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，但并非没有问题。副作用往往有限，其供应增加导致其滥用的重大社会问题。临床上使用的大多数阿片类药物通过μ受体起作用，μ受体是由Oprm基因编码的G蛋白偶联受体。对许多μ阿片类药物的广泛临床反应提出了多个μ受体亚型的问题，这一概念已被克隆研究证实。μ阿片受体（莫尔-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。有两组变体。一种是由全长7个跨膜结构域受体组成，具有3'剪接，仅在细胞内C-末端的尖端不同。另一组涉及由不清楚意义的5'剪接产生的截短变体。我们最近产生了一系列具有独特药理学特征的阿片类镇痛药，并发现它们通过涉及截短的莫尔-1变体的新型受体靶点起作用。本提案的目的是进一步了解这些莫尔-1剪接变异体。第一个目标集中在IBNtxA和六个跨膜结构域变体的目标上，这些变体似乎是使用各种方法的组件。第二个着眼于单跨膜结构域的变体和它们在吗啡镇痛和耐受中的作用，而第三个探索了两个全长变体中3'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.