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）：滥用阿片类药物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（一般是药物疗效或安全性；18-19）。药物滥用领域在药物遗传学的应用方面严重落后，无法识别发生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mu阿片受体（MOR）的OPRM1基因的功能多态性（A118G）介导个体对阿片药物的反应，并与阿片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，这将有助于将药物滥用领域推进药物遗传学方法的治疗，并建立一个先例，使用控制和良好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。我们建议开展一项实验室研究，通过评估对双盲给药阿片类药物的主观和生理反应，来评估A118G SNP和其他OPRM1标记SNP是否与多种不同的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（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）的贡献。这项研究将是一项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，将在一个住院临床研究单位进行6天以上。在一项随机、平衡的研究设计中，参与者（n=100）将接受双盲剂量口服氢吗啡酮或安慰剂。药物作用的自我报告、生理和唾液皮质醇测量将在给药后的6个时间点收集，延迟折扣将在筛选和药物作用高峰期进行。我们还将在安慰剂或氢吗啡酮给药的情况下进行2种不同的手术疼痛任务，提供可量化的疼痛敏感性评估。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的最严格、最全面、最受控制的研究。我们预计基因型将与阿片类药物介导的几种效应相关，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基于基因型假设的实验室检测的使用，并将有助于阿片类药物依赖预防策略和干预措施的发展，以治疗合并症疼痛和阿片类药物依赖。