A118G SNP and OPRM1 Gene Opioid-Mediated Effects in Humans

描述（由申请人提供）：阿片类药物滥用是一个重大的国家健康问题。药物遗传学，或个性化医疗，使用基因型信息来预测表型反应（一般药物疗效或安全性; 18-19）。药物滥用领域严重落后于药物遗传学的应用，用于识别发展阿片类药物滥用障碍风险增加的个体，或使用个人遗传信息指导治疗。越来越多的证据表明，编码μ阿片受体（莫尔）的OPRM 1基因中的功能多态性（A118 G）介导了对阿片类药物的个体反应，并与阿片类药物依赖的发展直接相关（20-25）。迄今为止，没有对照的人类实验室研究检查了A118 G SNP或OPRM 1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OPRM 1单核苷酸多态性（SNP）的差异是否驱动个体对阿片类药物的反应，这将有助于推进药物滥用领域的药物遗传学治疗方法，并建立使用受控和经过验证的实验室方法来研究阿片类药物的基因型-表型相互作用的先例。我们建议进行一项实验室研究，通过评估对阿片类药物双盲给药的主观和生理反应，评估A118 G SNP和其他OPRM 1标记SNP是否与各种不同的MOR介导的功能相关。我们还将评估OPRM 1对与莫尔活性或阿片类药物依赖相关的其他复杂表型的贡献（例如，疼痛敏感性、内源性阿片样物质介导的皮质醇应激反应和延迟贴现行为经济任务）。本研究将是基因型和性别的组间评价，以及阿片类药物剂量反应的受试者内评价，将在住院临床研究单位进行6天。受试者（n=100）将接受双盲剂量的口服氢吗啡酮或安慰剂，采用随机、平衡研究设计。将在给药后6个时间点收集药物效应的自我报告、生理和唾液皮质醇测量值，并在筛选和药物效应峰值期间进行延迟折扣。我们还将在安慰剂或氢吗啡酮给药的条件下进行2种不同的操作性疼痛任务，以提供疼痛敏感性的可量化估计。这项研究将是迄今为止对A118 G SNP和OPRM 1基因与阿片类药物介导的作用进行的最严格，最全面的检查。我们预计基因型将与几种阿片类药物介导的效应相关，并且这些结果将促进我们对OPRM 1对特定行为表型的贡献的理解。这些数据将推动药物遗传学在药物滥用中的应用，以及基于基因型假设的实验室检测的应用，并将有助于制定阿片类药物依赖预防策略和干预措施，以治疗共病疼痛和阿片类药物依赖。

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.