Contribution of Various Genetic Polymorphisms to Oxycodone's Abuse Liability

各种基因多态性对羟考酮滥用的影响

• 批准号: 8472467
• 负责人: JERMAINE D JONES
• 金额: $ 18.15万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-15 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8472467
• 关键词: Address; Affect; Age Factors; Agonist; Alleles; Analgesics; Award; Behavioral; Blood specimen; CYP2D6 gene; Cognitive; Cytochrome P-450 CYP2D6; Cytochrome P450; Data; Dependence; Development Plans; Disease; Dose; Drug Kinetics; Drug abuse; Drug effect disorder; Early Intervention; Ensure; Enzymes; Epidemiology; Ethics; Excretory function; Frequencies; Genes; Genetic; Genetic Polymorphism; Genetic Research; Genetic Variation; Genotype; Goals; Grant; Hand; Hepatic; Heritability; Heroin; Heroin Users; Human; Immersion Investigative Technique; Individual; Individual Differences; Inflammatory; Interleukin-1; Interleukin-12; Interleukins; Investigation; Knowledge; Laboratories; McGill Pain Scale; Measures; Mediating; Medical; Mentorship; Metabolism; Methodology; Opiate Addiction; Opioid; Opioid Receptor; Oxycodone; Oxymorphone; Participant; Pharmaceutical Preparations; Pharmacodynamics; Pharmacogenetics; Physiological; Plasma; Population; Prevalence; Recording of previous events; Recruitment Activity; Reporting; Research; Research Personnel; Risk; Safety; Sampling; Signal Transduction; Social Problems; Source; Structure; Sum; Testing; Training; Variant; Water; Writing; absorption; career development; cytokine; drug abuser; genetic analysis; genetic variant; immune activation; innovation; interest; non-drug; opioid abuse; prescription opioid; prescription opioid abuse; response; skills; volunteer

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.

描述（由申请人提供）：该提案将为杰梅因·琼斯博士提供必要的技能，以开始独立的研究。在此期间，Jones博士将完成以下培训目标：1)获得更全面的关于人类精神活性物质研究的方法论、安全性和伦理方面的知识；2)获得流行病学和遗传学研究的当代统计方法方面的专业知识；3)进一步提高他的拨款写作和拨款管理技能。我们将试图阐明三种常见的基因变异与羟考酮滥用风险之间的关系。目前，处方阿片类药物的滥用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常见滥用阿片类药物对人类的主观和行为影响。该研究将首先研究编码阿片受体（OPRM1）、促炎细胞因子（IL-12）和细胞色素P450肝代谢酶（CYP2D6）的基因多态性的普遍性。来自各种来源的数据表明，这些特定snp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。因此，本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遗传分析。在这些参与者的一个子集中，我们将量化在单次实验中增加羟考酮剂量（0、10和30毫克）的效果。每个目标基因型（OPRM1:118G, IL-12- 511C（或31T）， CYP2D6零等位基因：*3，*4,*5,*6，*7或*8）来自两个样本人群（处方阿片类药物滥用者和非阿片类药物滥用者为每个感兴趣的变体纯合）的10个个体将完成实验室会议，在此期间，我们将量化羟可酮的主观影响（见下图）。我们的主要依赖测量将是羟考酮的积极主观效应（例如，“我感觉药物效果很好”）。二级依赖测量将包括其他主观评分（例如，“我感到恶心”），McGill疼痛问卷的总得分，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（118G、12-511C/12-31T、CYP2D6:*3、*4、*5、*6、*7或*8）的频率更高，并且这些等位基因的存在将与对羟可酮的主观反应改变有关。如果从这项调查中获得的数据支持我们的假设，它可能表明单基因多态性介导某些阿片类药物滥用潜力的机制。通过其结构化指导、课程作业和创新研究的结合，该奖项将确保琼斯博士成功过渡到独立研究者。