A118G SNP and OPRM1 Gene Opioid-Mediated Effects in Humans

A118G SNP 和 OPRM1 基因阿片类药物介导的人类作用

• 批准号: 9276637
• 负责人: Kelly E Dunn
• 金额: $ 65.5万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9276637
• 关键词: Acquired Immunodeficiency Syndrome; Adverse effects; Alcohol or Other Drugs use; Alleles; Analgesics; Behavior; Behavioral; Blood Pressure; Caliber; Clinical Research; Code; Comorbidity; Complex; Cytochrome P450; Data; Development; Disease; Dose; Double-Blind Method; Drug Addiction; Enzymes; Evaluation; Gender; Genes; Genetic; Genetic Polymorphism; Genotype; Goals; Health; Hepatitis C; Heroin; Human; Hydrocortisone; Hydromorphone; Individual; Individual Differences; Intervention; Laboratories; Laboratory Study; Measures; Mediating; Methodology; Minor; Modeling; Narcotics; Nicotine; Opiate Addiction; Opioid; Oral; Outcome; Pain; Pain Threshold; Pain management; Participant; Patient Self-Report; Patients; Personal Genetic Information; Pharmaceutical Preparations; Pharmacogenetics; Phenotype; Physicians; Physiological; Placebos; Prevention strategy; Preventive Intervention; Property; Pupil; Randomized; Research; Research Design; Research Personnel; Risk; Safety; Salivary; Single Nucleotide Polymorphism; Societies; Stimulus; Subgroup; Substance abuse problem; Testing; Time; United States Food and Drug Administration; Warfarin; alcohol abuse therapy; base; behavioral economics; biological adaptation to stress; design; discount; discounting; endogenous opioids; genome wide association study; individualized medicine; innovation; leukemia; malignant breast neoplasm; mu opioid receptors; opioid abuse; personalized medicine; prevent; public health relevance; response; screening; treatment response

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.

描述（由申请人提供）：阿片类药物的滥用是一个重大的全国健康问题。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（通常是药物疗效或安全性；18-19）。药物滥用领域在应用药物遗传学来识别阿片类药物滥用障碍高风险个体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，编码 mu 阿片受体 (MOR) 的 OPRM1 基因中的功能多态性 (A118G) 介导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)。迄今为止，还没有对照人类实验室研究检验 A118G SNP 或 OPRM1 基因对个体对阿片类药物反应的影响。下一个合乎逻辑的步骤是评估 OPRM1 单核苷酸多态性 (SNP) 的差异是否会驱动个体对阿片类药物的反应，这将有助于推动药物滥用领域朝着药物遗传学方法进行治疗，并为使用受控和良好的治疗方法建立先例。经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。我们提议进行一项实验室研究，通过评估阿片类药物双盲给药的主观和生理反应，评估 A118G SNP 和其他 OPRM1 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 OPRM1 对与 MOR 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、内源性阿片类药物介导的皮质醇应激反应和延迟贴现行为经济任务）。这项研究将是基因型和性别的组间评估，以及阿片类药物剂量反应的受试者内评估，将在住宅临床研究单位进行 6 天以上。参与者（n = 100）将在随机、平衡的研究设计中接受双盲剂量的口服氢吗啡酮或安慰剂。将在给药后的 6 个时间点收集药物作用的自我报告、生理和唾液皮​​质醇测量值，并在筛选时和药物作用高峰期间进行延迟折扣。我们还将执行 2 种不同的操作性疼痛任务，在安慰剂或氢吗啡酮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 A118G SNP 和 OPRM1 基因与阿片类药物介导作用进行的最受控制、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，并且结果将增进我们对 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在药物滥用中的应用以及基于基因型假设的实验室测试的应用，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。