MU OPIOID RECEPTOR GENE IN HEROIN ADDICTS

海洛因成瘾是一个严重的社会问题，影响着美国一百多万人。在身体和大脑中，海洛因被水解成吗啡，吗啡作用于阿片受体，产生欣快的效果，从而赋予药物强化特性，并导致成瘾。药物成瘾是一个复杂的过程，被认为是社会、环境和生物因素（包括遗传因素）相互作用的结果。在我们最初的建议中，我们假设mu阿片受体可能存在遗传多态性并改变受体功能，从而导致个体对海洛因滥用的易感性差异。在目前的资助期间，我们已经观察到五种不同的单核苷酸多态性（snp）；其中两个snp相对常见（10.5%和6.6%的等位基因频率），并且在种族群体中都表现出差异分布。其中一种似乎对其中一个种族的阿片类药物成瘾有保护作用；它还改变了-内啡肽的结合亲和力和激动剂的效力。另一种常见变异在前海洛因成瘾者中发生的频率要高得多，这表明对阿片类药物依赖有遗传倾向。在这个竞争性的更新应用中，我们建议扩展我们对人类mu阿片受体遗传变异的临床和功能意义的研究。我们将检查更多的研究对象，并确定前海洛因依赖者和不同种族的对照组的等位基因分布。我们还将研究它们对神经元Ca2+通道受体调节和腺苷酸环化酶活性抑制的影响。此外，我们将确定mu受体多态性对慢性吗啡治疗的细胞反应的影响，因为海洛因成瘾期间发生的主要问题来自于长期暴露于阿片类药物。本次更新申请的研究结果将在两个方面提供有价值的信息：首先，通过研究序列变异对mu受体细胞功能的影响，我们将了解遗传多态性如何影响受体活性和神经元兴奋性。此外，通过确定这些遗传变异在阿片类药物依赖个体和正常对照之间的分布，我们将开始认识到遗传多态性在阿片类药物依赖倾向或保护中的作用。

Addiction to heroin is a major social problem, affecting over a million people in the United States. In the body and brain, heroin is hydrolyzed to morphine, which acts at the mu opioid receptor and results in a euphoric effect, thus conferring the reinforcing properties of the drug and contributing to addiction. Drug addiction is a complex process, thought to result from the interaction of social, environmental, and biological factors including a genetic component. In our original proposal, we hypothesized that genetic polymorphisms might exist in the mu opioid receptor and alter receptor function, contributing to variation in individual susceptibility to heroin abuse. During the current funding period we have observed five different single nucleiotide polymorphisms (SNPs); two of these SNPs were relatively common (10.5 percent and 6.6 percent allelic frequency), and both showed differential distributions among ethnic groups. One appeared to exert a protective effect against opioid addiction in one of the ethnic groups; it also altered beta-endorphin binding affinity and agonist potency. The other common variant occurred with a significantly higher frequency in former heroin addicts, suggesting a genetic predisposition for opioid dependence. In this competing renewal application, we propose to extend our study of the clinical and functional significance of genetic variation in the human mu opioid receptor. We will examine a larger number of study subjects, and determine the allele distribution in former heroin addicts and controls among different ethnic groups. We will also examine their impact on receptor modulation of neuronal Ca2+ channels and inhibition of adenylyl cyclase activity. Furthermore, we will determine the effects of the mu receptor polymorphisms on the cellular responses to chronic morphine treatment, since the primary problems that develop during heroin addiction come from prolonged exposure to the opioid drug. Results from the proposed study in this renewal application will provide valuable information in two areas: First of all, by studying the effects of sequence variants on the cellular function of the mu receptor, we will understand how genetic polymorphisms impact on receptor activity and neuronal excitability. Furthermore, by determining distribution of these genetic variations between opioid-dependent individuals and normal controls, we will start to appreciate the role of genetic polymorphism is predisposition for or protection against opioid dependence.