Understanding the Effects of Chronic Opioids Therapy in Humans

简介（由申请人提供）：PI是一名新独立的科学家（1R01DA029078-01A1），是斯坦福大学的医生和临床研究员。该奖项将提供一段时间的密集研究重点，这将使PI提高他的研究生涯（见研究）。该奖项也将用于促进候选人的发展，以扩大他的潜力，做出重大的研究贡献（见候选人）。候选人：该PI是一名新独立的科学家（1R01DA029078-01A1），以前曾获得NIH职业发展奖资助（K23GM071400； NIH临床研究LRP），他将使用K02奖进行进一步的职业发展活动，以扩大他的潜力，做出重大的研究贡献。这些活动包括培训负责任的研究行为，与高级研究人员合作开发新的研究模式，参加会议，提出进一步的研究建议，指导研究，以及发表直接转化为患者护理的高质量研究。环境：PI有400平方英尺。斯坦福大学的人类阿片类药物生理学实验室位于斯坦福医学院，这是一个科学活动的中心，也是2008年和2011年卓越疼痛管理中心的所在地。除了与流行病学和健康研究政策部门的资深科学家保持持续的关系外，PI还与斯坦福大学的人类免疫监测核心和卢卡斯功能磁共振成像中心设施进行了积极的研究合作。这些设施和合作关系使斯坦福大学成为支持该奖项目标的最佳环境。研究：目前，阿片类药物是美国医生开的最常见的药物之一，维柯丁（氢可酮/对乙酰氨基酚）是所有类别中开得最多的药物。然而，身体依赖（PD）、成瘾和阿片类药物戒断（OW）使处方阿片类药物的使用复杂化。2006年，在所有12岁及以上的美国人中，13.6%（超过3300万人）报告至少一次因非医疗目的使用处方阿片类药物，前一年超过1200万人，前一个月520万人。基于单倍型计算图谱的药物遗传学研究表明，5HT3受体与PD和OW有关。来自PI初步研究的其他数据表明，5HT3受体拮抗剂（RAs）可以显着降低人类阿片类药物戒断的客观测量。PI目前的研究将评估5HT3-RAs在治疗和预防处方阿片类药物滥用中的新适应症的使用。PI实验室的其他研究旨在通过新的方式揭示慢性阿片类药物治疗对人体生理的影响，包括fMRI和阿片类药物诱导变化的免疫调节。这些研究结果的意义是重大的。通过提供一种有效、易于交付、低成本的方法来减轻OW的症状，防止PD的发展或进展，5HT3-RA药物可以大大改善疼痛的治疗。

DESCRIPTION (provided by applicant): The PI is a newly independent scientist (1R01DA029078-01A1) who is a physician and clinical researcher at Stanford University. This award will provide a period of intensive research focus that will allow the PI to enhance his research career (see RESEARCH). This award will also be used to foster the development of the candidate in order to expand his potential to make significant research contributions (see CANDIDATE). CANDIDATE: The PI is a newly independent scientist (1R01DA029078-01A1) with a history of previous NIH career development award funding (K23GM071400; NIH Clinical Research LRP), who will use the K02 award to pursue further career development activities in order to expand his potential to make significant research contributions. These activities include training in the responsible conduct of research, collaboration with senior researchers to develop new modes of inquiry, conference participation, further study proposals, research mentorship, and publication of quality research that translates directly to patient care. ENVIRONMENT: The PI's 400 sq. ft. human opioid physiology laboratory is situated in the Stanford School of Medicine, a hub of scientific activity and home to the 2008 and 2011 Center of Excellence-Winning Pain Management Center. The PI has active research collaborations with the Human Immune Monitoring Core and Lucas fMRI Imaging Center facilities at Stanford, in addition to ongoing relationships with senior scientists in the Epidemiology and Health Research Policy Departments. These facilities and collaborative relationships make Stanford an optimal environment to support the objectives of this award. RESEARCH: Currently, opioids are among the most common medications prescribed by physicians in the US and Vicodin (hydrocodone/acetaminophen) is the most prescribed medication of any category. However, physical dependence (PD), addiction, and opioid withdrawal (OW) complicate the use of prescription opioids. Among all Americans age 12 years and older in 2006, 13.6% (more than 33 million) reported having used prescription opioids for nonmedical purposes at least once, more than 12 million in the prior year, and 5.2 million in the prior month. Recent evidence from studies employing pharmacogenetic haplotype-based computational mapping have linked the 5HT3 receptor to PD and OW. Additional data from the PI's preliminary research show that 5HT3 receptor antagonists (RAs) can significantly decrease objective measures of opioid withdrawal in humans. The PI's current studies will evaluate the use of 5HT3-RAs for new indications in the treatment and prevention of prescription opioid drug abuse. Additional studies in the PI's lab aim to uncover the effects of chronic opioid therapy on human physiology through novel modalities, including fMRI and immunomodulation of opioid-induced changes. The implications of these research findings are substantial. By providing an effective, easily deliverable, low-cost method to mitigate the symptoms of OW and prevent the development or progression of PD, 5HT3-RA medications could drastically improve the treatment of pain.