Biochemical Characterization of Opioid BInding Sites

描述(由申请人提供)：阿片类药物在疼痛管理中发挥着重要作用，但并不是没有问题。副作用往往是有限的，而且它们可获得性的增加导致了滥用它们的重大社会问题。临床上使用的大多数阿片类药物都是通过Mu受体发挥作用的，Mu受体是一种由Oprm基因编码的G蛋白偶联受体。对多种Mu阿片类药物的广泛临床反应提出了多个Mu受体亚型的问题，这一概念已被克隆研究证实。Mu阿片受体(MOR-1)具有广泛的剪接变体，在小鼠、大鼠和人类中具有相似的剪接模式。有两组变种。一种是由具有3‘剪接的全长7个跨膜区受体组成，只是在细胞内C末端的末端不同。另一组涉及由5‘端剪接产生的截断变体，其意义不清楚。我们最近产生了一系列具有独特药理特征的阿片类止痛药，并发现它们通过一个新的受体靶点发挥作用，涉及一个截短的MOR-1变体。这项建议的目的是进一步了解这些MOR-1剪接变体。第一个目标是IBNtxA的靶标和六个跨膜结构域变体，它们似乎是使用各种方法的一个组成部分。第二个研究着眼于单个跨膜结构域变异及其在吗啡镇痛和耐受中的作用，第三个研究探讨了两个全长变异中3‘端剪接的影响。

DESCRIPTION (provided by applicant): Opiates play a major role in the management of pain, but not without problems. Side-effects are often limiting and their increased availability has led to major societal problems with their abuse. Most opioids used clinically act through the mu receptor, a G-protein-coupled receptor encoded by the Oprm gene. The wide range of clinical responses to a number of mu opioids raised the question of multiple mu receptor subtypes, a concept that has been confirmed with cloning studies. The mu opioid receptor (MOR-1) has a wide range of splice variants, with similar splicing patterns in mice, rats and humans. There are two groups of variants. One is comprised of full length 7 transmembrane domain receptors with 3' splicing, differing only at the tip of the intracellular C-terminus. The other set involve truncated variants generated from 5' splicing of unclear significance. We recently generated a series of opioid analgesics with unique pharmacological profiles and found that they act through a novel receptor target involving a truncated MOR-1 variant. The objective of this proposal is to further understand these MOR-1 splice variants. The first aim focuses upon the target for IBNtxA and the six transmembrane domain variants that appear to be a component using a variety of approaches. The second looks at single transmembrane domain variants and their role in morphine analgesia and tolerance while the third explores the effects of 3' splicing in two full length variants.