This project proposes to continue use of a human drug discrimination procedure to conduct comparative evaluations of the discriminative stimulus characteristics, subjective and physiological effects of opioid agonists, antagonists, and mixed agonist/antagonists and to test some of the parameters of the drug discrimination procedure in humans. Animal laboratory data suggest that opioids acting at different receptor sites (e.g., mu- receptors vs. kappa and/or sigma receptors) possess distinctive discriminative stimulus characteristics which permit the use of drug discrimination procedures to classify opioids with respect to their pharmacological profiles of action. Previous work in our laboratory in developing and using a human drug discrimination paradigm has indicated the utility of this procedure for characterizing and for identifying subtle differences among opioids. Also, these studies provide an opportunity to assess the relationship between discriminative stimulus properties of drugs and their subjective effects in humans. In a residential human experimental laboratory volunteers are trained to discriminate between the effects of two active drugs (or drug doses) and saline. Following the successful acquisition of the three-choice discrimination, various doses of the training drugs and/or other test drugs are administered in experimental sessions to determine the similarity of the test drug/dose to the training drugs. Comparisons to test drugs to training drugs is based on the behavioral discrimination data and on descriptive subjective and physiological data collected in each session. In one group of studies (Experiments 1-5), the stimulus properties of various opioids, agonists and mixed agonist-antagonists will be examined when given alone or in combination with an antagonist. Another group of studies (Experiments 6-10) will examine several methodological parameters of drug discrimination including: drug class specificity with parenterally given opioids and orally given opioids; instructional effects; effects of training dose on the discrimination of drug stimulus properties; and the threshold dose for opioid agonist discrimination. These studies will provide valuable data concerning opioid clinical pharmacology, concerning the parameters and determinants of drug discrimination procedures and outcomes, and concerning the relationship of drug discrimination measures to other measures of opioid actions in humans.
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