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

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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 µ 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 µ 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 µ 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 µ-opioid tolerance and physical dependence, and that these effects are similar to those produced by chronic opioid administration.

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Acknowledgements

This study was supported by Davidson College and US Public Service Grants DA13461 and DA14255 from the National Institute on Drug Abuse. The authors wish to thank Amy Becton for expert technical assistance and Drs. Drake Morgan and Mitchell Picker for helpful comments made on an earlier version of this manuscript. Portions of these data were presented at the 2000 annual meeting of the Society for Neuroscience in San Diego, Calif., USA.

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  1. Department of Psychology, Davidson College, Davidson, NC 28035-7037, USA

    Mark A. Smith & David L. Yancey

  2. Program in Neuroscience, Davidson College, Davidson, NC 28035-7037, USA

    Mark A. Smith

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  1. Mark A. Smith
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  2. David L. Yancey
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Correspondence to Mark A. Smith.

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Smith, M.A., Yancey, D.L. Sensitivity to the effects of opioids in rats with free access to exercise wheels: µ-opioid tolerance and physical dependence. Psychopharmacology 168, 426–434 (2003). https://doi.org/10.1007/s00213-003-1471-5

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  • DOI: https://doi.org/10.1007/s00213-003-1471-5

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