Sex-Differences in Peripheral Opioid Receptor Mechanisms

描述(由申请人提供)：这项提案调查了导致外周阿片受体(POR)系统中分子、细胞和功能特性性别差异的因素。我们将重点研究外周应用阿片类激动剂的性别差异在炎症性肌肉疼痛条件下表达的新机制。该项目的中心假设是POR机制的性别差异在初级传入信号传递过程中的多个水平上表达，损伤或炎症对POR信号的影响在性别之间存在差异。研究将确定在正常和炎症条件下，是否存在性别差异：(1)三种ORs亚型、4和：ORS的表达水平；(2)三种ORs亚型的亚细胞定位；(3)主要下游靶标G蛋白偶联和ATP依赖的内向整流钾通道(GIRK和KATP)的表达。这些研究中的每一项都将伴随着评估分子和细胞变化的功能相关性的行为测试。这些研究具有很高的临床意义，因为涉及咀嚼肌和TMJ的疼痛和处理，例如在TMJMD中，是性别二态的，而且越来越多的临床和临床前证据表明，Pors是治疗各种类型慢性疼痛的潜在靶点。了解POR功能性别差异的机制基础将有助于制定针对持续性口面部肌肉疼痛的性别管理策略。公共卫生相关性这个项目研究了在炎症性乳房疼痛的情况下，外周阿片受体(POR)效应中可能存在性别二型性的新机制。PORs，即MU、Delta和Kappa ORs，正日益被认为是重要的治疗靶点，在炎症性疼痛条件下介导抗伤害性和/或抗痛觉过度，而不产生中枢介导的副作用。许多类型的慢性疼痛状况，如颞下颌关节肌肉疾患(TMJMD)，都表现出性二态疼痛和止痛反应。因此，该项目的结果可以为基于机制的性别特异性治疗替代方案的开发提供重要的新见解，这些替代方案可以针对外周阿片受体系统来改善持续性口面部肌肉疼痛。

DESCRIPTION (provided by applicant): This proposal investigates the factors that contribute to sex-differences in molecular, cellular, and function properties in peripheral opioid receptor (POR) systems. We will focus on examining novel mechanisms by which sex-differences in peripherally applied opioid agonists are expressed in the context of inflammatory muscle pain conditions. The central hypotheses of this project are that sex-differences in POR mechanisms are expressed at multiple levels in primary afferent signaling process and injury or inflammation differentially impacts POR signaling between the sexes. Studies will determine whether there are sex-differences in (1) expression levels of the three subtypes of ORs, <, 4, and : ORs; (2) sub-cellular localizations of the three OR subtypes; and (3) the expression of major downstream targets, G-protein coupled and ATP dependent inward rectifying potassium channels (GIRK and KATP), under normal and inflammatory conditions. Each of these studies will be accompanied by behavioral tests to assess functional relevance of molecular and cellular changes. These studies bear high clinical significance since the pain and management involving masticatory muscles and TMJ, such as in TMJMD, are sexually dimorphic, and since there is increasing clinical as well as pre-clinical evidence that indicate PORs as potential therapeutic targets for treating various types of chronic pain conditions. Understanding mechanic bases for sex-differences in POR function will help develop sex-specific management strategies for persistent types of orofacial muscle pain. PUBLIC HEALTH RELEVANCE This project examines novel mechaisms that may underlie sexual dimorphism in peripheral opioid receptor (POR) effects in the context of inflammatory msucle pain conditions. PORs, namely, mu, delta and kappa ORs, are being increasingly recognized as important therapeutic targets that mediate anti-nociception and/or anti-hyperlagesia in inflammatory pain conditions without producing centrally-mediated side effects. Many types of chronic pain conditions such as temporomandibular joint muscle disorders (TMJMD) exhibit sexually dimorphic pain and analgesic responses. Therefore, outcomes of this project can offer important new insights for the development of mechanism-based sex-specific treatment alternatives that can be directed at the peripheral opioid receptor system to ameliorate persistent orofacial muscle pain.