OPIOID DELTA SUBTYPES: CORRELATION IN VITRO AND IN VIVO

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The specific goals of the proposed work are to (a) directly identify opioid delta receptor subtypes in brain and other tissues using radioligand binding techniques in wholebrain control membranes, in membranes pretreated with selective and irreversible ligands, in membranes from different strains of mice which have been reported to show differences in populations of opioid receptors (e.g., the mu-receptor deficient CXBK mouse), and in membranes from specific brain regions; (b) investigate possible differences in the regulation of interactions of the receptor subtypes with their respective effector systems by evaluation of radioligand binding in the presence of guanine nucleotides, cations (or both), or following pretreatment with pertussis toxin in vitro or in vivo; (c) use radioligand binding techniques to evaluate possible mechanism of tolerance and supersensitivity following repeated/continuous exposure of the brain to compounds with selectivity for the opioid delta receptor subtypes, and (d) use some of the above approaches in an effector system by measuring adenylyl cyclase activity in NG 108-15 cells. Such approaches will provide insights into opioid delta subtypes, and their mechanisms which may correlate with substantial data accumulated in vivo, and may be important in establishing the potential therapeutic utility of delta subtype selective drugs.