TOLERANCE AND CROSS-TOLERANCE TO THE RESPONSE RATE-DECREASING EFFECTSOF MU-OPIOIDS IN MORPHINE-MAINTAINED SQUIRREL-MONKEYS

The purpose of the present experiment was to assess the degree of tole rance and cross-tolerance to the response rate-decreasing effects of o pioids with different degrees of intrinsic efficacy at the mu receptor . The mu opioids included buprenorphine, etorphine, l-methadone, morph ine, and sufentanil. Lever pressing of squirrel monkeys was maintained by a fixed-ratio (FR) 30 schedule of food presentation, and dose-effe ct curves for each drug were obtained prior to, during, and after dail y administrations of morphine. Each of the mu opioids, and the non-opi oid pentobarbital, dose-dependently decreased response rates. Daily ad ministration of morphine produced approximately a 0.9 log unit rightwa rd shift in the morphine dose-effect curve. During this chronic-morphi ne phase of the experiment, the dose-effect curve for pentobarbital wa s not shifted consistently, whereas the dose-effect curves for bupreno rphine, etorphine, l-methadone, and sufentanil were shifted between 0. 4 and 0.6 log unit to the right. Therefore etorphine, I-methadone and sufentanil, mu opioids thought to have high intrinsic efficacy, and bu prenorphine, a mu opioid thought to have low intrinsic efficacy, all p roduced a smaller degree of cross-tolerance than that observed for mor phine, and pentobarbital, a non-opioid, did not produce cross-toleranc e.