Effect of Exercise on µ-Opioid Receptor Expression in the Rostral Ventromedial Medulla in Neuropathic Pain Rat Model

Abstract

ObjectiveTo 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.MethodsThirty-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).ResultsBody 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.ConclusionIn 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.

Short-duration physical activity prevents the development of activity-induced hyperalgesia through opioid and serotoninergic mechanisms

“…Data from the current study show that mu-opioid receptors mediate the analgesia produced by short-duration wheel running which is consistent prior work showing systemic blockade of opioid receptors prevents exercise-induced analgesia in healthy human subjects, normal uninjured animals, and animal models of pain, and increased endogenous opioid peptides and altered MOR expression occurs in central nervous system sites including the RVM[4, 15, 18, 20, 27, 30, 34, 39, 58]. The current study also shows that short-duration running wheel activity reduces SERT expression in the RVM, which is consistent with prior studies showing regular exercise increases 5-HT in central nervous system sites, and reduces SERT in RVM, and increases 5-HT-receptor expression in RVM, in normal uninjured animals and animals with nerve injury[4, 6, 7, 17, 39, 58].…”

“…Two populations of neurons in the RVM, ON-cells and OFF-cells, modulate nociception, with increased activation of ON-cells promoting nociception, and increased activity of OFF-cells promoting analgesia [19, 24, 26, 29, 34]. MOR are expressed on ON-cells, MOR agonists directly inhibit ON-cells, and removal of ON-cells prevents secondary hyperalgesia[42, 43].…”

Modest Amounts of Voluntary Exercise Reduce Pain- and Stress-Related Outcomes in a Rat Model of Persistent Hind Limb Inflammation

“…While sedentary inflamed rats experienced ongoing deficits in weight bearing over the three-week period, inflamed rats engaging in voluntary running exhibited a steady improvement in weight bearing capacity of the ipsilateral paw, achieving basal levels by three weeks post-CFA. In studies using forced exercise paradigms, while not all groups describe complete exercise-induced reversal of hypersensitivity to von Frey stimulation, most produce progressive improvements over spans of a few days to more than five weeks [9; 11; 18–24; 35; 54; 63; 69; 82; 93; 102; 103; 112; 132]. Strikingly, development of the CFA-induced thermal hypersensitivity observed in the sedentary inflamed group was prevented by only one week of voluntary running.…”

“…Strikingly, development of the CFA-induced thermal hypersensitivity observed in the sedentary inflamed group was prevented by only one week of voluntary running. The eight studies examining exercise-induced changes in thermal hypersensitivity all employed neuropathic pain models, generally describing progressive attenuation or delayed onset of thermal hypersensitivity [18–20; 23; 35; 63; 81; 112]. However, considering the differences between voluntary and forced exercise paradigms, the wide variability in exercise intensities used, the different pain models, and species/strain differences, it is difficult to directly compare study outcomes.…”

“…exercise initiated after injury) in human chronic pain populations are mixed, mainly due to differences in type of pain, type of exercise and exercise intensity [40; 55; 67; 72; 95]. In contrast, rodent studies employing therapeutic exercise uniformly show robust analgesic effects in a variety of persistent pain models and using a variety of exercise intensities [4; 9; 11; 18–24; 34; 35; 41; 54; 63; 69; 81; 82; 93; 102; 103; 112; 132]. Importantly, none of these studies assessed stress-related outcomes such as plasma corticosterone despite employing forced running paradigms that can be highly stressful [28; 36; 48; 62; 74; 80; 88; 89; 92].…”