Opiates have a unique place in medicine in the treatment of pain, although they also have problems due to the potential of abuse. Most clinically used opioids act through mu opioid receptors. Yet, the wide range of responses among patients and the demonstration of incomplete cross tolerance has raised questions regarding how these drugs could all be acting through a single mu receptor. Pharmacological studies going back over twenty years have suggested the existence of multiple subpopulations of mu receptors, a concept that has now been confirmed with the cloning of splice variants of the cloned mu receptor MOR-1 in mice, rats and humans. Understanding the role of these receptor variants in behavior is important for the optimal use of these drugs. In this application we propose to extend ongoing studies correlating the cloned MOR-1 variants with the functional roles of opioid receptors in vivo. The major focus is upon the mu receptors, although additional studies will examine delta and kappa receptors as well. Prior studies have shown that the traditional seven transmembrane domain MOR-1 variants all bind mu opioids selectively and with similar high affinities. Yet, recent studies indicate that the efficacy of these drugs for the variants varies widely despite their similarities in receptor binding assays. We believe that the effects of mu opioids in vivo reflect the summation of actions from a number of mu receptor variants and that differences among the mu drugs reflects their differing efficacies for these receptor populations. We propose to examine this hypothesis using both antisense mapping, knockout animals and traditional behavioral approaches. We also will map the expression of the variants in these models immunohistochemically. Additional studies will focus on topical mechanisms of opioid action as a model system to examine these variangs in a more defined system. We also will examine the role of genetic backgrounds in opioid pharmacology. Finally, we will expand upon our studies with the transporter P-glycoprotein. In addition to its well documented role in the blood brain barrier, evidence suggests it also is important in the production of opioid tolerance. Together, these studies should provide insights into the role of the MOR-1 splice variants on opioid action and a better understanding of the use of these drugs.
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