Sex-Differences in Peripheral Opioid Receptor Mechanisms

外周阿片受体机制的性别差异

• 批准号: 7566337
• 负责人: JIN Y Ro
• 金额: $ 35.63万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7566337
• 关键词: Absence of pain sensation; Address; Adverse effects; Afferent Neurons; Agonist; Analgesics; Area; Attention; Attenuated; Behavioral; Biochemical; Cell physiology; Cell surface; Clinical; Clinical Management; Condition; Coupled; Cytokine Activation; Data; Development; Etiology; Exhibits; Female; G-Protein-Coupled Receptors; GTP-Binding Proteins; Hyperalgesia; Inflammation; Inflammatory; Injury; Intramuscular Injections; Investigation; Ischemia; Masticatory muscles; Mechanics; Mediating; Methods; Molecular; Myalgia; Myopathy; Neurons; Nociception; Opioid; Opioid Receptor; Outcome; Pain; Pain management; Pathologic; Pathology; Patients; Peripheral; Potassium Channel; Property; Proteins; Public Health; Rattus; Receptor Signaling; Relative (related person); Reporting; Severities; Sex Characteristics; Signal Pathway; Stimulus; Structure of trigeminal ganglion; Study models; Symptoms; System; Temporomandibular Joint; Testing; Therapeutic Intervention; Ursidae Family; Woman; base; behavior test; chronic pain; clinically significant; computerized data processing; cytokine; inflammatory pain; insight; interdisciplinary approach; male; men; novel; novel therapeutics; orofacial; pre-clinical; psychologic; receptor function; research study; response; sex; sexual dimorphism; therapeutic target

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.

描述（由申请人提供）：该提案研究了导致外周阿片受体（POR）系统分子、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的阿片类激动剂在炎症性肌肉疼痛情况下表达性别差异的新机制。该项目的核心假设是，POR 机制的性别差异在初级传入信号传导过程的多个层面上表达，并且损伤或炎症对性别之间的 POR 信号传导有不同的影响。研究将确定以下方面是否存在性别差异：（1）ORs、<、4和：ORs的三种亚型的表达水平； (2) 三种 OR 亚型的亚细胞定位； (3) 在正常和炎症条件下主要下游靶标、G 蛋白偶联和 ATP 依赖性内向整流钾通道（GIRK 和 KATP）的表达。每项研究都将伴随行为测试，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 TMJ 的疼痛和治疗（例如 TMJMD）具有性别二态性，并且越来越多的临床和临床前证据表明 POR 作为治疗各种类型的潜在治疗靶点慢性疼痛状况。了解 POR 功能性别差异的机制基础将有助于针对持续性口面部肌肉疼痛制定针对性别的管理策略。公共健康相关性 该项目研究了炎症性肌肉疼痛条件下外周阿片受体 (POR) 效应中可能存在性别二态性的新机制。 POR，即 mu、delta 和 kappa OR，越来越多地被认为是重要的治疗靶点，可在炎性疼痛病症中介导抗伤害感受和/或抗痛觉过敏，而不产生中枢介导的副作用。许多类型的慢性疼痛，例如颞下颌关节肌肉疾病 (TMJMD)，表现出性别二态性疼痛和镇痛反应。因此，该项目的成果可以为开发基于机制的性别特异性治疗替代方案提供重要的新见解，这些替代方案可以针对外周阿片受体系统，以改善持续性口面部肌肉疼痛。