MU OPIOID RECEPTOR--PHOSPHORYLATION AND DESENSITIZATION

描述：(申请人摘要) 这项拟议研究的总体目标是了解分子 阿片受体作用机制，尤其是阿片受体的作用机制 鸦片类药物成瘾作用的根本原因。一个突出的特点 类吗啡药物的特点是它们能够诱导耐受性和依赖性。 在人类身上。受体脱敏是细胞机制之一 可能在这些神经适应过程中发挥重要作用。 激动剂依赖的磷酸化参与血管紧张素转换酶的作用机制 多种G蛋白相关神经递质的脱敏作用 感受器。推测磷酸化在快速反应中起作用。 阿片受体介导的信号转导对阿片受体反应的减弱 鸦片类药物。受体磷酸化也有助于更长时间 脱敏事件，包括那些可能涉及耐受和 依赖。为了验证这一假说，一项关于磷酸化的研究 MU阿片受体和内源性MU阿片受体的克隆及其功能 提出了功能后果的概念。这项研究的具体目的是： (1)研究大鼠脑内Mu受体的磷酸化。 大鼠大脑，(2)定义受体的分子结构，这些分子结构 受体磷酸化所必需的，以及(3)研究Mu的作用 受体功能调节中的受体磷酸化。 这项工作将提供有价值的分子和细胞信息。 阿片受体的功能调节机制。它应该是 对我们对药物分子机制的认识产生了影响 宽容、依赖和上瘾。这样的理解对于 止痛药的药理分离及相加作用 鸦片类药物。对这些机制的理解有望导致 合理治疗和预防药物滥用。

DESCRIPTION: (Applicant's Abstract) The overall goal of the proposed research is to understand the molecular mechanisms of opiate receptors' function, especially the mechanisms underlying the addictive effect of opiate drugs. A prominent characteristic of morphine-like drugs is their ability to induce tolerance and dependence in humans. Receptor desensitization is one of the cellular mechanisms that could play a significant role in these neuroadaptive processes. Agonist-dependent phosphorylation contributes to the mechanisms of desensitization in a wide variety of G-protein linked neurotransmitter receptors. It is hypothesized that phosphorylation plays a role in rapid attenuation of opiate receptor-mediated signal transduction in response to opiate drugs. Receptor phosphorylation also contributes to longer term desensitization events including those that may be involved in tolerance and dependence. To test this hypothesis, a study on the phosphorylation of cloned mu opiate receptor as well as endogenous mu opiate receptors and its functional consequences is proposed. The specific aims of this study are: (1) to characterize mu receptor phosphorylation in neuronal tissues of the rat brain, (2) to define the molecular structures of the receptor that are required for receptor phosphorylation, and (3) to examine the roles of mu receptor phosphorylation in functional regulation of the receptor. This work will provide valuable information of molecular and cellular mechanisms on the functional regulation of the opiate receptors. It should have an impact on our knowledge to the molecular mechanism of drug tolerance, dependence and addiction. Such understanding is fundamental to the pharmacological segregation of the analgesic and additive effects of opiate drugs. An understanding of these mechanisms will hopefully result in rational therapy for treatment and prevention of drug abuse.