Sensitivity to the effects of opioids in rats with free access to exercise wheels: mu-opioid tolerance and physical dependence

Abstract

Rationale: Exercise stimulates the release of endogenous opioid peptides and increases nociceptive (i.e. pain) thresholds in both human and animal subjects. During chronic, long-term exercise, sensitivity to the effects of morphine and other mu opioids decreases, leading some investigators to propose that exercise may lead to the development of cross tolerance to exogenously administered opioid agonists.

Objective: The purpose of the present investigation was to examine the effects of chronic exercise on sensitivity to mu opioids, and to determine whether these effects can be attributed to the development of opioid tolerance and dependence.

Methods: Rats were obtained at weaning and housed singly in standard polycarbonate cages (sedentary) or modified cages equipped with exercise wheels (exercise). After 6 weeks under these conditions, opioids possessing a range of relative efficacy at the mu receptor (morphine, levorphanol, buprenorphine, butorphanol, nalbuphine) were examined in a warm-water tail-withdrawal procedure.

Results: Morphine, levorphanol and buprenorphine produced maximal levels of antinociception in both groups of rats, but all were more potent in sedentary rats than in exercising rats. Butorphanol and nalbuphine produced maximal levels of antinociception in sedentary rats under some conditions in which they failed to produce antinociception in exercising rats. Sensitivity to the effects of buprenorphine was decreased in sedentary rats that were transferred to cages equipped with exercise wheels, and increased in exercising rats that were transferred to sedentary housing conditions. In the latter group, exercise output prior to housing reassignment was positively correlated with increases in sensitivity to buprenorphine following housing reassignment. Naloxone administration precipitated a mild withdrawal syndrome in exercising rats that was not readily apparent in sedentary rats.

Conclusions: These data suggest that chronic exercise leads to the development of mu-opioid tolerance and physical dependence, and that these effects are similar to those produced by chronic opioid administration.