One of the most importance concepts to emerge in recent years in opiate research is the concept of multiple opioid receptors. Originally proposed as """"""""Receptor Dualism"""""""", this concept has now been expanded to include a variety of pharmacologically-defined receptor classes. Recent studies suggest two subtypes of mu receptors. The mu2 site corresponse to the classical morphine- selective mu recePtor previously characterized in peripheral bioassays and in the brain. The mul receptor was first recognize in receptor binding studies and has a unique selectivity, finding most, but not all, enkephalins with high affinities similar to morphine. Pharmacological studies using naloxonazine and naloxazone, two relatively selective mul anragonisers, have correlated these two mu1 receptor subtypes with different opiate actions. For example, mul receptors play a major role in supraspinal analgesia whereas mu2 receptors mediate morphine's inhibition of Kastrointesinial transit and respiratory depression. Together, the ability of both pharmacological and binding studies to distinguish between these two subtypes argues strongly for their existence. Recent work also suggests the existence of subtypes of kappa receptors. This application proposes to examine the concept of mu and kappa receptor heterogeneity. Membrane binding studies will focus upon the development of selective assays for the various subtypes which when be used to examine their selectivity and biochemical characteristics. Highly selective mul binding assays are now available and will be used to characterize more fully the Pharmacological selectivity, regional distribution, ontogeny and phylogeny of mul receptors. Other studies will examine recent evidence suggesting the formation of a very slowly-associating receptor conformation involving G-Proteins through a multiste process. Additional investigations possibly will employ several new radioligands synthesized in our laboratory to affinity label both mu2 and kappa receptor subtypes and characterize them biochemically. The studies proposed in this application should further our understanding of mu and kappa receptor hetereokeneity and, hopefully, the development of highly selective anathesics lacking undesirable opioid side-effects.
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