Pharmacology of opioid receptor subtype

鸦片类药物在治疗疼痛方面在医学上有独特的地位，尽管它们也有 由于可能被滥用而产生的问题。大多数临床使用的阿片类药物是通过Mu阿片类药物起作用的 感受器。然而，患者对个别药物的广泛反应和 MU阿片类药物之间的不完全交叉耐受性的证明引发了关于 这些药物是如何通过一个单一的Mu受体起作用的。药理研究 回溯到二十多年前，已经表明了亩的多个亚群的存在 受体，这一概念现在已经被克隆的剪接变体所证实 在小鼠、大鼠和人中克隆了Mu受体MOR-1。了解这些受体的作用 行为上的变异对于这些药物的最佳使用很重要。在此应用程序中，我们 建议扩大正在进行的将克隆的MOR-1变异体与其在 活着。我们认为，Mu阿片类药物在体内的作用反映了一种 Mu受体变异体的数量以及Mu药物之间的差异反映了它们的不同 对这些受体群体的疗效。我们建议使用两种方法来检验这一假设 反义图谱、基因敲除动物和传统的行为方法。我们还将绘制地图 用免疫组织化学方法检测这些模型中变异体的表达。更多的研究将 重点关注阿片类药物作用的局部机制，作为模型系统来检查这些变异体 更明确的系统。最后，我们将阐述转运蛋白在阿片类药物耐受中的作用。 总而言之，这些研究应该为MOR-1剪接变异体在 阿片类药物的作用和对这些药物的使用有更好的了解。

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.