Pharmacology of opioid receptor subtype

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，患者对单个药物的广泛反应以及μ阿片类药物之间不完全交叉耐受的证明提出了关于这些药物如何通过单个μ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变体与其体内功能相关联。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。我们还将以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。最后，我们将扩展转运蛋白在阿片类药物耐受性中的作用。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。 公共卫生相关性：吗啡和相关的μ阿片类药物通过一组μ受体产生作用，包括镇痛和大多数副作用。这些mu亚型已被克隆并在分子水平上表征。通过了解各种mu受体亚型的功能作用，有可能开发出没有这些副作用的镇痛药，甚至可能增强潜力。

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 to individual drugs and the demonstration of incomplete cross tolerance among mu opioids 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 their functions in vivo. 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 variants in a more defined system. Finally, we will expand upon the role of transporters in 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. PUBLIC HEALTH RELEVANCE: Morphine and related mu opiates produce their effects through a set of mu receptors, including both analgesia and most of their side-effects. These mu subtypes have been cloned and characterized at the molecular level. By understanding the functional roles of the various mu receptor subtypes, it may be come possible to develop analgesics lacking these side-effects, and possibly even reinforcing potential.