Current treatments for human opioid abuse incorporate a variety of chronic pharmacotherapies, including methadone maintenance and newer or experimental treatments with low efficacy opioid agonists (e.g., buprenorphine) or opioid antagonists (e.g., naltrexone). Preclinical studies of the behavioral sequelae of such maintenance therapies may be useful in predicting their psychomotor and subjective effects in humans. The proposed projects will use drug discrimination assays as a model system to assess how pharmacological and behavioral factors modulate development of tolerance during repeated treatment with selected opioid agonists, alone and in combination with non-opioid agents proposed to modulate opioid tolerance and/or dependence. We will pay particular attention to patterns of tolerance and cross-tolerance among opioids that appear to differ in intrinsic efficacy as agonists. Related experiments will evaluate several behavioral effects of opioids in opioid-dependent subjects, and in subjects treated with irreversible opioid receptor antagonists. The first proposed project will characterize patterns of tolerance and cross-tolerance to discriminative stimulus and antinociceptive effects of mu opioids as a function of agonist efficacy. Planned studies will focus on chronic administration of low efficacy mu agonists. The second project will study antagonism of antinociceptive and stimulus effects of agonists by irreversible antagonists, in order to provide an independent test of the hypothesis that differences in tolerance are related to differences in relative intrinsic efficacy. The third and fourth projects will characterize acute and chronic interventions that may modulate development of opioid tolerance or dependence. Specific compounds to be studied include putative neutral opioid antagonists, kinase inhibitors, NMDA-antagonists CCK-antagonists and NO synthase inhibitors. Experiments will determine effects of acute and chronic treatment with selected agents on development and expression of tolerance and dependence, using behavioral assays of antinociception, acute dependence, and discriminative stimulus effects of mu opioids.
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