Pharmacology of opioid receptor subtype

阿片类药物在治疗疼痛方面有着独特的地位，尽管它们也有 由于滥用的可能性。大多数临床使用的阿片类药物通过μ阿片类药物起作用 受体。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性的证明提出了以下问题 这些药物是如何通过单一的μ受体起作用的。药理研究 回溯到二十多年前，已经表明存在多个mu亚群， 受体，一个概念，现在已证实与克隆的剪接变异体， 在小鼠、大鼠和人中克隆μ受体莫尔-1。了解这些受体的作用 行为的变化对于这些药物的最佳使用是重要的。在本申请中，我们 我建议扩展正在进行的研究，将克隆的莫尔-1变体与它们在 vivo.我们认为，μ阿片类药物在体内的作用反映了一种药物的作用总和， 许多mu受体变体，mu药物之间的差异反映了它们的不同 对这些受体群体的功效。我们建议用这两种方法来检验这一假设。 反义定位、基因敲除动物和传统的行为方法。我们还将绘制 在这些模型中变异体的表达。其他研究将 重点关注阿片类药物作用的局部机制，作为模型系统，以检查这些变体， 更明确的制度。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，这些研究应该提供了对莫尔-1剪接变异体在细胞凋亡中的作用的见解。 阿片类药物的作用，并更好地了解这些药物的使用。

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.