In view of the many undesirable actions of morphine and other opium derivatives, considerable research has been devoted to developing new drugs that retain morphine's analgesic efficacy but are less likely to result in abuse and physical dependence. A class of drugs that has been developed specifically for these reasons are the partial mu agonists. Although these drugs have recently gained popularity for the management of pain and in the treatment of opioid abuse and dependence, they have not proven to be devoid of abuse potential or physical dependence liability. It is essential, therefore, to critically evaluate the behavioral and pharmacological properties of these opioids and develop reliable methods and strategies that can be used to further advance our understanding of this widely used and abused class of drugs. Moreover, given the exceptionally large number of partial mu agonists available, of which most are presumed to have varying degrees of activity at different opioid receptor types, this heterogeneous class of opioids can serve as a tool for delineating the fundamental properties of drugs with limited efficacy at a given receptor site, as well as drugs with simultaneous actions at multiple receptor types. Although these drugs have been examined extensively in physiological and antinociceptive assays, information concerning the nature of their stimulus properties, development of tolerance to their behavioral effects and the receptor mechanisms that underlie their diverse actions, have not been well documented. A goal of the proposed studies is to address these and other fundamental issues regarding the actions of partial mu agonists using different operant methodologies and pharmacological techniques. Specifically, we propose to (1) evaluate the relative contribution of activity at mu, kappa and delta opioid receptors to the stimulus effects of different partial mu agonists, and establish a discrimination between a full mu agonist and saline in order to determine if this procedure can be used to distinguish between partial mu agonists that share similar stimulus effects with morphine, yet can be differentiated from morphine in other assays, (2) evaluate the contribution of activity at the delta receptor in mediating the stimulus effects of partial mu agonists, (3) evaluate the extent to which the irreversible antagonists alter the behavioral effects of partial mu agonists with the goal of providing a quantitative estimate of rank ordering of their relative efficacy at the mu receptor, and (4) evaluate the behavioral consequences of long-term exposure to opioids and determine the extent to which tolerance development relates to the drug used to induce tolerance, the dose of the drug used to induce tolerance, and the test opioid's efficacy at and selectivity for the mu receptor. Although the work proposed here will evaluate the actions of partial mu agonists within the conceptual framework of receptor pharmacology, it also acknowledges the unique contribution of environmental determinants of drug action as well as the limitations of receptor theory as it applies under conditions in which multiple receptor types contribute to a drug's behavioral actions.
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