Sex-Differences in Peripheral Opioid Receptor Mechanisms

描述（由申请人提供）：本提案研究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过程中在多个水平上表达，并且损伤或炎症在性别之间差异地影响POR信号。研究将确定在正常和炎症条件下，（1）OR的三种亚型μ、δ和κ OR的表达水平;（2）三种OR亚型的亚细胞定位;和（3）主要下游靶点G蛋白偶联和ATP依赖性内向整流钾通道（GIRK和KATP）的表达是否存在性别差异。这些研究中的每一项都将伴随行为测试，以评估分子和细胞变化的功能相关性。这些研究具有很高的临床意义，因为涉及咀嚼肌和颞下颌关节的疼痛和管理（例如TMJMD）是性二态性的，并且越来越多的临床和临床前证据表明PORs是治疗的潜在治疗靶点。各种类型的慢性疼痛状况。了解POR功能性别差异的力学基础将有助于制定针对持续性口面部肌肉疼痛的性别特异性管理策略。

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, μ, δ, and κ 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.