Contribution of Various Genetic Polymorphisms to Oxycodone's Abuse Liability

描述(由申请人提供)：这项提案将为Jermaine Jones博士提供开始独立研究的必要技能。在获奖期间，琼斯博士将实现以下培训目标：1)获得更全面的人类精神活性物质研究的方法学、安全性和伦理学知识；2)获得流行病学和遗传学研究的当代统计学方法方面的专业知识；3)进一步发展他的赠款撰写和赠款管理技能。我们将试图阐明3种常见的基因变异与羟考酮滥用倾向的关系。目前，处方阿片类药物的滥用在美国是一个普遍的社会问题。为了了解导致处方阿片类药物滥用的一些变量，我们的实验室一直在量化经常滥用的阿片类药物对人类的主观和行为影响。这项拟议的研究将首先检查编码S阿片受体(OPRM1)、促炎细胞因子(IL-12)和细胞色素P450肝脏代谢酶(CYP2D6)的基因的多态发生率。来自各种来源的数据表明，这些特定SNP的每一个功能后果可能调节对阿片类药物的反应，因此有助于它们的滥用责任。因此，这项提案的第二个目标是确定这些单一参与者(150名海洛因滥用者+150名处方阿片类药物滥用者+150名非药物滥用者)的程度，并收集血液样本进行基因分析。在这些参与者中的一个子集中，我们将在单个实验室会议中量化递增剂量的羟考酮(0、10和30毫克)的影响。来自两个抽样人群(处方阿片类药物滥用者和非阿片类药物滥用者，每种感兴趣的纯合子)的每个目标基因(OPRM1：118G，IL-12-511C(或31T)，CYP2D6无效等位基因：*3，*4，*5，*6，*7或*8)的10个人将完成实验室环节，在此期间，我们将量化羟考酮的主观影响(见下图)。我们的主要依赖指标将是羟考酮的积极主观效果(例如，“我感觉很好的药物效果”)。次级依赖测量将包括其他主观评分(例如，我感到恶心)、麦吉尔疼痛问卷的总分、认知效果和生理反应。我们推测，与海洛因滥用者和非药物滥用者相比，处方阿片类药物滥用者中这些特定等位基因(118G、12-511C/12-31T、CYP2D6：*3、*4、*5、*6、*7或*8)的频率会更高，这些等位基因的存在将与羟考酮主观反应的改变有关。如果从这项研究中获得的数据支持我们的假设，它可能表明一种机制，即单基因多态介导某些阿片类药物的滥用潜力。通过其结构化的指导、课程作业和创新研究的结合，该奖项将确保琼斯博士成功地过渡到一名独立的研究员。 与公共卫生相关：以前的研究表明，特定基因中的SNP导致的功能后果可能会改变对阿片类药物的主观反应，从而影响它们的滥用倾向。本研究将检测三种基因变异(OPRM1：118G，IL-12：IL-12：IL-1 2-511和IL-1B-31，以及CYP2D6：*3，*4，*5，*6，*7，*8)在三个人群(处方类阿片滥用者、海洛因滥用者和非吸毒者)中的患病率，并观察这些变异的存在与羟考酮改变的主观和生理效应的相关性。这项研究的结果应该会产生关于遗传变异与一种常见滥用阿片类药物滥用潜力之间关系的重要信息。

DESCRIPTION (provided by applicant): This proposal will provide Dr. Jermaine Jones with the necessary skills to begin an independent line of research. During the award period, Dr. Jones will accomplish the following training goals: 1) acquire a more comprehensive knowledge of the methodology, safety, and ethics of conducting research with psychoactive substances in humans, 2) gain expertise in contemporary statistical approaches to epidemiological and genetics research, and 3) further develop his grant writing and grant management skills. We will attempt to elucidate the relationship between 3 common gene variants and the abuse liability of oxycodone. Currently, the abuse of prescription opioid medications is a pervasive social problem in the U.S. In an effort to understand some of the variables contributing to prescription opioid abuse, our laboratory has been quantifying the subjective and behavioral effects of commonly abused opioid drugs in humans. The proposed study will first examine the prevalence of polymorphisms of genes that encode the: s opioid receptor (OPRM1), proinflammatory cytokine (IL-12), and cytochrome P450 hepatic metabolizing enzymes (CYP2D6). Data from a variety of sources suggest that functional consequences of each of these particular SNPs may mediate response to opioid drugs and therefore contribute to their abuse liability. Accordingly the second goal of this proposal is to identify the extent to which each of these single participants (150 Heroin Abusers + 150 Prescription Opioid Abusers + 150 Non-Drug Abusers) and collect blood samples for genetic analyses. In a subset of these participants, we will quantify the effects of ascending doses of oxycodone (0, 10, and 30 mg) in a single laboratory session. Ten individuals of each target genotype (OPRM1:118G, IL-12- 511C (or 31T), CYP2D6 null alleles: *3,*4,*5,*6,*7, or*8) from two of the populations sampled (prescription opioid abusers and non-opioid abusers homozygous for each variant of interest) will complete the laboratory session during which we will quantify the subjective effects of oxycodone (see figure below). Our primary dependent measure will be the positive subjective effects of oxycodone (e.g., "I feel a good drug effect"). Secondary dependent measures will include other subjective ratings (e.g., "I feel nauseated"), sum scores on the McGill Pain Questionnaire, cognitive effects, and physiological responses. We hypothesize that there will be a higher frequency of these specific alleles (118G, 12-511C/12-31T, CYP2D6:*3,*4,*5,*6,*7, or*8) among prescription opioid abusers compared to heroin abusers and non-drug abusers, and that the presence of these alleles will be associated with altered subjective response to oxycodone. If the data gained from this investigation support our hypotheses, it may suggest a mechanism by which a single gene polymorphism mediates the abuse potential of certain opioids. Through its combination of structured mentorship, coursework, and innovative research, this award will ensure Dr. Jones' successful transition to an independent investigator. PUBLIC HEALTH RELEVANCE: Previous studies suggest that functional consequences resulting from SNPs in select genes have the potential to alter subjective response to opioid drugs, consequently affecting their abuse liability. This study will examine the prevalence of three gene variants (OPRM1: 118G, Interleukin IL-12: IL-1 2-511 and IL-1B-31, and CYP2D6: *3, *4, *5, *6, *7, *8) among three populations (prescription opioid abusers, heroin abusers, non-drug abusers) and observe for correlations between the presence of these variants and altered subjective and physiological effects of oxycodone. The results of this study should yield important information concerning the relationship between genetic variation and the abuse potential of a commonly abused opioid.