima
- Physical Therapy, School of Health Sciences, Kagoshima University, Kagoshima, JPN
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Chan KM, Griffith JL, Pacheco YC, Allen KD. Wheel Running Exacerbates Joint Damage after Meniscal Injury in Mice, but Does Not Alter Gait or Physical Activity Levels. Med Sci Sports Exerc 2023; 55:1564-1576. [PMID: 37144624 PMCID: PMC10524358 DOI: 10.1249/mss.0000000000003198] [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] [Indexed: 05/06/2023]
Abstract
PURPOSE Exercise and physical activity are recommended to reduce pain and improve joint function in patients with knee osteoarthritis (OA). However, exercise has dose effects, with excessive exercise accelerating OA development and sedentary behaviors also promoting OA development. Prior work evaluating exercise in preclinical models has typically used prescribed exercise regimens; however, in-cage voluntary wheel running creates opportunities to evaluate how OA progression affects self-selected physical activity levels. This study aimed to evaluate how voluntary wheel running after a surgically induced meniscal injury affects gait characteristics and joint remodeling in C57Bl/6 mice. We hypothesize that injured mice will reduce physical activity levels as OA develops after meniscal injury and will engage in wheel running to a lesser extent than the uninjured animals. METHODS Seventy-two C57Bl/6 mice were divided into experimental groups based on sex, lifestyle (physically active vs sedentary), and surgery (meniscal injury or sham control). Voluntary wheel running data were continuously collected throughout the study, and gait data were collected at 3, 7, 11, and 15 wk after surgery. At end point, joints were processed for histology to assess cartilage damage. RESULTS After meniscal injury, physically active mice showed more severe joint damage relative to sedentary mice. Nevertheless, injured mice engaged in voluntary wheel running at the same rates and distances as mice with sham surgery. In addition, physically active mice and sedentary mice both developed a limp as meniscal injury progressed, yet exercise did not further exacerbate gait changes in the physically active mice, despite worsened joint damage. CONCLUSIONS Taken together, these data indicate a discordance between structural joint damage and joint function. Although wheel running after meniscal injury did worsen OA-related joint damage, physical activity did not necessarily inhibit or worsen OA-related joint dysfunction or pain in mice.
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Affiliation(s)
- Kiara M. Chan
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL
- Department of Kinesiology, Indiana University, Bloomington, IN
| | - Jacob L. Griffith
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL
| | - Yan Carlos Pacheco
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL
- Phil and Penny Knight Campus for Accelerating Scientific Impact, University of Oregon, Eugene
| | - Kyle D. Allen
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL
- Department of Orthopedics and Sports Medicine, University of Florida, Gainesville, FL
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Khan J, Wang Q, Korczeniewska OA, McNeil R, Ren Y, Benoliel R, Eliav E. Response profile in a rat model of exercise-induced hypoalgesia is associated with duloxetine, pregabalin and diclofenac effect on constriction-induced neuropathy. Eur J Pain 2023; 27:129-147. [PMID: 36198034 DOI: 10.1002/ejp.2044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Revised: 09/28/2022] [Accepted: 10/03/2022] [Indexed: 12/15/2022]
Abstract
BACKGROUND Exercise is a known trigger of the inhibitory pain modulation system and its analgesic effect is termed exercise-induced hypoalgesia (EIH). Previous studies have demonstrated that rats with deficient analgesic response following exercise develop more significant hypersensitivity following nerve injury compared to rats with substantial analgesic response following exercise. OBJECTIVES A rat model of EIH as an indicator of the pain inhibitory system's efficiency was used to explore the association between EIH profiles and the effect of pharmacotherapy on rat's neuropathic pain. METHODS EIH profiles were assessed by evaluating paw responses to mechanical stimuli before and after exercise on a rotating rod. Rats with a reduction of ≤33% in responses were classified as low EIH and those with ≥67% as high EIH. Low and high EIH rats underwent sciatic nerve chronic constriction injury (CCI). Paw responses to mechanical stimuli were measured at baseline, following CCI, and after treatment with diclofenac, duloxetine or pregabalin. In a different group of low and high EIH rats, EIH was measured before and following treatment with the same medications. RESULTS Low EIH rats developed more significant hypersensitivity following CCI. Duloxetine and pregabalin successfully reduced hypersensitivity, although significantly more so in low EIH rats. Diclofenac had limited effects, and only on low EIH rats. Four days of duloxetine administration transformed low EIH rats' profiles to high EIH. CONCLUSIONS The findings of this study suggest that EIH profiles in rats can not only predict the development of hypersensitivity following injury but may also support targeted pharmacological treatment. SIGNIFICANCE Exercise is a known trigger of the inhibitory pain modulation. Rats with deficient analgesic response following exercise develop more significant hypersensitivity following nerve injury. Pain modulation profiles in rats can also support targeted pharmacological treatment; rats with deficient analgesic response following exercise benefit more from treatment with duloxetine and gabapentin. Treatment with duloxetine can improve pain modulation profile.
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Affiliation(s)
- Junad Khan
- Eastman Institute for Oral Health, University of Rochester Medical Center, Rochester, New York, USA
| | - Qian Wang
- Eastman Institute for Oral Health, University of Rochester Medical Center, Rochester, New York, USA
| | | | | | - Yanfang Ren
- Eastman Institute for Oral Health, University of Rochester Medical Center, Rochester, New York, USA
| | - Rafael Benoliel
- Rutgers School of Dental Medicine, Rutgers university, Newark, New Jersey, USA
| | - Eli Eliav
- Eastman Institute for Oral Health, University of Rochester Medical Center, Rochester, New York, USA
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Sumizono M, Yoshizato Y, Yamamoto R, Imai T, Tani A, Nakanishi K, Nakakogawa T, Matsuoka T, Matsuzaki R, Tanaka T, Sakakima H. Mechanisms of Neuropathic Pain and Pain-Relieving Effects of Exercise Therapy in a Rat Neuropathic Pain Model. J Pain Res 2022; 15:1925-1938. [PMID: 35860420 PMCID: PMC9289275 DOI: 10.2147/jpr.s367818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 06/14/2022] [Indexed: 12/04/2022] Open
Abstract
Purpose Pain disrupts the daily and social lives of patients with neuropathic pain. Effective treatment of neuropathic pain is difficult. Pharmacological treatments for neuropathic pain are limited, and 40–60% of patients do not achieve even partial relief of their pain. This study created a chronic constriction injury (CCI) model in rats to examine the effects of regular exercise on neuropathic pain relief, elucidate the mechanism, and determine the effects of neuropathic pain in the hippocampus. Methods CCI model rats were randomly divided into exercise (Ex) and no exercise (No-Ex) groups. Normal rats (Normal group) were used as controls. The Ex group exercised on a treadmill at 20 m/min for 30 min, 5 days per week for 5 weeks post-CCI. The 50% pain response threshold was assessed by mechanical stimulation. Using immunohistochemistry, we examined activation of glial cells (microglia and astrocytes) by CCR2 and TRAF6 expression in the spinal cord dorsal horn and DCX and PROX1 expression in the hippocampal dentate gyrus. Results The 50% pain response threshold was significantly lower in the Ex than in the No-Ex group at 5 weeks post-CCI, indicating pain relief. In the spinal cord dorsal horn, IBA1, CCR2, and TRAF6 expression was markedly lower in the Ex group than in the No-Ex group at 3 weeks post-CCI. IBA1, GFAP, CCR2, and TRAF6 expression was markedly lower in the Ex group than in the No-Ex group at 5 weeks post-CCI. In the hippocampus, DCX, but not PROX1, expression was significantly higher in the Ex group than in the No-Ex group at 3 weeks post-CCI. At 5 weeks post-CCI, both DCX and PROX1 expression was markedly increased in the Ex group compared to the No-Ex group. Conclusion Our findings suggest that regular exercise can improve the neuropathic pain-induced neurogenic dysfunction in the hippocampal dentate gyrus.
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Affiliation(s)
- Megumi Sumizono
- Department of Rehabilitation, Kyushu University of Nursing and Social Welfare, Kumamoto, Japan.,Department of Physical Therapy, School of Health Sciences, Faculty of Medicine, Kagoshima University, Kagoshima, Japan
| | - Yushin Yoshizato
- Department of Rehabilitation, Kyushu University of Nursing and Social Welfare, Kumamoto, Japan
| | - Ryohei Yamamoto
- Department of Rehabilitation, Kyushu University of Nursing and Social Welfare, Kumamoto, Japan
| | - Takaki Imai
- Department of Rehabilitation, Kyushu University of Nursing and Social Welfare, Kumamoto, Japan
| | - Akira Tani
- Department of Physical Therapy, School of Health Sciences, Faculty of Medicine, Kagoshima University, Kagoshima, Japan
| | - Kazuki Nakanishi
- Department of Physical Therapy, School of Health Sciences, Faculty of Medicine, Kagoshima University, Kagoshima, Japan
| | - Tomomi Nakakogawa
- Department of Physical Therapy, School of Health Sciences, Faculty of Medicine, Kagoshima University, Kagoshima, Japan
| | - Teruki Matsuoka
- Department of Physical Therapy, School of Health Sciences, Faculty of Medicine, Kagoshima University, Kagoshima, Japan
| | - Ryoma Matsuzaki
- Department of Physical Therapy, School of Health Sciences, Faculty of Medicine, Kagoshima University, Kagoshima, Japan
| | - Takashi Tanaka
- Department of Rehabilitation, Kumamoto Health Science University, Kumamoto, Japan
| | - Harutoshi Sakakima
- Department of Physical Therapy, School of Health Sciences, Faculty of Medicine, Kagoshima University, Kagoshima, Japan
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Saanijoki T, Kantonen T, Pekkarinen L, Kalliokoski K, Hirvonen J, Malén T, Tuominen L, Tuulari JJ, Arponen E, Nuutila P, Nummenmaa L. Aerobic Fitness Is Associated with Cerebral μ-Opioid Receptor Activation in Healthy Humans. Med Sci Sports Exerc 2022; 54:1076-1084. [PMID: 35195103 DOI: 10.1249/mss.0000000000002895] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
INTRODUCTION Central μ-opioid receptors (MORs) modulate affective responses to physical exercise. Individuals with higher aerobic fitness report greater exercise-induced mood improvements than those with lower fitness, but the link between cardiorespiratory fitness and the MOR system remains unresolved. Here we tested whether maximal oxygen uptake (V̇O2peak) and physical activity level are associated with cerebral MOR availability and whether these phenotypes predict endogenous opioid release after a session of exercise. METHODS We studied 64 healthy lean men who performed a maximal incremental cycling test for V̇O2peak determination, completed a questionnaire assessing moderate-to-vigorous physical activity (MVPA; in minutes per week), and underwent positron emission tomography with [11C]carfentanil, a specific radioligand for MOR. A subset of 24 subjects underwent additional positron emission tomography scan also after a 1-h session of moderate-intensity exercise and 12 of them also after a bout of high-intensity interval training. RESULTS Higher self-reported MVPA level predicted greater opioid release after high-intensity interval training, and both V̇O2peak and MVPA level were associated with a larger decrease in cerebral MOR binding after aerobic exercise in the ventral striatum, orbitofrontal cortex, and insula. That is, more trained individuals showed greater opioid release acutely after exercise in brain regions especially relevant for reward and cognitive processing. Fitness was not associated with MOR availability. CONCLUSIONS We conclude that regular exercise training and higher aerobic fitness may induce neuroadaptation within the MOR system, which might contribute to improved emotional and behavioral responses associated with long-term exercise.
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Affiliation(s)
| | | | | | | | | | - Tuulia Malén
- Turku PET Centre, University of Turku, Turku, FINLAND
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Brum ES, Becker G, Fialho MFP, Oliveira SM. Animal models of fibromyalgia: What is the best choice? Pharmacol Ther 2021; 230:107959. [PMID: 34265360 DOI: 10.1016/j.pharmthera.2021.107959] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Revised: 07/06/2021] [Accepted: 07/07/2021] [Indexed: 12/11/2022]
Abstract
Fibromyalgia (FM) is a complex syndrome, with an indefinite aetiology and intricate pathophysiology that affects 2 - 3% of the world population. From the beginning of the 2000s, experimental animal models have been developed to mimic clinical FM and help obtain a better understanding of the relevant neurobiology. These animal models have enabled a broad study of FM symptoms and mechanisms, as well as new treatment strategies. Current experimental FM models include the reserpine-induced systemic depletion of biogenic amines, muscle application of acid saline, and stress-based (cold, sound, or swim) approaches, among other emerging models. FM models should: (i) mimic the cardinal symptoms and complaints reported by FM patients (e.g., spontaneous nociception, muscle pain, hypersensitivity); (ii) mimic primary comorbidities that can aggravate quality of life and lead to worse outcomes (e.g., fatigue, sleep disturbance, depression, anxiety); (iii) mimic the prevalent pathological mechanisms (e.g., peripheral and central sensitization, inflammation/neuroinflammation, change in the levels of the excitatory and inhibitory neurotransmitters); and (iv) demonstrate a pharmacological profile similar to the clinical treatment of FM. However, it is difficult for any one of these models to include the entire spectrum of clinical FM features once even FM patients are highly heterogeneous. In the past six years (2015 - 2020), a wide range of experimental FM studies has amounted to the literature reinforcing the need for an updated review. Here we have described, in detail, several approaches used to experimentally study FM, with a focus on recent studies in the field and in previously less discussed mechanisms. We highlight each model's challenges, limitations, and future directions, intending to help preclinical researchers establish the correct experimental FM model to use depending on their goals.
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Affiliation(s)
- Evelyne Silva Brum
- Graduate Program in Biological Sciences: Biochemistry Toxicology, Centre of Natural and Exact Sciences, Federal University of Santa Maria, Santa Maria, RS, Brazil
| | - Gabriela Becker
- Graduate Program in Biological Sciences: Biochemistry Toxicology, Centre of Natural and Exact Sciences, Federal University of Santa Maria, Santa Maria, RS, Brazil
| | - Maria Fernanda Pessano Fialho
- Graduate Program in Biological Sciences: Biochemistry Toxicology, Centre of Natural and Exact Sciences, Federal University of Santa Maria, Santa Maria, RS, Brazil
| | - Sara Marchesan Oliveira
- Graduate Program in Biological Sciences: Biochemistry Toxicology, Centre of Natural and Exact Sciences, Federal University of Santa Maria, Santa Maria, RS, Brazil; Department of Biochemistry and Molecular Biology, Centre of Natural and Exact Sciences, Federal University of Santa Maria, Santa Maria, RS, Brazil.
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Khan J, Wang Q, Ren Y, Eliav R, Korczeniewska OA, Benoliel R, Eliav E. Exercise induced hypoalgesia profile in rats is associated with IL-10 and IL-1 β levels and pain severity following nerve injury. Cytokine 2021; 143:155540. [PMID: 33902989 DOI: 10.1016/j.cyto.2021.155540] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 04/05/2021] [Accepted: 04/07/2021] [Indexed: 12/20/2022]
Abstract
BACKGROUND Pain may undergo modulation in the central nervous system prior to reaching the primary somatosensory cortex and being perceived as pain. Faulty pain modulation mechanisms have been linked to various chronic pain conditions. Cytokines such as IL-10 and IL-1beta, are known to be involved in initiation and maintenance of neuropathic pain. In this study, we investigated the association between pain modulation profile, pain intensity and cytokines (IL-10 and IL-1beta) levels in a rat model of neuropathic pain. METHODS Exercise-Induced Hypoalgesia (EIH) was assessed by evaluating the percentage of responses to a train of 60g mechanical stimuli before and after 180 seconds of exercise on a rotating rod. The differences in the response rates before and after the exercise were used to divide the rats into low and high EIH responders. Rats from low and high EIH groups underwent constriction injury of the left sciatic nerve. Pain behavior (allodynia and hyperalgesia) were assessed by measuring responses to mechanical and thermal stimuli applied to the plantar surface of the foot. Serum, sciatic nerve and the related Dorsal Root Ganglia (DRG) levels of IL-10 and IL-1beta were determined by ELISA. The DRG mRNA levels of IL-10 and IL-1beta measured with PCR. A comparison between the low and high EIH rats of all measured parameters was made. RESULTS The low EIH rats developed significantly more severe allodynia and hyperalgesia in the affected paw and allodynia in the contralateral paw compared to the high EIH rats, 7 days following the injury. The low EIH rats had higher IL-1beta protein levels in serum prior to and following injury, higher affected and contralateral sciatic nerve IL-1beta levels following injury and higher IL-1beta levels in the contralateral DRG (protein and mRNA) following injury when compared to high EIH rats. The high EIH rats had higher affected sciatic nerve IL-10 levels following nerve injury and higher IL-10 levels of both protein and mRNA in the affected and contralateral DRG at baseline and following injury. CONCLUSION EIH profile was found to be predictive of pain behavior following nerve injury, low EIH rats developed more severe allodynia and hyperalgesia. IL-1beta may be associated with painful neuropathy developed in rats with low EIH while the anti-inflammatory cytokine IL-10 may have a protective role, inhibiting the development of painful.
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Affiliation(s)
- Junad Khan
- Eastman Institute for Oral Health, University of Rochester, Rochester, NY, USA.
| | - Qian Wang
- Eastman Institute for Oral Health, University of Rochester, Rochester, NY, USA
| | - Yanfang Ren
- Eastman Institute for Oral Health, University of Rochester, Rochester, NY, USA
| | | | | | | | - Eli Eliav
- Eastman Institute for Oral Health, University of Rochester, Rochester, NY, USA
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Kale MB, Bajaj K, Umare M, Wankhede NL, Taksande BG, Umekar MJ, Upaganlawar A. Exercise and Nutraceuticals: Eminent approach for Diabetic Neuropathy. Curr Mol Pharmacol 2021; 15:108-128. [PMID: 34191703 DOI: 10.2174/1874467214666210629123010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 02/28/2021] [Accepted: 03/05/2021] [Indexed: 11/22/2022]
Abstract
Diabetic neuropathy is an incapacitating chronic pathological condition that encompasses a large group of diseases and manifestations of nerve damage. It affects approximately 50% of patients with diabetes mellitus. Autonomic, sensory, and motor neurons are affected. Disabilities are severe, along with poor recovery and diverse pathophysiology. Physical exercise and herbal-based therapies have the potential to decrease the disabilities associated with diabetic neuropathy. Aerobic exercises like walking, weight lifting, the use of nutraceuticals and herbal extracts are found to be effective. Literature from the public domain was studied emphasizing various beneficial effects of different exercises, use of herbal and nutraceuticals for their therapeutic action in diabetic neuropathy. Routine exercises and administration of herbal and nutraceuticals, either the extract of plant material containing the active phytoconstituent or isolated phytoconstituent at safe concentration, have been shown to have promising positive action in the treatment of diabetic neuropathy. Exercise has shown promising effects on vascular and neuronal health and has proven to be well effective in the treatment as well as prevention of diabetic neuropathy by various novel mechanisms, including herbal and nutraceuticals therapy is also beneficial for the condition. They primarily show the anti-oxidant effect, secretagogue, anti-inflammatory, analgesic, and neuroprotective action. Severe adverse events are rare with these therapies. The current review investigates the benefits of exercise and nutraceutical therapies in the treatment of diabetic neuropathy.
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Affiliation(s)
- Mayur Bhimrao Kale
- Shrimati Kishoritai Bhoyar College of Pharmacy, New Kamptee, Nagpur 441002, Maharashtra, India
| | - Komal Bajaj
- Shrimati Kishoritai Bhoyar College of Pharmacy, New Kamptee, Nagpur 441002, Maharashtra, India
| | - Mohit Umare
- Shrimati Kishoritai Bhoyar College of Pharmacy, New Kamptee, Nagpur 441002, Maharashtra, India
| | - Nitu L Wankhede
- Shrimati Kishoritai Bhoyar College of Pharmacy, New Kamptee, Nagpur 441002, Maharashtra, India
| | | | - Milind Janrao Umekar
- Shrimati Kishoritai Bhoyar College of Pharmacy, New Kamptee, Nagpur 441002, Maharashtra, India
| | - Aman Upaganlawar
- SNJB's Shriman Sureshdada Jain College of Pharmacy, Neminagar, Chandwad-42310, Nasik, Maharashtra, India
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Sonza A, Sanada LS, de Oliveira LR, Bernardo-Filho M, de Sá-Caputo DDC, Zaro MA, Achaval M. Whole-body vibration mediates mechanical hypersensitivity through Aβ-fiber and C-fiber thermal sensation in a chronic pain model. Exp Biol Med (Maywood) 2021; 246:1210-1218. [PMID: 33593110 PMCID: PMC8142106 DOI: 10.1177/1535370221991147] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Accepted: 01/08/2021] [Indexed: 01/20/2023] Open
Abstract
Whole-body vibration (WBV), which is widely used as a type of exercise, involves the use of vibratory stimuli and it is used for rehabilitation and sports performance programmes. This study aimed to investigate the effect of WBV treatment in a chronic pain model after 10 WBV sessions. An animal model (chronic pain) was applied in 60 male Wistar rats (±180 g, 12 weeks old) and the animals were treated with low intensity exercise (treadmill), WBV (vibrating platform), and a combined treatment involving both. The controls on the platform were set to a frequency of 42 Hz with 2 mm peak-to-peak displacement, g ≈ 7, in a spiral mode. Before and after the vibration exposure, sensitivity was determined. Aβ-fibers-mediated mechanical sensitivity thresholds (touch-pressure) were measured using a pressure meter. C-fibers-mediated thermal perception thresholds (hot pain) were measured with a hot plate. After each session, WBV influenced the discharge of skin touch-pressure receptors, reducing mechanical sensitivity in the WBV groups (P < 0.05). Comparing the conditions "before vs. after", thermal perception thresholds (hot pain) started to decrease significantly after the third WBV session (P < 0.05). WBV decreases mechanical hyperalgesia after all sessions and thermal sensitivity after the third session with the use of WBV.
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Affiliation(s)
- Anelise Sonza
- Post-graduate Program in Physiotherapy, Centro de Ciências da Saúde e do Esporte (CEFID), Universidade do Estado de Santa Catarina (UDESC), Florianópolis 88080-350, Brazil
- Post-graduate Program in Human Movement Sciences, UDESC, Florianópolis 88080-350, Brazil
- Post-graduate Program in Neurosciences, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre 90050-170, Brazil
| | - Luciana Sayuri Sanada
- Post-graduate Program in Physiotherapy, Centro de Ciências da Saúde e do Esporte (CEFID), Universidade do Estado de Santa Catarina (UDESC), Florianópolis 88080-350, Brazil
| | - Luiza Raulino de Oliveira
- Post-graduate Program in Physiotherapy, Centro de Ciências da Saúde e do Esporte (CEFID), Universidade do Estado de Santa Catarina (UDESC), Florianópolis 88080-350, Brazil
| | - Mario Bernardo-Filho
- Laboratório de Vibrações Mecânicas, Policlínica Piquet Carneiro, Instituto de Biología Roberto Alcantara Gomes, Rio de Janeiro State University (UERJ), Rio de Janeiro 20551-030, Brazil
| | - Danúbia da Cunha de Sá-Caputo
- Laboratório de Vibrações Mecânicas, Policlínica Piquet Carneiro, Instituto de Biología Roberto Alcantara Gomes, Rio de Janeiro State University (UERJ), Rio de Janeiro 20551-030, Brazil
| | - Milton Antonio Zaro
- Post-graduate Program in Neurosciences, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre 90050-170, Brazil
| | - Matilde Achaval
- Post-graduate Program in Neurosciences, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre 90050-170, Brazil
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12
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Abstract
Chronic pain affects approximately one-third of the population worldwide. The primary goal of animal research is to understand the neural mechanisms underlying pain so better treatments can be developed. Despite an enormous investment in time and money, almost no novel treatments for pain have been developed. There are many factors that contribute to this lack of translation in drug development. The mismatch between the goals of drug development in animals (inhibition of pain-evoked responses) and treatment in humans (restoration of function) is a major problem. To solve this problem, a number of pain-depressed behavioral tests have been developed to assess changes in normal behavior in laboratory animals. The use of home cage wheel running as a pain assessment tool is especially useful in that it is easy to use, provides an objective measurement of the magnitude and duration of pain, and is a clinically relevant method to screen novel drugs. Pain depresses activity in humans and animals, and effective analgesic treatments restore activity. Unlike traditional pain-evoked tests (e.g., hot plate, tail flick, von Frey test), restoration of home cage wheel running evaluates treatments for both antinociceptive efficacy and the absence of disruptive side effects (e.g., sedation, paralysis, nausea). This article reviews the literature using wheel running to assess pain and makes the case for home cage wheel running as an effective and clinically relevant method to screen novel analgesics for therapeutic potential.
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Affiliation(s)
- Ram Kandasamy
- Department of Psychology, California State University, East Bay, Hayward, CA, USA
| | - Michael M. Morgan
- Department of Psychology, Washington State University Vancouver, Vancouver, WA, USA
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13
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Running wheel exercise induces therapeutic and preventive effects on inflammatory stimulus-induced persistent hyperalgesia in mice. PLoS One 2020; 15:e0240115. [PMID: 33048957 PMCID: PMC7553300 DOI: 10.1371/journal.pone.0240115] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Accepted: 09/19/2020] [Indexed: 02/07/2023] Open
Abstract
Chronic pain affects significant portion of the world's population and physical exercise has been extensively indicated as non-pharmacological clinical intervention to relieve symptoms in chronic pain conditions. In general, studies on pain chronification and physical exercise intervention have focused on neuropathic pain, although chronic pain commonly results from an original inflammatory episode. Based on this, the objective of the present study was to investigate the therapeutic and preventive effect of the running wheel exercise on the persistent hyperalgesia induced by repetitive inflammatory stimulus, a rodent model that simulates clinical conditions of chronic pain that persist even with no more inflammatory stimulus present. To evaluate the therapeutic effect of physical exercise, we first induced persistent hyperalgesia through 14 days of PGE2 hind paw injections and, after that, mice have access to the regular voluntary running wheel. To evaluate the preventive effect of physical exercise, we first left the mice with access to the regular voluntary running wheel and, after that, we performed 14 days of PGE2 hind paw injection. Our results showed that voluntary running wheel exercise reduced persistent mechanical and chemical hyperalgesia intensity induced by repetitive inflammatory stimulus. In addition, we showed that this therapeutic effect is long-lasting and is observed even if started belatedly, i.e. two weeks after the development of hyperalgesia. Also, our results showed that voluntary running wheel exercise absolutely prevented persistent mechanical and chemical hyperalgesia induction. We can conclude that physical exercise has therapeutic and preventive effect on inflammatory stimulus-induced persistent hyperalgesia. Our data from animal experiments bypass placebo effects bias of the human studies and reinforce physical exercise clinical recommendations to treat and prevent chronic pain.
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Lesnak JB, Sluka KA. Mechanism of exercise-induced analgesia: what we can learn from physically active animals. Pain Rep 2020; 5:e850. [PMID: 33490844 PMCID: PMC7808683 DOI: 10.1097/pr9.0000000000000850] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Revised: 05/26/2020] [Accepted: 07/31/2020] [Indexed: 12/29/2022] Open
Abstract
Physical activity has become a first-line treatment in rehabilitation settings for individuals with chronic pain. However, research has only recently begun to elucidate the mechanisms of exercise-induced analgesia. Through the study of animal models, exercise has been shown to induce changes in the brain, spinal cord, immune system, and at the site of injury to prevent and reduce pain. Animal models have also explored beneficial effects of exercise through different modes of exercise including running, swimming, and resistance training. This review will discuss the central and peripheral mechanisms of exercise-induced analgesia through different modes, intensity, and duration of exercise as well as clinical applications of exercise with suggestions for future research directions.
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Affiliation(s)
- Joseph B. Lesnak
- Department of Physical Therapy and Rehabilitation Sciences, University of Iowa, Iowa City, IA, USA
| | - Kathleen A. Sluka
- Department of Physical Therapy and Rehabilitation Sciences, University of Iowa, Iowa City, IA, USA
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15
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Medeiros LF, Nunes ÉA, Lopes BC, de Souza A, Cappellari AR, de Freitas JS, de Macedo IC, Kuo J, Cioato SG, Battastini AMDO, Caumo W, Torres ILS. Single exercise stress reduces central neurotrophins levels and adenosine A 1 and A 2 receptors expression, but does not revert opioid-induced hyperalgesia in rats. Int J Dev Neurosci 2020; 80:636-647. [PMID: 32798310 DOI: 10.1002/jdn.10059] [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: 05/01/2020] [Revised: 08/06/2020] [Accepted: 08/07/2020] [Indexed: 11/07/2022] Open
Abstract
BACKGROUND This study assessed the effects of an acute stress model upon the long-term hyperalgesia induced by repeated morphine administration in neonatal rats. We also evaluated neurotrophins and cytokines levels; expressions of adenosine and acetylcholine receptors, and acetylcholinesterase enzyme at the spinal cord. MATERIAL AND METHODS Male Wistar rats were subjected to morphine or saline administration from P8 to P14. Thermal hyperalgesia and mechanical hyperesthesia were assessed using the hot plate (HP) and von Frey (vF) tests, respectively, at postnatal day P30 and P60. After baseline measurements, rats were subjected to a single exercise session, as an acute stress model, at P30 or P60. We measured the levels of BDNF and NGF, interleukin-6, and IL-10 in the cerebral cortex and the brainstem; and the expression levels of adenosine and muscarinic receptors, as well as acetylcholinesterase (AChE) enzyme at the spinal cord. RESULTS A stress exercise session was not able to revert the morphine-induced hyperalgesia. The morphine and exercise association in rats induced a decrease in the neurotrophins brainstem levels, and A1 , A2A , A2B receptors expression in the spinal cord, and an increase in the IL-6 cortical levels. The exercise reduced M2 receptors expression in the spinal cord of naive rats, while morphine prevented this effect. CONCLUSIONS Single session of exercise does not revert hyperalgesia induced by morphine in rats; however, morphine plus exercise modulate neurotrophins, IL-6 central levels, and expression of adenosine receptors.
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Affiliation(s)
- Liciane Fernandes Medeiros
- Laboratório de Farmacologia da Dor e Neuromodulação: Investigações Pré-clínicas, Centro de Pesquisa Experimental (CPE), Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil.,Programa de Pós-Graduação em Saúde e Desenvolvimento Humano, Universidade La Salle, Canoas, Brazil
| | - Éllen Almeida Nunes
- Laboratório de Farmacologia da Dor e Neuromodulação: Investigações Pré-clínicas, Centro de Pesquisa Experimental (CPE), Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil.,Programa de Pós-Graduação em Ciências Biológicas: Fisiologia, Instituto de Ciências Básicas da Saúde (ICBS), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
| | - Bettega Costa Lopes
- Laboratório de Farmacologia da Dor e Neuromodulação: Investigações Pré-clínicas, Centro de Pesquisa Experimental (CPE), Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil.,Programa de Pós-Graduação em Ciências Biológicas: Fisiologia, Instituto de Ciências Básicas da Saúde (ICBS), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
| | - Andressa de Souza
- Laboratório de Farmacologia da Dor e Neuromodulação: Investigações Pré-clínicas, Centro de Pesquisa Experimental (CPE), Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil.,Programa de Pós-Graduação em Saúde e Desenvolvimento Humano, Universidade La Salle, Canoas, Brazil.,Programa de Pós-Graduação em Medicina: Ciências Médicas, Faculdade de Medicina, UFRGS, Porto Alegre, Brazil
| | - Angélica Regina Cappellari
- Programa de Pós-Graduação em Biologia Celular e Molecular, Escola de Ciências da Saúde e da Vida, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
| | - Joice Soares de Freitas
- Laboratório de Farmacologia da Dor e Neuromodulação: Investigações Pré-clínicas, Centro de Pesquisa Experimental (CPE), Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil
| | - Isabel Cristina de Macedo
- Laboratório de Farmacologia da Dor e Neuromodulação: Investigações Pré-clínicas, Centro de Pesquisa Experimental (CPE), Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil
| | - Jonnsin Kuo
- Laboratório de Farmacologia da Dor e Neuromodulação: Investigações Pré-clínicas, Centro de Pesquisa Experimental (CPE), Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil
| | - Stefania Giotti Cioato
- Laboratório de Farmacologia da Dor e Neuromodulação: Investigações Pré-clínicas, Centro de Pesquisa Experimental (CPE), Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil
| | | | - Wolnei Caumo
- Programa de Pós-Graduação em Medicina: Ciências Médicas, Faculdade de Medicina, UFRGS, Porto Alegre, Brazil
| | - Iraci L S Torres
- Laboratório de Farmacologia da Dor e Neuromodulação: Investigações Pré-clínicas, Centro de Pesquisa Experimental (CPE), Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil.,Programa de Pós-Graduação em Ciências Biológicas: Fisiologia, Instituto de Ciências Básicas da Saúde (ICBS), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.,Programa de Pós-Graduação em Medicina: Ciências Médicas, Faculdade de Medicina, UFRGS, Porto Alegre, Brazil
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16
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Sex Difference in Trigeminal Neuropathic Pain Response to Exercise: Role of Oxidative Stress. Pain Res Manag 2020; 2020:3939757. [PMID: 32676135 PMCID: PMC7341438 DOI: 10.1155/2020/3939757] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Revised: 05/17/2020] [Accepted: 06/08/2020] [Indexed: 11/17/2022]
Abstract
Aim Orofacial chronic neuropathic pain commonly occurs following trigeminal nerve injuries. We investigated whether swimming exercise can reduce trigeminal neuropathic pain through improving antioxidant capacity. Materials and Methods Twenty-eight Wistar rats of either sex and 180–220 grams were divided into 4 groups as sham, neuropathy, neuropathy + single bout exercise, and neuropathy + 2 weeks of exercise. Trigeminal neuropathy was carried out through chronic constriction injury (CCI) of infraorbital nerve. Protocols of exercise were included a single bout session (45 minutes) and a 2-week (45 minutes/day/6 days a week) swimming exercise. Mechanical allodynia was detected using Von Frey filaments. The activity of the serum antioxidant enzymes glutathione peroxidase and superoxides dismutase was assayed using ELISA kits. Results We found that CCI significantly reduced facial pain threshold in both sexes (P < 0.05). Both swimming exercise protocols significantly reduced mechanical allodynia in female rats compared to the sham group; however, only 2 weeks of exercise were significantly effective in male rats. The activity of antioxidant enzyme glutathione peroxidase significantly (P < 0.05) decreased following CCI in female rats against that in the sham group and 2-week exercise significantly (P < 0.05) increased it toward the control level. The levels of glutathione peroxidase in male rats and superoxidase dismutase in both sexes were not significantly different compared to their sham groups. Conclusion Swimming exercise alleviates trigeminal neuropathic pain in both sexes. Oxidative stress as a possible mechanism was involved in the effect of exercise on female rat trigeminal neuropathy.
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Swimming Physical Training Prevented the Onset of Acute Muscle Pain by a Mechanism Dependent of PPARγ Receptors and CINC-1. Neuroscience 2020; 427:64-74. [DOI: 10.1016/j.neuroscience.2019.12.017] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Revised: 12/08/2019] [Accepted: 12/09/2019] [Indexed: 12/17/2022]
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Developing Improved Translational Models of Pain: A Role for the Behavioral Scientist. Perspect Behav Sci 2020; 43:39-55. [PMID: 32440644 DOI: 10.1007/s40614-019-00239-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
The effective management of pain is a longstanding public health concern. Although opioids have been frontline analgesics for decades, they also have well-known undesirable effects that limit their clinical utility, such as abuse liability and respiratory depression. The failure to develop better analgesics has, in some ways, contributed to the escalating opioid epidemic that has claimed tens of thousands of lives and has cost hundreds of billions of dollars in health-care expenses. A paradigm shift is needed in the pharmacotherapy of pain management that will require extensive efforts throughout biomedical science. The purpose of the present review is to highlight the critical role of the behavioral scientist to devise improved translational models of pain for drug development. Despite high heterogeneity of painful conditions that involve cortical-dependent pain processing, current models often feature an overreliance on simple reflex-based measures and an emphasis on the absence, rather than presence, of behavior as evidence of analgesic efficacy. Novel approaches should focus on the restoration of operant and other CNS-mediated behavior under painful conditions.
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Pagliusi M, Bonet I, Brandão A, Magalhães S, Tambeli C, Parada C, Sartori C. Therapeutic and Preventive Effect of Voluntary Running Wheel Exercise on Social Defeat Stress (SDS)-induced Depressive-like Behavior and Chronic Pain in Mice. Neuroscience 2020; 428:165-177. [DOI: 10.1016/j.neuroscience.2019.12.037] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Revised: 11/29/2019] [Accepted: 12/23/2019] [Indexed: 01/21/2023]
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Slivicki RA, Mali SS, Hohmann AG. Voluntary exercise reduces both chemotherapy-induced neuropathic nociception and deficits in hippocampal cellular proliferation in a mouse model of paclitaxel-induced peripheral neuropathy. NEUROBIOLOGY OF PAIN 2019; 6:100035. [PMID: 31528755 PMCID: PMC6739464 DOI: 10.1016/j.ynpai.2019.100035] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Revised: 08/21/2019] [Accepted: 08/25/2019] [Indexed: 12/18/2022]
Abstract
Paclitaxel treatment did not alter voluntary running activity. Voluntary running reduced mechanical and cold allodynia induced by paclitaxel. Voluntary running reduced paclitaxel-induced deficits in hippocampal cellular proliferation. Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting side-effect of all major chemotherapeutic agents. Here, we explored efficacy of voluntary exercise as a nonpharmacological strategy for suppressing two distinct adverse side effects of chemotherapy treatment. We evaluated whether voluntary running would suppress both neuropathic pain and deficits in hippocampal cell proliferation in a mouse model of CIPN induced by the taxane chemotherapeutic agent paclitaxel. Mice were given free access to running wheels or were housed without running wheels during one of three different intervention phases: 1) during the onset (i.e. development phase) of paclitaxel-induced neuropathy, 2) prior to dosing with paclitaxel or its vehicle, or 3) following the establishment (i.e. maintenance phase) of paclitaxel-induced neuropathy. Paclitaxel treatment did not alter running wheel behavior relative to vehicle-treated animals in any study. Animals that engaged in voluntary running during the development phase of paclitaxel-induced neuropathy failed to display mechanical or cold hypersensitivities relative to sedentary control animals that did not have access to running wheels. A prior history of voluntary running delayed the onset of, but did not fully prevent, development of paclitaxel-induced neuropathic pain behavior. Voluntary running reduced already established mechanical and cold allodynia induced by paclitaxel. Importantly, voluntary running did not alter mechanical or cold responsivity in vehicle-treated animals, suggesting that the observed antinociceptive effect of exercise was dependent upon the presence of the pathological pain state. In the same animals evaluated for nociceptive responding, paclitaxel also reduced cellular proliferation but not cellular survival in the dentate gyrus of the hippocampus, as measured by immunohistochemistry for Ki67 and BrdU expression, respectively. Voluntary running abrogated paclitaxel-induced reductions in cellular proliferation to levels observed in vehicle-treated mice and also increased BrdU expression levels irrespective of chemotherapy treatment. Our studies support the hypothesis that voluntary exercise may be beneficial in suppressing both neuropathic pain and markers of hippocampal cellular function that are impacted by toxic challenge with chemotherapeutic agents.
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Affiliation(s)
- Richard A. Slivicki
- Program in Neuroscience, Indiana University, Bloomington, IN, United States
- Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, United States
| | - Sonali S. Mali
- Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, United States
| | - Andrea G. Hohmann
- Program in Neuroscience, Indiana University, Bloomington, IN, United States
- Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, United States
- Gill Center for Biomolecular Science, Indiana University, Bloomington, IN, United States
- Corresponding author at: Department of Psychological and Brain Sciences, Indiana University, 1101 E 10th Street, Bloomington, IN 47405-7007, United States.
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21
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OHLMAN THOMAS, MILLER LEAH, NAUGLE KEITHE, NAUGLE KELLYM. Physical Activity Levels Predict Exercise-induced Hypoalgesia in Older Adults. Med Sci Sports Exerc 2018; 50:2101-2109. [DOI: 10.1249/mss.0000000000001661] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
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22
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Abstract
PURPOSE OF REVIEW Physical activity is increasingly recommended for chronic pain. In this review, we briefly survey recent, high-quality meta-analyses on the effects of exercise in human chronic pain populations, followed by a critical discussion of the rodent literature. RECENT FINDINGS Most meta-analytical studies on the effects of exercise in human chronic pain populations describe moderate improvements in various types of chronic pain, despite substantial variability in the outcomes reported in the primary literature. The most consistent findings suggest that while greater adherence to exercise programs produces better outcomes, there is minimal support for the superiority of one type of exercise over another. The rodent literature similarly suggests that while regular exercise reduces hypersensitivity in rodent models of chronic pain, exercise benefits do not appear to relate to either the type of injury or any particular facet of the exercise paradigm. Potential factors underlying these results are discussed, including the putative involvement of stress-induced analgesic effects associated with certain types of exercise paradigms. Exercise research using rodent models of chronic pain would benefit from increased attention to the role of stress in exercise-induced analgesia, as well as the incorporation of more clinically relevant exercise paradigms.
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Affiliation(s)
- Mark Henry Pitcher
- Pain and Integrative Neuroscience Laboratory, National Center for Complementary and Integrative Health, National Institutes of Health, Room 1E-420, 35A Convent Drive, Bethesda, MD, 20892, USA.
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Ye H, Du X, Hua Q. Effects of voluntary exercise on antiretroviral therapy-induced neuropathic pain in mice. J Physiol Sci 2018; 68:521-530. [PMID: 28975573 PMCID: PMC10717227 DOI: 10.1007/s12576-017-0570-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2017] [Accepted: 09/19/2017] [Indexed: 12/12/2022]
Abstract
Antiretroviral therapy (ART) often results in painful peripheral neuropathy. Given that voluntary exercise has been shown to be beneficial in terms of modulating pain-like behaviors in various animal models of peripheral neuropathy, we have investigated the effects of voluntary wheel running on neuropathic pain induced by chronic ART. We first established an animal model of peripheral neuropathy induced by chronic 2',3'-dideoxycytidine (ddC) treatment. We showed that mice receiving ddC (3 mg/kg/day) had increased mechanical and thermal sensitivity at 9 weeks after the onset of the treatment. We also found that voluntary wheel running attenuated or delayed the onset of ddC-induced peripheral neuropathy. This phenomenon was associated with the attenuation of dorsal root ganglion nociceptive neuron membrane excitability and reduction in the expression of the transient receptor potential cation channel subfamily V member 1 (TRPV1). Taken together, these results suggest that voluntary exercise is an effective strategy by which ART-induced peripheral neuropathy can be alleviated.
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Affiliation(s)
- Hong Ye
- Department of Anesthesiology, Daqing Oil Field General Hospital, No. 9 Saertu District, Daqing, 163000, Heilongjiang, China
| | - Xingguang Du
- Department of Anesthesiology, Daqing Oil Field General Hospital, No. 9 Saertu District, Daqing, 163000, Heilongjiang, China
| | - Qingli Hua
- Department of Anesthesiology, Daqing Longnan Hospital, No. 35 Patriotic Road, Ranghulu District, Daqing, 163000, Heilongjiang, China.
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24
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Ahmadi S, Radahmadi M, Alaei H, Ramshini E. Effect of Aerobic Exercise on Morphine Self-administration and Pain Modulation in Rats. Adv Biomed Res 2018; 7:70. [PMID: 29862219 PMCID: PMC5952535 DOI: 10.4103/abr.abr_181_17] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
Background: Exercise reverses retention deficit induced by morphine. The present study investigated the effect of aerobic exercise on tolerance to morphine usage and pain modulation. Materials and Methods: Male Wistar rats were divided into four groups as follows: (1) saline group (S), (2) morphine group (M), (3) saline + exercise (S + E), and (4) morphine + exercise group (M + E). The rats were initially trained to receive small pellets of food by pressing an active lever in the self-administration apparatus. The tail-flick and hot-plate tests were used for pain assessment. To perform the experiment, the jugular vein was exposed and cannulated. After recovery, the animals were placed in the self-administration apparatus and allowed to self-administer morphine in 2 h sessions over 11 consecutive days. Results: The morphine group was found to record a higher number of active lever pressings than did the saline one while this parameter decreased in the morphine + exercise group compared with the morphine one. Moreover, the morphine + exercise exhibited lowered pain sensitivity as evidenced to have reduced morphine use in the hot plate test. Conclusion: The exercise might be suggested to reduce using of morphine and modulate pain probably through the release of endogenous opioid.
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Affiliation(s)
- Somayeh Ahmadi
- Department of Physiology, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Maryam Radahmadi
- Department of Physiology, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Hojjatallah Alaei
- Department of Physiology, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Effat Ramshini
- Department of Physiology, Kerman University of Medical Sciences, Kerman, Iran
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Raoof M, Shakoori A, Kooshki R, Abbasnejad M, Amanpour S. The effects of regular exercise on capsaicin-induced pulpal pain and pain-induced changes in passive avoidance learning and memory in rats. Korean J Pain 2017; 30:258-264. [PMID: 29123620 PMCID: PMC5665737 DOI: 10.3344/kjp.2017.30.4.258] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2017] [Revised: 07/25/2017] [Accepted: 07/27/2017] [Indexed: 11/07/2022] Open
Abstract
Background Pulpal pain is one of the most common and severe orofacial pain conditions with considerable adverse effects on physiological processes including learning and memory. Regular exercise is known to be effective on cognitive function as well as pain processing in the central nervous system. Here, the possible effects of regular exercise on pulpal pain response as well as pain-induced changes in learning and memory efficiency in rats were investigated. Methods Twenty-four male Wistar rats were randomly assigned to the control, capsaicin, exercise, and exercise plus capsaicin groups. Rats in exercise groups were forced to run on a treadmill with a moderate exercise protocol for 4 weeks. Capsaicin was used to induce dental pulp pain. Passive avoidance learning and memory performance was assessed by using a shuttle box apparatus. Results According to the results, regular exercise could decrease the time course of capsaicin-induced pulpal pain (P < 0.001). Moreover, in capsaicin-treated rats, passive avoidance acquisition was impaired as compared to the control (P < 0.05) and exercise (P < 0.001) groups. Additionally, regular exercise before capsaicin injection could attenuate capsaicin-induced memory impairments (P < 0.05). Conclusions Taken together, the present data showed that regular exercise has inhibitory effects on capsaicin-induced pulpal pain as well as pain-induced cognitive dysfunction in rats.
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Affiliation(s)
- Maryam Raoof
- Endodontology Research Center, Kerman University of Medical Sciences, Kerman, Iran.,Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Afshin Shakoori
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Razieh Kooshki
- Department of Biology, Faculty of Sciences, Shahid Bahonar University of Kerman, Iran
| | - Mehdi Abbasnejad
- Department of Biology, Faculty of Sciences, Shahid Bahonar University of Kerman, Iran
| | - Sara Amanpour
- Oral and Dental Diseases Research Center, Kerman University of Medical Sciences, Kerman, Iran.,Kerman Social Determinants on Oral Health Research Center, Kerman University of Medical Sciences, Kerman, Iran
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Lima LV, DeSantana JM, Rasmussen LA, Sluka KA. Short-duration physical activity prevents the development of activity-induced hyperalgesia through opioid and serotoninergic mechanisms. Pain 2017; 158:1697-1710. [PMID: 28621702 PMCID: PMC5561491 DOI: 10.1097/j.pain.0000000000000967] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Regular physical activity prevents the development of chronic muscle pain through the modulation of central mechanisms that involve rostral ventromedial medulla (RVM). We tested if pharmacological blockade or genetic deletion of mu-opioid receptors in physically active mice modulates excitatory and inhibitory systems in the RVM in an activity-induced hyperalgesia model. We examined response frequency to mechanical stimulation of the paw, muscle withdrawal thresholds, and expression of phosphorylation of the NR1 subunit of the N-methyl-D-aspartate receptor (p-NR1) and serotonin transporter (SERT) in the RVM. Mice that had performed 5 days of voluntary wheel running prior to the induction of the model were compared with sedentary mice. Sedentary mice showed significant increases in mechanical paw withdrawal frequency and a reduction in muscle withdrawal threshold; wheel running prevented the increase in paw withdrawal frequency. Naloxone-treated and MOR mice had increases in withdrawal frequency that were significantly greater than that in physically active control mice and similar to sedentary mice. Immunohistochemistry in the RVM showed increases in p-NR1 and SERT expression in sedentary mice 24 hours after the induction of the model. Wheel running prevented the increase in SERT, but not p-NR1. Physically active, naloxone-treated, and MOR mice showed significant increases in SERT immunoreactivity when compared with wild-type physically active control mice. Blockade of SERT in the RVM in sedentary mice reversed the activity-induced hyperalgesia of the paw and muscle. These results suggest that analgesia induced by 5 days of wheel running is mediated by mu-opioid receptors through the modulation of SERT, but not p-NR1, in RVM.
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MESH Headings
- Animals
- Disease Models, Animal
- Female
- Gene Expression Regulation/physiology
- Hyperalgesia/etiology
- Hyperalgesia/prevention & control
- Male
- Medulla Oblongata/metabolism
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Nerve Tissue Proteins/metabolism
- Pain Measurement
- Pain Threshold/physiology
- Physical Conditioning, Animal/methods
- Physical Stimulation/adverse effects
- Receptors, N-Methyl-D-Aspartate/metabolism
- Receptors, Opioid, mu/genetics
- Receptors, Opioid, mu/metabolism
- Serotonin Plasma Membrane Transport Proteins/metabolism
- Statistics, Nonparametric
- Time Factors
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Affiliation(s)
- Lucas V Lima
- Department of Physical Therapy and Rehabilitation Science, University of Iowa, Iowa City, IA, USA
- Graduate Program in Health Sciences, Federal University of Sergipe, Aracaju/Se, Brazil
| | - Josimari M DeSantana
- Graduate Program in Health Sciences, Federal University of Sergipe, Aracaju/Se, Brazil
- Department of Physical Therapy, Federal University of Sergipe, Aracaju/Se, Brazil
| | - Lynn A Rasmussen
- Department of Physical Therapy and Rehabilitation Science, University of Iowa, Iowa City, IA, USA
| | - Kathleen A Sluka
- Department of Physical Therapy and Rehabilitation Science, University of Iowa, Iowa City, IA, USA
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Regular physical activity prevents development of chronic muscle pain through modulation of supraspinal opioid and serotonergic mechanisms. Pain Rep 2017; 2:e618. [PMID: 29392233 PMCID: PMC5777681 DOI: 10.1097/pr9.0000000000000618] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2016] [Revised: 07/06/2017] [Accepted: 07/07/2017] [Indexed: 11/26/2022] Open
Abstract
The current study shows that blockade of opioid receptors systemically in the periaqueductal gray and the rostral ventromedial medulla prevents analgesia by 8 weeks of wheel running in a chronic muscle pain model. We further show increases in serotonin transporter expression and reversal of hyperalgesia with a selective reuptake inhibitor in the rostral ventromedial medulla in the chronic muscle pain model, and exercise normalizes serotonin transporter expression. Introduction: It is generally believed that exercise produces its effects by activating central opioid receptors; there are little data that support this claim. The periaqueductal gray (PAG) and rostral ventromedial medulla (RVM) are key nuclei in opioid-induced analgesia, and opioids interact with serotonin to produce analgesia. Objectives: The purpose was to examine central inhibitory mechanisms involved in analgesia produced by wheel running. Methods: C57/Black6 mice were given access to running wheels in their home cages before induction of chronic muscle hyperalgesia and compared with those without running wheels. Systemic, intra-PAG, and intra-RVM naloxone tested the role of central opioid receptors in the antinociceptive effects of wheel running in animals with muscle insult. Immunohistochemistry for the serotonin transporter (SERT) in the spinal cord and RVM, and pharmacological blockade of SERT, tested whether the serotonin system was modulated by muscle insult and wheel running. Results: Wheel running prevented the development of muscle hyperalgesia. Systemic naloxone, intra-PAG naloxone, and intra-RVM naloxone reversed the antinociceptive effect of wheel running in animals that had received muscle insult. Induction of chronic muscle hyperalgesia increased SERT in the RVM, and blockade of SERT reversed the hyperalgesia in sedentary animals. Wheel running reduced SERT expression in animals with muscle insult. The serotonin transporter in the superficial dorsal horn of the spinal cord was unchanged after muscle insult, but increased after wheel running. Conclusion: These data support the hypothesis that wheel running produced analgesia through central inhibitory mechanisms involving opioidergic and serotonergic systems.
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Allen J, Imbert I, Havelin J, Henderson T, Stevenson G, Liaw L, King T. Effects of Treadmill Exercise on Advanced Osteoarthritis Pain in Rats. Arthritis Rheumatol 2017; 69:1407-1417. [PMID: 28320059 PMCID: PMC5489381 DOI: 10.1002/art.40101] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Accepted: 03/14/2017] [Indexed: 12/22/2022]
Abstract
OBJECTIVE Exercise is commonly recommended for patients with osteoarthritis (OA) pain. However, whether exercise is beneficial in ameliorating ongoing pain that is persistent, resistant to nonsteroidal antiinflammatory drugs (NSAIDs), and associated with advanced OA is unknown. METHODS Rats treated with intraarticular (IA) monosodium iodoacetate (MIA) or saline underwent treadmill exercise or remained sedentary starting 10 days postinjection. Tactile sensory thresholds and weight bearing were assessed, followed by radiography at weekly intervals. After 4 weeks of exercise, ongoing pain was assessed using conditioned place preference (CPP) to IA or rostral ventromedial medulla (RVM)-administered lidocaine. The possible role of endogenous opioids in exercise-induced pain relief was examined by systemic administration of naloxone. Knee joints were collected for micro-computed tomography (micro-CT) analysis to examine pathologic changes to subchondral bone and metaphysis of the tibia. RESULTS Treadmill exercise for 4 weeks reversed MIA-induced tactile hypersensitivity and weight asymmetry. Both IA and RVM lidocaine D35, administered post-MIA, induced CPP in sedentary but not exercised MIA-treated rats, indicating that exercise blocks MIA-induced ongoing pain. Naloxone reestablished weight asymmetry in MIA-treated rats undergoing exercise and induced conditioned place aversion, indicating that exercise-induced pain relief is dependent on endogenous opioids. Exercise did not alter radiographic evidence of OA. However, micro-CT analysis indicated that exercise did not block lateral subchondral bone loss or trabecular bone loss in the metaphysis, but did block MIA-induced medial bone loss. CONCLUSION These findings support the conclusion that exercise induces pain relief in advanced, NSAID-resistant OA, likely through increased endogenous opioid signaling. In addition, treadmill exercise blocked MIA-induced bone loss in this model, indicating a potential bone-stabilizing effect of exercise on the OA joint.
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MESH Headings
- Anesthetics, Local/pharmacology
- Animals
- Arthralgia/physiopathology
- Arthritis, Experimental/chemically induced
- Arthritis, Experimental/diagnostic imaging
- Arthritis, Experimental/physiopathology
- Behavior, Animal/drug effects
- Disease Models, Animal
- Enzyme Inhibitors/toxicity
- Hyperalgesia/chemically induced
- Hyperalgesia/physiopathology
- Injections, Intra-Articular
- Iodoacetic Acid/toxicity
- Knee Joint/diagnostic imaging
- Knee Joint/drug effects
- Knee Joint/physiopathology
- Lidocaine/pharmacology
- Male
- Medulla Oblongata
- Naloxone/pharmacology
- Narcotic Antagonists/pharmacology
- Osteoarthritis, Knee/chemically induced
- Osteoarthritis, Knee/diagnostic imaging
- Osteoarthritis, Knee/physiopathology
- Physical Conditioning, Animal
- Rats
- Rats, Sprague-Dawley
- Tibia/diagnostic imaging
- Weight-Bearing
- X-Ray Microtomography
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Affiliation(s)
- Joshua Allen
- Department of Biomedical Sciences, College of Osteopathic Medicine, University of New England, Biddeford ME
| | - Ian Imbert
- Department of Biomedical Sciences, College of Osteopathic Medicine, University of New England, Biddeford ME
| | - Joshua Havelin
- Department of Biomedical Sciences, College of Osteopathic Medicine, University of New England, Biddeford ME
| | - Terry Henderson
- Center for Molecular Medicine, Maine Medical Center Research Institute, 81 Research Drive, Scarborough, ME 04074, USA
| | - Glenn Stevenson
- Department of Psychology, College of Arts and Sciences, University of New England, Biddeford ME
- Center for Excellence in the Neurosciences, University of New England, Biddeford ME
| | - Lucy Liaw
- Center for Molecular Medicine, Maine Medical Center Research Institute, 81 Research Drive, Scarborough, ME 04074, USA
| | - Tamara King
- Department of Biomedical Sciences, College of Osteopathic Medicine, University of New England, Biddeford ME
- Center for Excellence in the Neurosciences, University of New England, Biddeford ME
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Lima LV, Abner TSS, Sluka KA. Does exercise increase or decrease pain? Central mechanisms underlying these two phenomena. J Physiol 2017; 595:4141-4150. [PMID: 28369946 PMCID: PMC5491894 DOI: 10.1113/jp273355] [Citation(s) in RCA: 237] [Impact Index Per Article: 29.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2016] [Accepted: 03/07/2017] [Indexed: 01/13/2023] Open
Abstract
Exercise is an integral part of the rehabilitation of patients suffering a variety of chronic musculoskeletal conditions, such as fibromyalgia, chronic low back pain and myofascial pain. Regular physical activity is recommended for treatment of chronic pain and its effectiveness has been established in clinical trials for people with a variety of pain conditions. However, exercise can also increase pain making participation in rehabilitation challenging for the person with pain. Animal models of exercise-induced pain have been developed and point to central mechanisms underlying this phenomena, such as increased activation of NMDA receptors in pain-modulating areas. Meanwhile, a variety of basic science studies testing different exercise protocols, show exercise-induced analgesia involves activation of central inhibitory pathways. Opioid, serotonin and NMDA mechanisms acting in rostral ventromedial medulla promote analgesia associated with exercise. This review explores and discusses current evidence on central mechanisms underlying exercised-induced pain and analgesia.
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Affiliation(s)
- Lucas V. Lima
- Department of Physical Therapy and Rehabilitation Science, Pain Research ProgramUniversity of IowaIowa CityIA52242USA
| | - Thiago S. S. Abner
- Department of Physical Therapy and Rehabilitation Science, Pain Research ProgramUniversity of IowaIowa CityIA52242USA
| | - Kathleen A. Sluka
- Department of Physical Therapy and Rehabilitation Science, Pain Research ProgramUniversity of IowaIowa CityIA52242USA
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Safakhah HA, Moradi Kor N, Bazargani A, Bandegi AR, Gholami Pourbadie H, Khoshkholgh-Sima B, Ghanbari A. Forced exercise attenuates neuropathic pain in chronic constriction injury of male rat: an investigation of oxidative stress and inflammation. J Pain Res 2017; 10:1457-1466. [PMID: 28721088 PMCID: PMC5499951 DOI: 10.2147/jpr.s135081] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND AND OBJECTIVE Initial peripheral/central nerve injuries, such as chronic constriction injury (CCI)/spinal cord injury, are often compounded by secondary mechanisms, including inflammation and oxidative stress, which may lead to chronic neuropathic pain characterized by hyperalgesia or allodynia. On the other hand, exercise as a behavioral and non-pharmacological treatment has been shown to alleviate chronic neuropathic pain. Therefore, this study was conducted to examine whether or not exercise reduces neuropathic pain through modifying oxidative stress and inflammation in chronic constriction injury of the sciatic nerve. MATERIALS AND METHODS Wistar male rats weighing 200±20 g were randomly divided into five groups (normal, sham, CCI, pre-CCI exercise, and post-CCI exercise group). Sciatic nerve of anesthetized rats was loosely ligated to induce CCI, and they were then housed in separate cages. The rats ran on treadmill at a moderate speed for 3 weeks. Mechanical allodynia and thermal hyperalgesia were determined using von Frey filament and plantar test, respectively. Tumor necrosis factor-alpha (TNF-α) assayed in the cerebrospinal fluid, malondialdehyde, and total antioxidant capacity were measured in the serum using Western blot test, thiobarbituric acid, and ferric reducing ability of plasma (FRAP), respectively. RESULTS The mechanical allodynia (P=0.024) and thermal hyperalgesia (P=0.002) in the CCI group were higher than those in the sham group. Exercise after CCI reduced (P=0.004) mechanical allodynia and thermal hyperalgesia (P=0.025) compared with the CCI group. Moreover, the level of FRAP in the CCI group was (P=0.001) lower than that in the sham group, and post-CCI exercise reversed FRAP amount toward the control level (P=0.019). The amount of malondialdehyde did not differ between groups. Level of TNF-α increased in the CCI group (P=0.0002) compared with sham group and post-CCI exercise could reverse it toward the level of control (P=0.005). CONCLUSION Post CCI-exercise but not pre CCI-exercise reduces CCI-induced neuropathic pain. One of the possible involved mechanisms is increasing the total antioxidant capacity and reducing the amount of TNF-α.
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Affiliation(s)
- Hossein Ali Safakhah
- Department of Physiology, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran.,Research Center of Physiology, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Nasroallah Moradi Kor
- Research Center of Physiology, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran.,Student Research Committee, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Atiyeh Bazargani
- Student Research Committee, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Ahmad Reza Bandegi
- Department of Biochemistry, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | | | | | - Ali Ghanbari
- Research Center of Physiology, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
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Byrnes K, Wu PJ, Whillier S. Is Pilates an effective rehabilitation tool? A systematic review. J Bodyw Mov Ther 2017; 22:192-202. [PMID: 29332746 DOI: 10.1016/j.jbmt.2017.04.008] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2017] [Revised: 03/26/2017] [Accepted: 04/04/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND Pilates is a system of exercise focusing upon controlled movement, stretching and breathing. Pilates is popular today not only for physical fitness but also for rehabilitation programs. This paper is a review of the literature on the effectiveness of Pilates as a rehabilitation tool in a wide range of conditions in an adult population. METHODS A systematic literature review was carried out according to the PRISMA guidelines. Electronic databases were searched for cohort studies or randomised controlled trials (RCTs), and inclusion and exclusion criteria were applied. The final RCTs were assessed using the PEDro and CONSORT 2010 checklists. RESULTS Twenty-three studies, published between 2005 and 2016, met the inclusion criteria. These papers assessed the efficacy of Pilates in the rehabilitation of low back pain, ankylosing spondylitis, multiple sclerosis, post-menopausal osteoporosis, non-structural scoliosis, hypertension and chronic neck pain. Nineteen papers found Pilates to be more effective than the control or comparator group at improving outcomes including pain and disability levels. When assessed using the CONSORT and PEDro scales, the quality of the papers varied, with more falling toward the upper end of the scale. CONCLUSION The majority of the clinical trials in the last five years into the use of Pilates as a rehabilitation tool have found it to be effective in achieving desired outcomes, particularly in the area of reducing pain and disability. It indicates the need for further research in these many areas, and especially into the benefits of particular Pilates exercises in the rehabilitation of specific conditions.
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Affiliation(s)
- Keira Byrnes
- Department of Chiropractic, Faculty of Science and Engineering, Macquarie University, Australia
| | - Ping-Jung Wu
- Department of Chiropractic, Faculty of Science and Engineering, Macquarie University, Australia
| | - Stephney Whillier
- Department of Chiropractic, Faculty of Science and Engineering, Macquarie University, Australia.
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Abstract
Exercise is known to exert a systemic anti-inflammatory influence, but whether its effects are sufficient to protect against subsequent neuropathic pain is underinvestigated. We report that 6 weeks of voluntary wheel running terminating before chronic constriction injury (CCI) prevented the full development of allodynia for the ∼3-month duration of the injury. Neuroimmune signaling was assessed at 3 and 14 days after CCI. Prior exercise normalized ipsilateral dorsal spinal cord expression of neuroexcitatory interleukin (IL)-1β production and the attendant glutamate transporter GLT-1 decrease, as well as expression of the disinhibitory P2X4R-BDNF axis. The expression of the macrophage marker Iba1 and the chemokine CCL2 (MCP-1), and a neuronal injury marker (activating transcription factor 3), was attenuated by prior running in the ipsilateral lumbar dorsal root ganglia. Prior exercise suppressed macrophage infiltration and/or injury site proliferation, given decreased presence of macrophage markers Iba1, iNOS (M1), and Arg-1 (M2; expression was time dependent). Chronic constriction injury-driven increases in serum proinflammatory chemokines were suppressed by prior running, whereas IL-10 was increased. Peripheral blood mononuclear cells were also stimulated with lipopolysaccharide ex vivo, wherein CCI-induced increases in IL-1β, nitrite, and IL-10 were suppressed by prior exercise. Last, unrestricted voluntary wheel running, beginning either the day of, or 2 weeks after, CCI, progressively reversed neuropathic pain. This study is the first to investigate the behavioral and neuroimmune consequences of regular exercise terminating before nerve injury. This study suggests that chronic pain should be considered a component of "the diseasome of physical inactivity," and that an active lifestyle may prevent neuropathic pain.
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Tsai KL, Huang PC, Wang LK, Hung CH, Chen YW. Incline treadmill exercise suppresses pain hypersensitivity associated with the modulation of pro-inflammatory cytokines and anti-inflammatory cytokine in rats with peripheral nerve injury. Neurosci Lett 2017; 643:27-31. [PMID: 28215879 DOI: 10.1016/j.neulet.2017.02.021] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Revised: 01/30/2017] [Accepted: 02/08/2017] [Indexed: 12/12/2022]
Abstract
We aimed to investigate the impact of 3 weeks of incline treadmill exercise (TE) on withdrawal responses elicited by thermal and mechanical stimuli, and on anti-inflammatory cytokine (interleukin-10, IL-10) and pro-inflammatory cytokines (IL-6 and tumor necrosis factor-alpha [TNF-α]) expression in the sciatic nerve of rats underwent chronic constriction injury (CCI). Group 1 received a sham-operation where the sciatic nerve was exposed but not ligated, while Group 2 underwent a sham-operation followed by exercising on an 8%-incline treadmill (TE8). Group 3 underwent only the CCI procedure, and Groups 4 and 5 underwent the CCI procedure followed by exercising on an 0%-incline treadmill (TE0) and TE8, respectively. Mechanical and thermal sensitivity and protein expression of IL-10, IL-6 and TNF-α were evaluated on postoperative days 12 and 26. Among the five groups, Group 5 displayed the least weight gain. Compared with Group 3, Group 5 had smaller decreases in mechanical withdrawal thresholds and heat withdrawal latencies. The CCI rats who received TE at 8% incline showed the downregulation of TNF-α and IL-6 in their sciatic nerves on postoperative days 12 and 26, as was found in the Group 3 rats. TE at 8% incline also prevented the downregulation of IL-10 in their sciatic nerves on postoperative day 12. The results demonstrated that increased incline improves the anti-nociceptive effects of treadmill running. Inclined exercise reduces the levels of pro-inflammatory cytokines and increases the level of an anti-inflammatory cytokine.
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Affiliation(s)
- Kun-Ling Tsai
- Department of Physical Therapy, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Po-Ching Huang
- Department of Physical Therapy, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Li-Kai Wang
- Department of Anesthesiology, Chi Mei Medical Center, Tainan, Taiwan
| | - Ching-Hsia Hung
- Department of Physical Therapy, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Institute of Allied Health Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yu-Wen Chen
- Department of Medical Research, Chi Mei Medical Center, Tainan, Taiwan; Department of Physical Therapy and Graduate Institute of Rehabilitation Science, College of Health Care, China Medical University, Taichung, Taiwan.
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Modest Amounts of Voluntary Exercise Reduce Pain- and Stress-Related Outcomes in a Rat Model of Persistent Hind Limb Inflammation. THE JOURNAL OF PAIN 2017; 18:687-701. [PMID: 28185925 DOI: 10.1016/j.jpain.2017.01.006] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/02/2016] [Revised: 01/13/2017] [Accepted: 01/17/2017] [Indexed: 11/23/2022]
Abstract
Aerobic exercise improves outcomes in a variety of chronic health conditions, yet the support for exercise-induced effects on chronic pain in humans is mixed. Although many rodent studies have examined the effects of exercise on persistent hypersensitivity, the most used forced exercise paradigms that are known to be highly stressful. Because stress can also produce analgesic effects, we studied how voluntary exercise, known to reduce stress in healthy subjects, alters hypersensitivity, stress, and swelling in a rat model of persistent hind paw inflammation. Our data indicate that voluntary exercise rapidly and effectively reduces hypersensitivity as well as stress-related outcomes without altering swelling. Moreover, the level of exercise is unrelated to the analgesic and stress-reducing effects, suggesting that even modest amounts of exercise may impart significant benefit in persistent inflammatory pain states. PERSPECTIVE Modest levels of voluntary exercise reduce pain- and stress-related outcomes in a rat model of persistent inflammatory pain, independently of the amount of exercise. As such, consistent, self-regulated activity levels may be more relevant to health improvement in persistent pain states than standardized exercise goals.
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35
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Exercise prevents development of autonomic dysregulation and hyperalgesia in a mouse model of chronic muscle pain. Pain 2016; 157:387-398. [PMID: 26313406 DOI: 10.1097/j.pain.0000000000000330] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Chronic musculoskeletal pain (CMP) conditions, like fibromyalgia, are associated with widespread pain and alterations in autonomic functions. Regular physical activity prevents the development of CMP and can reduce autonomic dysfunction. We tested if there were alterations in autonomic function of sedentary mice with CMP, and whether exercise reduced the autonomic dysfunction and pain induced by CMP. Chronic musculoskeletal pain was induced by 2 intramuscular injections of pH 5.0 in combination with a single fatiguing exercise task. A running wheel was placed into cages so that the mouse had free access to it for either 5 days or 8 weeks (exercise groups) and these animals were compared to sedentary mice without running wheels. Autonomic function and nociceptive withdrawal thresholds of the paw and muscle were assessed before and after induction of CMP in exercised and sedentary mice. In sedentary mice, we show decreased baroreflex sensitivity, increased blood pressure variability, decreased heart rate variability, and decreased withdrawal thresholds of the paw and muscle 24 hours after induction of CMP. There were no sex differences after induction of the CMP in any outcome measure. We further show that both 5 days and 8 weeks of physical activity prevent the development of autonomic dysfunction and decreases in withdrawal threshold induced by CMP. Thus, this study uniquely shows the development of autonomic dysfunction in animals with chronic muscle hyperalgesia, which can be prevented with as little as 5 days of physical activity, and suggest that physical activity may prevent the development of pain and autonomic dysfunction in people with CMP.
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Therapeutic Ultrasound and Treadmill Training Suppress Peripheral Nerve Injury-Induced Pain in Rats. Phys Ther 2016; 96:1545-1553. [PMID: 27126126 DOI: 10.2522/ptj.20140379] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Accepted: 04/24/2016] [Indexed: 02/09/2023]
Abstract
BACKGROUND Although evidence suggests that therapeutic ultrasound (TU) in combination with treadmill training (TT) suppresses nerve injury-associated pain, the molecular mechanisms for this action are not clear. OBJECTIVE The purpose of this research was to study the possible beneficial effects of TU and TT, alone and in combination, on 2 clinical indicators of neuropathic pain and correlate these findings with changes in inflammatory mediators within the spinal cord. Our experimental model used the well-known chronic constriction injury (CCI) of the rat sciatic nerve. DESIGN This was an experimental study. METHODS Each group contained 10 rats. Group 1 underwent only the CCI procedure. Group 2 underwent a sham operation where the sciatic nerve was exposed but not ligated. Group 3 had the sham operation followed by both TT and TU. Groups 4, 5, and 6 underwent the CCI procedure followed by TT alone, TU alone, and both the TT and TU interventions, respectively. Heat and mechanical sensitivity, interleukin-6 (IL-6), interleukin-10 (IL-10), and ionized calcium binding adaptor molecule 1 (Iba1) were evaluated. RESULTS Compared with group 1 animals, TT or TU, or both, produced smaller decreases in mechanical withdrawal threshold and heat withdrawal latencies. The combination of TT and TU was more effective than either treatment alone. In addition, rats that received these treatments did not express the upregulation of IL-6 and Iba1 in their spinal cords on postoperative days 14 and 28, as was found in the group 1 animals. LIMITATIONS These experimental findings may not be generalizable to humans. CONCLUSIONS The combination of TU and TT reduces neuropathic pain more than either modality alone. This beneficial effect appears related to downregulation of proinflammatory IL-6 and Iba1, while upregulating the anti-inflammatory IL-10.
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Bobinski F, Ferreira TAA, Córdova MM, Dombrowski PA, da Cunha C, Santo CCDE, Poli A, Pires RGW, Martins-Silva C, Sluka KA, Santos ARS. Role of brainstem serotonin in analgesia produced by low-intensity exercise on neuropathic pain after sciatic nerve injury in mice. Pain 2016; 156:2595-2606. [PMID: 26447701 DOI: 10.1097/j.pain.0000000000000372] [Citation(s) in RCA: 110] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Physical exercise is a low-cost, safe, and efficient intervention for the reduction of neuropathic chronic pain in humans. However, the underlying mechanisms for how exercise reduces neuropathic pain are not yet well understood. Central monoaminergic systems play a critical role in endogenous analgesia leading us to hypothesize that the analgesic effect of low-intensity exercise occurs through activation of monoaminergic neurotransmission in descending inhibitory systems. To test this hypothesis, we induced peripheral nerve injury (PNI) by crushing the sciatic nerve. The exercise intervention consisted of low-intensity treadmill running for 2 weeks immediately after injury. Animals with PNI showed an increase in pain-like behaviors that were reduced by treadmill running. Reduction of serotonin (5-hydroxytryptamine) synthesis using the tryptophan hydroxylase inhibitor para-chlorophenylalanine methyl ester prevented the analgesic effect of exercise. However, blockade catecholamine synthesis with the tyrosine hydroxylase inhibitor alpha-methyl-para-tyrosine had no effect. In parallel, 2 weeks of exercise increased brainstem levels of the 5-HT and its metabolites (5-hydroxyindoleacetic acid), decreased expression of the serotonin transporter, and increased expression of 5-HT receptors (5HT-1B, 2A, 2C). Finally, PNI-induced increase in inflammatory cytokines, tumor necrosis factor-alpha, and interleukin-1 beta, in the brainstem, was reversed by 2 weeks of exercise. These findings provide new evidence indicating that low-intensity aerobic treadmill exercise suppresses pain-like behaviors in animals with neuropathic pain by enhancing brainstem 5-HT neurotransmission. These data provide a rationale for the analgesia produced by exercise to provide an alternative approach to the treatment of chronic neuropathic pain.
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Affiliation(s)
- Franciane Bobinski
- Laboratory of Neurobiology of Pain and Inflammation, Department of Physiological Sciences, Center of Biological Sciences, Federal University of Santa Catarina, Trindade, Florianopolis, Brazil Graduate Program in Neuroscience, Center of Biological Sciences, Federal University of Santa Catarina, Trindade, Florianopolis, Brazil Laboratory of Molecular and Behavioral Neurobiology, Department of Physiological Sciences, Federal University of Espírito Santo, Vitória, Brazil Department of Pharmacology, Federal University of Paraná, Curitiba, Brazil Department of Pharmacology, Center of Biological Sciences, Federal University of Santa Catarina, Trindade, Florianopolis, Brazil Department of Physical Therapy and Rehabilitation Science, Pain Research Program, University of Iowa, Iowa City, IA, USA
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Neurobiology of fibromyalgia and chronic widespread pain. Neuroscience 2016; 338:114-129. [PMID: 27291641 DOI: 10.1016/j.neuroscience.2016.06.006] [Citation(s) in RCA: 437] [Impact Index Per Article: 48.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2016] [Revised: 06/02/2016] [Accepted: 06/03/2016] [Indexed: 12/13/2022]
Abstract
Fibromyalgia is the current term for chronic widespread musculoskeletal pain for which no alternative cause can be identified. The underlying mechanisms, in both human and animal studies, for the continued pain in individuals with fibromyalgia will be explored in this review. There is a substantial amount of support for alterations of central nervous system nociceptive processing in people with fibromyalgia, and that psychological factors such as stress can enhance the pain experience. Emerging evidence has begun exploring other potential mechanisms including a peripheral nervous system component to the generation of pain and the role of systemic inflammation. We will explore the data and neurobiology related to the role of the CNS in nociceptive processing, followed by a short review of studies examining potential peripheral nervous system changes and cytokine involvement. We will not only explore the data from human subjects with fibromyalgia but will relate this to findings from animal models of fibromyalgia. We conclude that fibromyalgia and related disorders are heterogenous conditions with a complicated pathobiology with patients falling along a continuum with one end a purely peripherally driven painful condition and the other end of the continuum is when pain is purely centrally driven.
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Naugle KM, Naugle KE, Riley JL. Reduced Modulation of Pain in Older Adults After Isometric and Aerobic Exercise. THE JOURNAL OF PAIN 2016; 17:719-28. [PMID: 26993959 DOI: 10.1016/j.jpain.2016.02.013] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/13/2015] [Revised: 12/18/2015] [Accepted: 02/23/2016] [Indexed: 01/08/2023]
Abstract
UNLABELLED Laboratory-based studies show that acute aerobic and isometric exercise reduces sensitivity to painful stimuli in young healthy individuals, indicative of a hypoalgesic response. However, little is known regarding the effect of aging on exercise-induced hypoalgesia (EIH). The purpose of this study was to examine age differences in EIH after submaximal isometric exercise and moderate and vigorous aerobic exercise. Healthy older and younger adults completed 1 training session and 4 testing sessions consisting of a submaximal isometric handgrip exercise, vigorous or moderate intensity stationary cycling, or quiet rest (control). The following measures were taken before and after exercise/quiet rest: 1) pressure pain thresholds, 2) suprathreshold pressure pain ratings, 3) pain ratings during 30 seconds of prolonged noxious heat stimulation, and 4) temporal summation of heat pain. The results revealed age differences in EIH after isometric and aerobic exercise, with younger adults experiencing greater EIH compared with older adults. The age differences in EIH varied across pain induction techniques and exercise type. These results provide evidence for abnormal pain modulation after acute exercise in older adults. PERSPECTIVE This article enhances our understanding of the influence of a single bout of exercise on pain sensitivity and perception in healthy older compared with younger adults. This knowledge could help clinicians optimize exercise as a method of pain management.
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Affiliation(s)
- Kelly M Naugle
- Pain Research and Intervention Center of Excellence, College of Dentistry, University of Florida, Gainesville, Florida.
| | - Keith E Naugle
- Department of Kinesiology, Indiana University Purdue University Indianapolis, Indianapolis, Indiana
| | - Joseph L Riley
- Pain Research and Intervention Center of Excellence, College of Dentistry, University of Florida, Gainesville, Florida
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Abstract
Much evidence from pain patients and animal models shows that chronic pain does not exist in a vacuum but has varied comorbidities and far-reaching consequences. Patients with long-term pain often develop anxiety and depression and can manifest changes in cognitive functioning, particularly with working memory. Longitudinal studies in rodent models also show the development of anxiety-like behavior and cognitive changes weeks to months after an injury causing long-term pain. Brain imaging studies in pain patients and rodent models find that chronic pain is associated with anatomical and functional alterations in the brain. Nevertheless, studies in humans reveal that lifestyle choices, such as the practice of meditation or yoga, can reduce pain perception and have the opposite effect on the brain as does chronic pain. In rodent models, studies show that physical activity and a socially enriched environment reduce pain behavior and normalize brain function. Together, these studies suggest that the burden of chronic pain can be reduced by nonpharmacological interventions.
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Suzuki K. Effects of exercise on antibody production. World J Immunol 2015; 5:160-166. [DOI: 10.5411/wji.v5.i3.160] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2015] [Revised: 07/18/2015] [Accepted: 09/16/2015] [Indexed: 02/05/2023] Open
Abstract
In this review, we have focused on the effects of exercise on infection or antibody production. In the past, exercise immunologists largely focused on exercise and its effects on infection. Research on the effects of exercise on antibody response began in the 1970s with a primary focus on whether regular exercise helps to minimize the risk of infection. Positive results from these early studies indicated that exercise affects higher survival rate. Based on the results of these studies, researchers then investigated the exercise-induced elevation of plasma antibody levels. It has been suggested that exercise of moderate intensity could be a helpful and effective adjuvant for human health. Other studies have examined the effects of exercise on antibody-producing cells, and the levels of protection conferred by the produced antibodies. We have attempted to summarize the current understanding of exercise-induced elevations in plasma antibody levels. We also propose some future directions for investigating the relationship between exercise and antibody response.
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Abstract
Both clinical and animal studies suggest that exercise may be an effective way to manage inflammatory and neuropathic pain conditions. However, existing animal studies commonly use forced exercise paradigms that incorporate varying degrees of stress, which itself can elicit analgesia, and thus may complicate the interpretation of the effects of exercise on pain. We investigated the analgesic potential of voluntary wheel running in the formalin model of acute inflammatory pain and the spared nerve injury model of neuropathic pain in mice. In uninjured, adult C57BL/6J mice, 1 to 4 weeks of exercise training did not alter nociceptive thresholds, lumbar dorsal root ganglia neuronal excitability, or hindpaw intraepidermal innervation. Further, exercise training failed to attenuate formalin-induced spontaneous pain. Lastly, 2 weeks of exercise training was ineffective in reversing spared nerve injury-induced mechanical hypersensitivity or in improving muscle wasting or hindpaw denervation. These findings indicate that in contrast to rodent forced exercise paradigms, short durations of voluntary wheel running do not improve pain-like symptoms in mouse models of acute inflammation and peripheral nerve injury.
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Hernandez S, Cruz ML, Torres-Reveron A, Appleyard CB. Impact of physical activity on pain perception in an animal model of endometriosis. JOURNAL OF ENDOMETRIOSIS AND PELVIC PAIN DISORDERS 2015; 7:89-114. [PMID: 28217664 PMCID: PMC5310711 DOI: 10.5301/je.5000231] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
BACKGROUND Symptoms of endometriosis, such as pain and infertility, are considered significant sources of stress. In many chronic conditions, exercise can act as a stress buffer and influence pain perception. We tested the impact of swimming exercise on pain perception and pain receptors in an animal model of endometriosis. METHODS Endometriosis (Endo) was induced in female rats by suturing uterine horn tissue next to the intestinal mesentery. Sham rats received sutures only. Rats were exposed to swimming exercise for 7 consecutive days, while no-exercise rats were left in the home cage. Fecal pellets were counted after swimming as an index of anxiety, and serum corticosterone levels measured. Pain perception was assessed using the hot plate test for hyperalgesia and Von Frey test for allodynia. Mu-opioid receptor (MOR) and neurokinin-1 receptor expression in the spinal cord was measured by immunofluorescence. RESULTS Fecal pellet counts were higher in those animals that swam (p<0.05), but no significant difference in corticosterone was found. Although Endo-exercise rats had higher colonic damage (p<0.05) with more cellular infiltration, the lesions were smaller than in Endo-no exercise rats (p<0.05). Exercise did not ameliorate the hyperalgesia, whereas it improved allodynia in both groups. MOR expression was significantly higher in Endo-exercise vs. Endo-no exercise rats (p<0.01), similar to Sham-no exercise levels. CONCLUSIONS Our results point toward beneficial effects of swimming exercise during endometriosis progression. Physical interventions might be investigated further for their ability to reduce perceived stress and improve outcomes in endometriosis.
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Affiliation(s)
- Siomara Hernandez
- Physiology Division, Department of Basic Sciences, Ponce Health Sciences University, Ponce Research Institute, Ponce, Puerto Rico - USA
| | - Myrella L. Cruz
- Physiology Division, Department of Basic Sciences, Ponce Health Sciences University, Ponce Research Institute, Ponce, Puerto Rico - USA
| | - Annelyn Torres-Reveron
- Physiology Division, Department of Basic Sciences, Ponce Health Sciences University, Ponce Research Institute, Ponce, Puerto Rico - USA
- Neuroscience Division, Department of Basic Sciences, Ponce Health Sciences University, Ponce Research Institute, Ponce, Puerto Rico - USA
| | - Caroline B. Appleyard
- Physiology Division, Department of Basic Sciences, Ponce Health Sciences University, Ponce Research Institute, Ponce, Puerto Rico - USA
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Kim YJ, Byun JH, Choi IS. Effect of Exercise on µ-Opioid Receptor Expression in the Rostral Ventromedial Medulla in Neuropathic Pain Rat Model. Ann Rehabil Med 2015; 39:331-9. [PMID: 26161338 PMCID: PMC4496503 DOI: 10.5535/arm.2015.39.3.331] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2014] [Accepted: 10/10/2014] [Indexed: 12/03/2022] Open
Abstract
OBJECTIVE To investigate the effects of aerobic exercise on neuropathic pain and verify whether regular treadmill exercise alters opioid receptor expression in the rostral ventral medulla (RVM) in a neuropathic pain rat model. METHODS Thirty-two male Sprague-Dawley rats were used in the study. All rats were divided into 3 groups, i.e., group A, sham group (n=10); group B, chronic constriction injury (CCI) group (n=11); and group C, CCI+exercise group (n=11). Regular treadmill exercise was performed for 30 minutes a day, 5 days a week, for 4 weeks at the speed of 8 m/min for 5 minutes, 11 m/min for 5 minutes, and 22 m/min for 20 minutes. Withdrawal threshold and withdrawal latency were measured before and after the regular exercise program. Immunohistochemistry and Western blots analyses were performed using antibodies against µ-opioid receptor (MOR). RESULTS Body weight of group C was the lowest among all groups. Withdrawal thresholds and withdrawal latencies were increased with time in groups B and C. There were significant differences of withdrawal thresholds between group B and group C at 1st, 2nd, 3rd, and 4th weeks after exercise. There were significant differences of withdrawal latencies between group B and group C at 3rd and 4th weeks after exercise. MOR expression of group C was significantly decreased, as compared to that of group B in the RVM and spinal cord. CONCLUSION In neuropathic pain, exercise induced analgesia could be mediated by desensitization of central MOR by endogenous opioids, leading to the shift of RVM circuitry balance to pain inhibition.
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Affiliation(s)
- Young-Jin Kim
- Department of Physical and Rehabilitation Medicine, Research Institute of Medical Sciences, Center for Aging and Geriatrics, and Regional Cardiocerebrovascular Center, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju, Korea
| | - Jeong-Hyun Byun
- Department of Physical and Rehabilitation Medicine, Research Institute of Medical Sciences, Center for Aging and Geriatrics, and Regional Cardiocerebrovascular Center, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju, Korea
| | - In-Sung Choi
- Department of Physical and Rehabilitation Medicine, Research Institute of Medical Sciences, Center for Aging and Geriatrics, and Regional Cardiocerebrovascular Center, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju, Korea
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Central sensitization and changes in conditioned pain modulation in people with chronic nonspecific low back pain: a case-control study. Exp Brain Res 2015; 233:2391-9. [PMID: 25963754 DOI: 10.1007/s00221-015-4309-6] [Citation(s) in RCA: 121] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2014] [Accepted: 04/30/2015] [Indexed: 12/11/2022]
Abstract
Quantitative sensory testing is widely used in human research to investigate the state of the peripheral and central nervous system contributions in pain processing. It is a valuable tool to help identify central sensitization and may be important in the treatment of low back pain. The aim of this study was to evaluate changes in local and segmental hypersensitivity and endogenous pain inhibition in people with chronic nonspecific low back pain. Thirty patients with chronic low back pain and thirty healthy subjects were studied. Pressure pain thresholds (PPTs) were measured from the lumbar region and over the tibialis anterior muscle (TA). A cold pressor test was used to assess the activation of conditioned pain modulation (CPM), and PPTs in the lumbar region were recorded 30 s after immersion of participant's foot in a bucket with cold water. People with chronic low back pain have significantly lower PPT than controls at both the lumbar region [89.5 kPa (mean difference) 95 % CI 40.9-131.1 kPa] and TA [59.45 kPa (mean difference) 95 % CI 13.49-105.42 kPa]. During CPM, people with chronic low back pain have significantly lower PPT than controls in lumbar region [118.6 kPa (mean difference) 95 % CI 77.9-159.2 kPa]. Women had significantly lower PPTs than men in both lumbar region [101.7 kPa (mean difference) 95 % CI 37.9-165.7 kPa] and over the TA [189.7 kPa (mean difference) 95 % CI 14.2-145.2 kPa]. There was no significant difference in PPTs in men between healthy controls and those with low back pain, suggesting the significant differences are mediated primarily by difference between women.
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Dugan EA, Sagen J. An Intensive Locomotor Training Paradigm Improves Neuropathic Pain following Spinal Cord Compression Injury in Rats. J Neurotrauma 2015; 32:622-32. [DOI: 10.1089/neu.2014.3692] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
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Laurin J, Pertici V, Dousset E, Marqueste T, Decherchi P. Group III and IV muscle afferents: Role on central motor drive and clinical implications. Neuroscience 2015; 290:543-51. [DOI: 10.1016/j.neuroscience.2015.01.065] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2014] [Revised: 01/27/2015] [Accepted: 01/28/2015] [Indexed: 12/12/2022]
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Exercise therapy normalizes BDNF upregulation and glial hyperactivity in a mouse model of neuropathic pain. Pain 2015; 156:504-513. [DOI: 10.1097/01.j.pain.0000460339.23976.12] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
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Naugle KM, Naugle KE, Fillingim RB, Samuels B, Riley JL. Intensity thresholds for aerobic exercise-induced hypoalgesia. Med Sci Sports Exerc 2015; 46:817-25. [PMID: 24002342 DOI: 10.1249/mss.0000000000000143] [Citation(s) in RCA: 87] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
INTRODUCTION Despite many studies investigating exercise-induced hypoalgesia, there is limited understanding of the optimal intensity of aerobic exercise in producing hypoalgesic effects across different types of pain stimuli. Given that not all individuals are willing or capable of engaging in high-intensity aerobic exercise, whether moderate-intensity aerobic exercise (MAE) is associated with a hypoalgesic response and whether this response generalizes to multiple pain induction techniques needs to be substantiated. PURPOSE This study's purpose is to test for differences in the magnitude of pressure and heat pain modulation induced by MAE and vigorous-intensity aerobic exercise (VAE). METHODS Twelve healthy young males and 15 females completed one training session and three testing sessions consisting of 25 min of 1) stationary cycling at 70% HR reserve, 2) stationary cycling at 50% HR reserve, or 3) quiet rest (control). Pain testing was conducted on both forearms before and immediately after each condition and included the following tests: pressure pain thresholds, suprathreshold pressure pain test, static continuous heat test, and repetitive pulse heat pain test. Repeated-measures ANOVA was conducted on each pain measure. RESULTS VAE and MAE reduced pain ratings during static continuous heat stimuli and repetitive heat pulse stimuli, with VAE producing larger effects. VAE also increased pressure pain thresholds, whereas neither exercise influenced suprathreshold pressure pain ratings. CONCLUSION These results suggest that MAE is capable of producing a hypoalgesic effect using continuous and repetitive pulse heat stimuli. However, a dose-response effect was evident as VAE produced larger effects than MAE.
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Affiliation(s)
- Kelly Marie Naugle
- 1Pain Research and Intervention Center of Excellence, University of Florida, Gainesville, FL; and 2Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL
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Abstract
Animal models of disease states are valuable tools for developing new treatments and investigating underlying mechanisms. They should mimic the symptoms and pathology of the disease and importantly be predictive of effective treatments. Fibromyalgia is characterized by chronic widespread pain with associated co-morbid symptoms that include fatigue, depression, anxiety and sleep dysfunction. In this review, we present different animal models that mimic the signs and symptoms of fibromyalgia. These models are induced by a wide variety of methods that include repeated muscle insults, depletion of biogenic amines, and stress. All potential models produce widespread and long-lasting hyperalgesia without overt peripheral tissue damage and thus mimic the clinical presentation of fibromyalgia. We describe the methods for induction of the model, pathophysiological mechanisms for each model, and treatment profiles.
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