Ethnic differences in endogenous pain regulation: PET imaging of opioid receptors

描述（由申请人提供）：慢性疼痛是医疗保健利用的头号动机，影响超过1亿美国人，成本超过1万亿美元 每年都要遭受巨大的痛苦和身体残疾。相当多的证据表明，种族群体在急性和临床疼痛的经历中表现出很大的差异，与非西班牙裔白人（NHW）相比，非裔美国人（AA）的许多临床疼痛状况的患病率增加，并报告了更高水平的疼痛严重程度和疼痛相关残疾。有证据表明，这些群体之间的差异与其他人口统计学因素无关，如年龄，性别，社会经济地位，教育，就业，婚姻状况和其他潜在的混杂因素，如医学合并症和疾病持续时间。这些种族差异在实验室中得到了反映，在实验室中，对健康个体施加了受控的、系统的伤害性刺激。实验室疼痛反应的种族差异是公认的，这表明与NHWs相比，AA对伤害性刺激的敏感性增加。在我们以前的工作中，我们已经证明了增强的反应，在AA的伤害性刺激的几个任务，间接评估内源性疼痛抑制系统，至少部分阿片类药物介导的。中枢和外周神经系统内源性阿片类神经递质的种族差异表明，这些系统的功能效率较低的AA之间，并可能占很大比例的种族差异观察到的疼痛和镇痛反应。此外，药物遗传学研究表明，许多药物（包括镇痛药）的代谢、临床有效性和副作用特征存在显著的种族差异。绝大多数临床使用的阿片类药物通过激活μ-阿片受体产生作用，使其成为研究的一个非常相关的目标。我们建议使用正电子发射断层扫描（PET）成像的μ阿片受体采用μ-选择性激动剂[11 C]卡芬太尼检查种族差异在脊髓上的内源性阿片系统。健康AA和性别、年龄、SES匹配的NHW受试者将使用[11 C]卡芬太尼进行一次基线（无疼痛）和一次辣椒素诱导疼痛PET检查。目前的提案将测量μ阿片结合潜力，并研究其在疼痛敏感性种族差异中的作用。我们的总体目标是研究内源性阿片系统作为种族和疼痛敏感性之间的关联机制，从而提高我们对种族差异的神经生物学的理解。这些发现将产生深远的影响，包括阐明疼痛种族差异背后的有形生理机制，用于处方止痛药和推进个性化医疗。加强我们对疼痛种族差异的机制的理解可能有助于改善有针对性的干预措施，以减轻高危人群的临床疼痛，并有助于减少疼痛相关的健康问题。

DESCRIPTION (provided by applicant): Chronic pain is the number one motivator for healthcare utilization, affects over 100 million Americans, costs in excess of one trillion dollars annually and exacts profound suffering and physical disability. Considerable evidence has demonstrated that ethnic groups show substantial variability in the experience of acute and clinical pain, with African Americans (AAs) having increased prevalence of a number of clinical pain conditions and reporting higher levels of pain severity and pain-related disability in response to pain when compared to non-Hispanic whites (NHW). Evidence suggests that disparities between these groups are independent of other demographic factors such as age, sex, socioeconomic status, education, employment, marital status, and other potential confounders, such as medical comorbidities and disease duration. These ethnic differences have been mirrored in the laboratory where controlled, systematic noxious stimuli are applied to healthy individuals. Ethnic differences in laboratory pain responses are well-established, suggesting increased sensitivity to noxious stimulation among AAs compared to NHWs. In our previous work, we have demonstrated enhanced responsiveness in AAs to noxious stimulation on several tasks that indirectly assess endogenous pain-inhibitory systems that are at least partially opioid-mediated. Ethnic differences in endogenous opioid neurotransmitters in the central and peripheral nervous system suggest that these systems function less efficiently among AAs and may account for a substantial proportion of the ethnic differences observed in pain and analgesic responses. In addition, pharmacogenetic research shows substantial ethnic group differences in the metabolism, clinical effectiveness, and side-effect profiles of many drugs; including analgesics. The overwhelming majority of clinically used opioids elicit their effects through activation of the mu-opioid receptor, making it an extremely relevant target for investigation. We propose to examine ethnic differences in the supraspinal endogenous opioid system using positron emission tomography (PET) imaging of mu-opioid receptors employing the mu-selective agonist [11C] carfentanil. Healthy AAs and sex, age, SES matched, NHW participants will undergo one baseline (non-pain) and one capsaicin-induced pain PET session using [11C] carfentanil. The current proposal will measure mu-opioid binding potential and examine its role in ethnic group differences in pain sensitivity. Our overarching objective is to investigate the endogenous opioid system as the mechanism underlying the association between ethnicity and pain sensitivity, thereby enhancing our understanding of the neurobiology of ethnic differences. These findings will have far reaching implications; including elucidating a tangible, physiological mechanism underlying ethnic differences in pain, for prescribing analgesics and advancing personalized medicine. Enhancing our understanding of mechanisms underlying ethnic differences in pain is likely to assist in the refinement of targeted interventios to alleviate clinical pain in at-risk populations, and aid in reducing pain-related health disparites.