TRAFFICKING AND FUNCTION OF MU-OPIOD RECEPTOR GENETIC VARIANTS

描述(申请人提供)：阿片类止痛药构成了我们医院疼痛治疗的支柱。然而，它们的使用因两个主要问题而变得复杂：患者反应的变异性，以及导致成瘾的耐受性和依赖性的发展。阿片成瘾是一种慢性复发性疾病，目前尚无治疗方法 有效的治疗。据估计，美国约有10%的人口对某种非法药物上瘾，这使其成为一个重大的社会经济问题。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，遗传因素对阿片类药物的这两个复杂方面都有贡献。对疼痛的耐受性、确定的阿片类药物的有效剂量、一种药物对另一种药物的有效性、对成瘾的易感性以及成瘾疗法的有效性，这些都取决于在不同人群的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类药物生理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治疗方法，并为推进个性化药物提供关键步骤。已发现遗传变异的一个关键基因是OPRM1，它编码mU-阿片受体(MOR)，许多临床滥用药物的靶标。研究已经将MOR中普遍存在的单核苷酸多态与疼痛耐受性、止痛性、对阿片类药物耐受和依赖的易感性、酒精中毒和神经精神障碍的差异联系起来。重要的是，这些多态是否以及如何在分子水平上改变MOR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GPCR在活细胞中的运输，以研究普遍存在的MOR多态如何改变神经元中的MOR功能。将根据已知的等位基因频率和与临床疾病的联系对SNPs进行优先排序，从最普遍和临床相关的SNP A118G开始。具体地说，我们将测试激活诱导的MOR信号和运输--定义神经元中MOR功能的两个基本事件。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，并有助于开发一个开发个性化剂量和策略的平台，用于疼痛治疗和药物成瘾的管理。

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.