Tolerance and cross-tolerance to the response rate-decreasing effects of ?? opioids in morphine-maintained squirrel monkeys

Abstract

The purpose of the present experiment was to assess the degree of tolerance and cross-tolerance to the response rate-decreasing effects of opioids with different degrees of intrinsic efficacy at the mu receptor. The mu opioids included buprenorphine, etorphine, l-methadone, morphine, and sufentanil. Lever pressing of squirrel monkeys was maintained by a fixed-ratio (FR) 30 schedule of food presentation, and dose-effect curves for each drug were obtained prior to, during, and after daily administrations of morphine. Each of the mu opioids, and the non-opioid pentobarbital, dose-dependently decreased response rates. Daily administration of morphine produced approximately a 0.9 log unit rightward shift in the morphine dose-effect curve. During this chronic-morphine phase of the experiment, the dose-effect curve for pentobarbital was not shifted consistently, whereas the dose-effect curves for buprenorphine, etorphine, l-methadone, and sufentanil were shifted between 0.4 and 0.6 log unit to the right. Therefore etorphine, l-methadone and sufentanil, mu opioids thought to have high intrinsic efficacy, and buprenorphine, a mu opioid thought to have low intrinsic efficacy, all produced a smaller degree of cross-tolerance than that observed for morphine, and pentobarbital, a non-opioid, did not produce cross-tolerance.