Contribution of Various Genetic Polymorphisms to Oxycodone's Abuse Liability

描述（由申请人提供）：本提案将提供博士杰梅因琼斯与必要的技能，开始一个独立的研究线。 琼斯将完成以下培训目标：1）获得更全面的知识，方法，安全性和伦理进行研究与精神活性物质在人类中，2）获得专业知识，在当代统计方法流行病学和遗传学研究，和3）进一步发展他的赠款写作和赠款管理技能。我们将试图阐明3种常见基因变异与羟考酮滥用倾向之间的关系。目前，滥用处方阿片类药物是美国普遍存在的社会问题，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人类常用阿片类药物的主观和行为影响。该研究将首先检查编码阿片受体（OPRM 1）、促炎细胞因子（IL-12）和细胞色素P450肝代谢酶（CYP 2D 6）的基因多态性的患病率。来自各种来源的数据表明，这些特定SNP中的每一个的功能后果可能介导对阿片类药物的反应，因此有助于其滥用倾向。因此，本提案的第二个目标是确定这些单独参与者（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）中每一个人的基因水平，并采集血样进行基因分析。在这些受试者的一个子集中，我们将在单次实验室治疗中量化递增剂量羟考酮（0、10和30 mg）的影响。来自两个采样人群（处方阿片类药物滥用者和每种目标变体纯合子的非阿片类药物滥用者）的每种目标基因型（OPRM 1：118 G、IL-12- 511 C（或31 T）、CYP 2D 6无效等位基因：*3、*4、*5、*6、*7或 *8）的10名个体将完成实验室检查，在此期间，我们将量化羟考酮的主观效应（见下图）。我们的主要依赖性测量将是羟考酮的积极主观效应（例如，“我觉得药效很好”）。二级相关指标将包括其他主观评级（例如，“我感觉疼痛”），麦吉尔疼痛问卷的总分，认知效果和生理反应。我们假设，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（118 G、12- 511 C/12- 31 T、CYP 2D 6：*3、*4、*5、*6、*7或 *8）的频率更高，并且这些等位基因的存在与对羟考酮的主观反应改变相关。如果从这项调查中获得的数据支持我们的假设，它可能表明一种机制，即单一基因多态性介导某些阿片类药物的滥用潜力。通过其结构化的指导，课程和创新研究的结合，该奖项将确保琼斯博士成功过渡到独立调查员。

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.