Regular Exercise Reverses Sensory Hypersensitivity in a Rat Neuropathic Pain Model: Role of Endogenous Opioids
Open accessAbstract
Background: Exercise is often prescribed as a therapy for chronic pain. Short-term exercise briefly increases the production of endogenous analgesics, leading to transient antinociception. In limited studies, exercise produced sustained increases in endogenous opioids, sustained analgesia, or diminished measures of chronic pain. This study tests the hypothesis that regular aerobic exercise leads to sustained reversal of neuropathic pain by activating endogenous opioid-mediated pain modulatory systems. Methods: After baseline measurements, the L5 and L6 spinal nerves of male Sprague-Dawley rats were tightly ligated. Animals were randomized to sedentary or 5-week treadmill exercise-trained groups. Thermal and tactile sensitivities were assessed 23 h after exercise, using paw withdrawal thresholds to von Frey filaments and withdrawal latencies to noxious heat. Opioid receptor antagonists were administered by subcutaneous, intrathecal, or intracerebroventricular injection. Opioid peptides were quantified using immunohistochemistry with densitometry. Results: Exercise training ameliorated thermal and tactile hypersensitivity in spinal nerve-ligated animals within 3 weeks. Sensory hypersensitivity returned 5 days after discontinuation of exercise training. The effects of exercise were reversed by using systemically or intracerebroventricularly administered opioid receptor antagonists and prevented by continuous infusion of naltrexone. Exercise increased β-endorphin and met-enkephalin content in the rostral ventromedial medulla and the mid-brain periaqueductal gray area. Conclusions: Regular moderate aerobic exercise reversed signs of neuropathic pain and increased endogenous opioid content in brainstem regions important in pain modulation. Exercise effects were reversed by opioid receptor antagonists. These results suggest that exercise-induced reversal of neuropathic pain results from an up-regulation of endogenous opioids.
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A single exercise session increases endogenous opioid production, causing short-lived anti-nociception in animals and humans.
“a sin-gle bout of exercise increases the production of endogenous opioids, leading to transient anti-nociception in both animals and humans”
From Physical activity and exercise for chronic pain in adults: an overview of Cochrane Reviews (2017) · cites this paper as Stagg 2011
In animals not otherwise treated, repeated exercise leads to long-lasting anti-nociception.
“repeated exercise produces long-lasting anti-nociception in otherwise untreated animals (Stagg 2011)”
From Physical activity and exercise for chronic pain in adults: an overview of Cochrane Reviews (2017) · cites this paper as Stagg 2011
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- Authors
- Stagg, N. J., Mata, H. P., Ibrahim, M. M., Henriksen, E. J., Porreca, F., Vanderah, T. W., & Philip Malan, T.
- Affiliations
- University of Arizona (US)
- Research Specialist, Department of Anesthesiology.
- Medical Student.
- Professor of Physiology.
- Professor of Pharmacology and Anesthesiology.
- Professor of Anesthesiology and Pharmacology, The University of Arizona, Tucson, Arizona.
- Venue
- Anesthesiology
- Published
- 2011-04-01
- Volume
- 114
- Issue
- 4
- Pages
- 940-948
- ISSN
- 0003-3022 (ISSN-L)
- PMC
- PMC6345518
- OpenAlex
- W1990726115
- Cited by
- 314
- References
- 29
- Citations by year
- 2026: 15 · 2025: 20 · 2024: 18 · 2023: 18 · 2022: 23 · 2021: 31 · 2020: 28 · 2019: 21 · 2018: 25 · 2017: 24 · 2016: 22 · 2015: 18 · 2014: 14 · 2013: 18 · 2012: 12
- FWCI
- 10.69
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Anesthesiology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Drug Abuse (R01DA015866, R01DA015205)
- Topics
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Health Sciences › Medicine › Anesthesiology and Pain Medicine › Pain Management and Treatment
- Health Sciences › Medicine › Pharmacology › Musculoskeletal pain and rehabilitation
- Keywords
- aerobic exercise, neuropathic pain, sensory hypersensitivity, endogenous opioids, opioid antagonists, beta-endorphin, met-enkephalin, spinal nerve ligation, treadmill exercise, pain modulation, periaqueductal gray, ventromedial medulla, naltrexone
- MeSH terms
- Animals, beta-Endorphin, Brain Stem, Disease Models, Animal, Enkephalin, Methionine, Male, Naltrexone, Narcotic Antagonists, Neuralgia, Physical Conditioning, Animal, Random Allocation, Receptors, Opioid, Rats, Sprague-Dawley, Pain Threshold, Rats
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