Behavioral tolerance and cross-tolerance to the response rate-decreasing effects of mu opioids in rats

The present study was designed to characterize the degree of cross-tolerance between the response rate-decreasing effects of morphine and three mu opioids with varying relative intrinsic efficacies at the mu receptor, buprenorphine, butorphanol and fentanyl, and a non-opioid (+) amphetamine, in a behavioral-tolerance paradigm. Lever pressing of rats was maintained by a fixed-ratio 20-schedule of food presentation, and dose-effect curves for each drug were obtained prior to, during, and after daily administrations of morphine in separate groups of rats administered morphine either before (pre-session) or after (post-session) experimental sessions. Each of the mu opioids and the non-opioid (+)-amphetamine dose-dependently decreased response rates. In the pre-session group, daily administration of morphine shifted the morphine dose-effect curve 0.33 log unit rightward, indicating that tolerance had developed, and shifted the butorphanol dose-effect curve 0.96 log unit rightward. Daily pre-session administrations of morphine did not shift the dose-effect curves for buprenorphine, fentanyl, or (+)-amphetamine. In the post-session group, daily administration of morphine did not shift the morphine, butorphanol, buprenorphine, fentanyl, or (+)-amphetamine dose-effect curves. These data suggest that pharmacological variables, such as the drug's relative intrinsic efficacy at the mu receptor, can play a role in behavioral tolerance and cross-tolerance.