Drugs that have limited intrinsic efficacy at the mu-opioid receptor (i.e., partial agonists) are a unique class of opioids in that they bave minimal potential for abuse and physical dependence, yet retain many of the therapeutic properties of morphine of other full mu agonists. During the last two decades, these drugs have gained clinical importance as analgesics, substitutes for heroin dependence, and most recently as a treatment for cocaine dependence. As a consequence of their growing acceptance in clinical practice there is considerable interest in tbeir behavioral effects following both acute and chronic exposure. From a theoretical perspective, these drugs can be used as tools to advance our understanding of the fundamental properties of drugs with limited efficacy at the receptor site. It is the aim of the current proposal to examine the behavioral and pharmacological properties of partial mu agonists using assays of drug discrimination and schedule-controlled responding. Specifically, the proposed investigations are aimed at characterizing: (1) the discriminative stimulus properties of partial mu agonists, (2) the agonist and antagonist effects (i.e, their intrinsic efficacy) of partial mu agonists in discrimination tasks with high and low efficacy requirements, (3) the discriminative stimulus properties produced during withdrawal following chronic exposure to a partial mu agonist, (4) the relative potencies of naltrexone and the alkylating agent B-funaltrexamine as antagonists of the discriminative stimulus and rate-decreasing effects of partial mu agonists, and (5) the development of tolerance and cross-tolerance to the effects of partial mu agonists
