Opioids comprise a diverse group of compounds that display a broad array of agonist and antagonist properties, apparently as a consequence of differential interactions with multiple populations or receptors. There are major differences in behavioral pharmacology among opioids drugs, which often correspond to differences in abuse potential. This research program will evaluate systematically the behavioral effects of representative opioid drugs having differing spectra of activity in order to identify and study distinct components of drug action that reflect the various receptor types with whch the drugs interact, and which are fundamental determinants of the differences in abuse potential. Particular attention will be given to characterizing the behavioral effects of opioid peptides that interact with defined receptor populations, and to clarifying the role of endogenous opioid systems in the diverseness of the behavioral effects of opioid drugs. Many of the proposed experiments will address different aspects of two hypotheses: 1) activation of delta-opioid receptors can potentiate behavioral effects mediated by mu receptors; 2) mu-receptor agonists (eg, morphine) do not induce tolerance to delta-mediated opioid actions. Behavioral effects of opioid peptides will be determined and compared to those of prototypic opioid alkaloids, and interactions between opioid peptides and opioid agonists and antagonists will be studied. Drugs usually will be examined in two animal species, rat and squirrel monkey, and in several behavioral procedures to generate converging experimental findings having broad applicability. Principal experiments will include: a) evaluating morphine-like and nonmorphine-like discriminative stimulus efects of opioids; b) determining if opioid peptides modify effects of opioid drugs on locomotor activity and food-reinforced operant responding in the same way that they modify discriminative effects, and conversely, determining if behavioral effects of opioid peptides are modified differentially by chronic morphine administration; c) determining if stress-induced potentiation of opioid analgesia can serve as a mdel of """"""""natural"""""""" interactions between endogenous opioid systems and opioid drugs; d) characterizing pharmacologically single-dose sensitization by agonists to antagonist-induced disruption of food-maintained operant responding as a means of studying interactions between opioid drugs and specific receptor populations.
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