Pharmacology of opioid receptor subtype

描述(申请人提供)：鸦片类药物在治疗疼痛的医学中具有独特的地位，尽管它们也有可能被滥用的问题。大多数临床使用的阿片类药物是通过u阿片受体起作用的。然而，患者对个别药物的广泛反应以及u阿片类药物之间不完全交叉耐受的表现，引发了人们对这些药物如何都通过单一u受体起作用的问题。20多年前的药理学研究表明，存在多个mU受体亚群，这一概念现在已被克隆的mU受体MOR-1在小鼠、大鼠和人类中的剪接变体的克隆所证实。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。在这一应用中，我们建议扩展正在进行的将克隆的MOR-1变体与其在体内的功能相关的研究。我们认为，Mu阿片类药物在体内的作用反映了许多Mu受体变体的作用的总和，并且Mu药物之间的差异反映了它们对这些受体群体的不同疗效。我们建议使用反义图谱、基因敲除动物和传统的行为方法来检验这一假说。我们还将用免疫组织化学方法定位这些模型中的变异体的表达。其他研究将侧重于作为模型系统的阿片类药物作用的局部机制，以在更明确的系统中检查这些变体。最后，我们将阐述转运蛋白在阿片类药物耐受中的作用。总之，这些研究应该提供对MOR-1剪接变体在阿片类药物作用中的作用的见解，并更好地理解这些药物的使用。 公共卫生相关性：吗啡和相关的MU阿片类药物通过一组MU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，并在分子水平上进行了鉴定。通过了解不同Mu受体亚型的功能作用，有可能开发出没有这些副作用的止痛药，甚至有可能增强潜力。

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.