A118G SNP and OPRM1 Gene Opioid-Mediated Effects in Humans

描述(申请人提供)：阿片类药物滥用是一个重大的国家健康问题。药物遗传学，或个性化药物，使用基因信息来预测表型反应(通常药物疗效或安全性；18-19)。药物滥用领域在应用药物遗传学来识别患有阿片类药物滥用障碍的风险增加的个人或使用个人遗传信息指导治疗方面严重落后。越来越多的证据表明，OPRM1基因的一个功能多态性(A118G)编码了u阿片受体(Mor)，它介导了个体对阿片类药物的反应，并与阿片类药物依赖的发展直接相关(20-25)。到目前为止，还没有受控的人类实验室研究检验A118G SNP或OPRM1基因对阿片类药物个体反应的影响。下一个合乎逻辑的步骤是评估OPRM1单核苷酸多态(SNPs)的差异是否会推动个体对阿片类药物的反应，这将有助于将物质滥用领域推向药物遗传学治疗方法，并为使用受控和经过充分验证的实验室方法学来研究阿片类药物的基因-表型相互作用奠定先例。我们建议进行一项实验室研究，通过评估双盲服用阿片类药物的主观和生理反应，评估A118G SNP和额外的OPRM1标记SNP是否与各种不同的MOR介导功能有关。我们还将评估OPRM1在与MOR活性或阿片依赖相关的其他复杂表型上的贡献(例如，疼痛敏感性、内源性阿片类药物介导的皮质醇应激反应，以及延迟折扣行为经济任务)。这项研究将是一项基因和性别的组间评估，以及一项在住院临床研究单位进行的为期6天的阿片类药物剂量反应的受试者内评估。参与者(n=100)将在随机、反平衡研究设计中接受双盲剂量的口服氢吗啡酮或安慰剂。药物效应的自我报告、生理和唾液皮质醇测量将在给药后的6个时间点收集，并在筛查和药物效应高峰期实施延迟折扣。我们还将实施两种不同的可操作性疼痛任务，在安慰剂或氢吗啡给药的条件下，提供疼痛敏感性的量化估计。这项研究将是迄今为止对具有阿片介导效应的A118G SNP和OPRM1基因进行的最对照、最严格、最全面的检查。我们期望该基因将与几种阿片类药物介导的效应相关联，并且该结果将促进我们对OPRM1对特定行为表型的贡献的理解。这些数据将促进药物遗传学对药物滥用的使用和对基于基因的假说的实验室测试的使用，并将有助于制定阿片依赖预防战略和干预措施，以治疗共存的疼痛和阿片依赖。

DESCRIPTION (provided by applicant): Abuse of opioids is a significant national health problem. Pharmacogenetics, or personalized medicine, uses genotype information to predict phenotypic response (generally medication efficacy or safety; 18-19). The field of substance abuse is critically lagging behind in the application of pharmacogenetics for identifying individuals at increased risk for developing an opioid abuse disorder, or using personal genetic information to guide treatment. There is growing evidence to suggest a functional polymorphism (A118G) in the OPRM1 gene that codes for the mu opioid receptor (MOR) mediates individual response to opioid medications and has direct relevance for the development of opioid dependence (20-25). To date, no controlled human laboratory studies have examined the effect of the A118G SNP or OPRM1 gene on individual response to opioids. The next logical step is to evaluate whether differences in OPRM1 single nucleotide polymorphisms (SNPs) drive individual response to opioid medications, which will help advance the field of substance abuse towards a pharmacogenetics approach to treatment, and establish a precedent for using controlled and well-validated laboratory methodology to investigate the genotype-phenotype interactions of opioids. We are proposing to conduct a laboratory study to evaluate whether the A118G SNP and additional OPRM1 tagging SNPs are associated with a variety of different MOR-mediated functions by evaluating subjective and physiological response to double-blind administration of an opioid medication. We will also evaluate the contribution of OPRM1 on other complex phenotypes related to the MOR activity or opioid dependence (e.g., pain sensitivity, the endogenous opioid-mediated cortisol stress response, and a delay discounting behavioral economic task). This study will be a between-group evaluation of genotype and gender, and a within-subject evaluation of opioid dose-response that will be conducted over 6 days in a residential clinical research unit. Participants (n=100) will receive double-blind doses of oral hydromorphone or placebo in a randomized, counter-balanced research design. Self-report, physiological, and salivary cortisol measures of drug effects will be collected at 6 time points following drug administration, and delay discounting will be administered at screening and during peak drug effects. We will also administer 2 different operant pain tasks that provide quantifiable estimates of pain sensitivity, under conditions of placebo or hydromorphone administration. This study will be the most controlled, rigorous, comprehensive examination of the A118G SNP and OPRM1 gene with opioid-mediated effects to date. We expect that genotype will be associated with several opioid-mediated effects, and that the results will advance our understanding of the contribution of OPRM1 to specific behavioral phenotypes. These data will advance the use of pharmacogenetics for substance abuse and use of laboratory testing for genotype-based hypotheses, and will contribute to the development of opioid dependence prevention strategies and interventions to treat comorbid pain and opioid dependence.