TRAFFICKING AND FUNCTION OF MU-OPIOD RECEPTOR GENETIC VARIANTS

描述（由申请人提供）：阿片类镇痛药是我们医院疼痛管理的主要药物。然而，它们的使用由于两个主要问题而变得复杂：患者反应的可变性，以及导致成瘾的耐受性和依赖性的发展。阿片类药物成瘾是一种慢性和复发性疾病，目前没有 有效治疗。据估计，美国约有10%的人口对某种非法药物或其他药物上瘾，使其成为一个主要的社会经济问题。解决成瘾的主要问题是我们不了解成瘾的分子机制。现在已经确定，遗传因素有助于阿片类药物的这两个复杂方面。对疼痛的耐受性，确定的阿片类药物的有效剂量，一种药物与另一种药物的疗效，成瘾的脆弱性以及成瘾治疗的有效性，都取决于在人群中不同基因中发现的序列变异。了解这些变化如何改变大脑中的阿片生理学将增加我们对疼痛和成瘾的理解，有助于开发针对这两个问题的新疗法，并为推进个性化医疗提供关键步骤。已确定遗传变异的一个关键基因是OPRM 1，它编码μ阿片受体（莫尔），这是许多临床滥用药物的靶点。研究已经将莫尔中普遍存在的单核苷酸多态性与疼痛耐受性、镇痛、对阿片类药物耐受性和依赖性的脆弱性、酒精中毒和神经精神疾病的变化联系起来。重要的是，这些多态性是否以及如何在分子水平上改变莫尔功能尚不清楚。我们建议利用我们在开发高分辨率成像分析方面的专业知识来研究活细胞中的GPCR运输，以研究普遍的莫尔多态性如何改变神经元中的莫尔功能。SNP将根据已知的等位基因频率和与临床疾病的联系进行优先排序，从A118G开始，A118G是最普遍和临床相关的SNP。具体来说，我们将测试激活诱导的信号和运输的莫尔-两个基本事件，定义莫尔功能的神经元。这项研究的完成将使我们更好地了解生理相关神经元中阿片信号的正常变化，为临床相关药物的功能选择性提供见解，并有助于开发一个平台，以开发个性化的疼痛治疗和药物成瘾管理的剂量和策略。

DESCRIPTION (provided by applicant): Opioid analgesics form the mainstay of pain management in our hospitals. However, their use is complicated by two main problems: variability in patient responses, and the development of tolerance and dependence leading to addiction. Addiction to opioids is a chronic and relapsing disorder for which there is currently no effective treatment. It is estimated that about 10% of the population in the United States is addicted to some illicit drug or other, making it a major socioeconomic problem. The main problem in addressing addiction is that we do not understand the molecular mechanisms underlying addiction. It is now established that genetic factors contribute to both these complicating aspects of opioids. The tolerance to pain, effective dosage of a defined opioid, efficacy of one drug vs. another, vulnerability to addiction, and effectiveness of addiction therapies, all depend on sequence variations that have been identified in different genes across populations. Understanding how these variations change opioid physiology in the brain will increase our understanding of pain and addiction, help in the development of new treatments for both these problems, and provide key steps in advancing personalized medicine. One key gene where genetic variations have been identified is OPRM1, which encodes the mu-opioid receptor (MOR), the target of many clinically abused drugs. Studies have linked prevalent single nucleotide polymorphisms in MOR to variations in pain tolerance, analgesia, vulnerability to opioid tolerance and dependence, alcoholism, and neuropsychiatric disorders. Importantly, whether and how these polymorphisms change MOR function at a molecular level is not known. We propose to use our expertise in developing high-resolution imaging assays to study GPCR trafficking in living cells to study how prevalent MOR polymorphisms change MOR function in neurons. The SNPs will be prioritized based on the known allelic frequency and linkage to clinical disorders, starting with A118G, the most prevalent and clinically relevant SNP. Specifically, we will test activation-induced signaling and trafficking of MOR - two fundamental events that define MOR function in neurons. Completion of this study will give us a better understanding of the normal variation of opioid signaling in physiologically relevant neurons, provide insights into functional selectivity of clinically relevant drugs, and help in developing o a platform to develop personalized doses and strategies for pain therapy and management of drug addiction.