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

基本信息

批准号：
8660298
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
项目类别：
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/8660298
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

项目摘要

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 Jermaine Jones 博士提供开始独立研究所需的技能。在获奖期间，琼斯博士将实现以下培训目标：1）获得对人类精神活性物质进行研究的方法、安全性和伦理学的更全面的知识，2）获得当代流行病学和流行病学统计方法的专业知识。遗传学研究，3) 进一步发展他的资助写作和资助管理技能。我们将尝试阐明 3 种常见基因变异与羟考酮滥用倾向之间的关系。目前，处方阿片类药物的滥用在美国是一个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的阿片类药物对人类的主观和行为影响。拟议的研究将首先检查编码以下基因多态性的普遍性：s阿片受体（OPRM1）、促炎细胞因子（IL-12）和细胞色素P450肝代谢酶（CYP2D6）。来自各种来源的数据表明，这些特定 SNP 的功能后果可能会介导对阿片类药物的反应，从而导致其滥用倾向。因此，该提案的第二个目标是确定每个参与者（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。在这些参与者的子集中，我们将在一次实验室会议中量化羟考酮剂量递增（0、10 和 30 毫克）的效果。来自两个采样群体的每种目标基因型（OPRM1:118G、IL-12-511C（或 31T）、CYP2D6 无效等位基因：*3、*4、*5、*6、*7 或 *8）的 10 个个体（处方阿片类药物滥用者和非阿片类药物滥用者对于每种感兴趣的变异都是纯合的）将完成实验室会议，在此期间我们将量化主观影响羟考酮（见下图）。我们的主要依赖测量将是羟考酮的积极主观作用（例如，“我感觉药物效果很好”）。次要依赖性测量将包括其他主观评分（例如，“我感到恶心”）、麦吉尔疼痛问卷总分、认知影响和生理反应。我们假设与处方阿片类药物滥用者相比，这些特定等位基因（118G、12-511C/12-31T、CYP2D6:*3、*4、*5、*6、*7 或 *8）的频率更高海洛因滥用者和非药物滥用者，并且这些等位基因的存在将与改变对羟考酮的主观反应有关。如果从这项调查中获得的数据支持我们的假设，则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为独立研究者。