Pharmacology of opioid receptor subtypes

描述（由申请人提供）：阿片类药物在治疗疼痛方面具有独特的医学地位，尽管由于滥用的可能性，它们也存在问题。大多数临床使用的阿片类药物通过μ阿片受体起作用。然而，患者的广泛反应和不完全交叉耐受性的证明提出了关于这些药物如何通过单个mu受体起作用的问题。追溯到二十多年前的药理学研究已经表明存在μ受体的多个亚群，这一概念现在已经通过克隆小鼠、大鼠和人中克隆的μ受体莫尔-1的剪接变体的克隆得到证实。了解这些受体变体在行为中的作用对于这些药物的最佳使用非常重要。在本申请中，我们建议扩展正在进行的研究，将克隆的莫尔-1变体与体内阿片受体的功能作用相关联。主要的重点是在μ受体，虽然其他的研究将检查δ和κ受体以及。先前的研究已经表明，传统的七个跨膜结构域莫尔-1变体都选择性地结合μ阿片样物质，并且具有相似的高亲和力。然而，最近的研究表明，尽管这些药物在受体结合测定中具有相似性，但它们对变体的疗效差异很大。我们认为，μ阿片类药物在体内的作用反映了许多μ受体变体的作用总和，μ药物之间的差异反映了它们对这些受体群体的不同功效。我们建议使用反义定位，敲除动物和传统的行为方法来检验这一假设。我们还将通过免疫组织化学方法绘制这些模型中变体的表达。更多的研究将集中在阿片类药物作用的局部机制作为一个模型系统，以检查这些变量在一个更明确的系统。我们还将研究遗传背景在阿片类药物药理学中的作用。最后，我们将扩大我们的研究与转运蛋白P-糖蛋白。除了其在血脑屏障中的作用外，有证据表明它在阿片类药物耐受性的产生中也很重要。总之，这些研究应该提供见解的作用，莫尔-1剪接变异体阿片类药物的行动和更好地了解这些药物的使用。

DESCRIPTION (provided by applicant): 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.