Sex-Differences in Peripheral Opioid Receptor Mechanisms

外周阿片受体机制的性别差异

• 批准号: 7694342
• 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/7694342
• 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; 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; Rattus; Receptor Signaling; Relative (related person); Reporting; Severities; Sex Characteristics; Signal Pathway; Stimulus; Structure of trigeminal ganglion; Study models; Symptoms; System; Temporomandibular Joint; Testing; Ursidae Family; Woman; alternative treatment; base; behavior test; chronic pain; clinically significant; computerized data processing; cytokine; inflammatory pain; insight; interdisciplinary approach; male; men; novel; novel therapeutic intervention; orofacial; pre-clinical; psychologic; public health relevance; 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）：该提案研究了外围阿片受体（POR）系统中有助于分子，细胞和功能特性的性别差异的因素。我们将专注于检查新型机制，通过这些机制，在炎症性肌肉疼痛条件的背景下，外周施用的阿片类药物激动剂中的性别差异表达。该项目的中心假设是，POR机制的性别差异在主要传入信号传导过程中以多​​个水平表达，损伤或炎症对性别之间的POR信号差异影响。研究将确定（1）ORS的三个亚型的表达水平<，4和：ORS的表达水平是否存在性别差异； （2）三个或亚型的细胞局部定位； （3）在正常和炎症条件下，主要下游靶标，G蛋白耦合和ATP依赖于向内整流的钾通道（Girk和Katp）。这些研究中的每一个都将伴随行为测试，以评估分子和细胞变化的功能相关性。这些研究具有较高的临床意义，因为涉及咀嚼肌肉和TMJ的疼痛和管理（例如TMJMD中）是性二态性的，并且由于临床和临床前的证据增加了临床和临床前证据，这些证据表明鲍尔作为治疗各种慢性疼痛条件的潜在治疗靶标。了解POR功能中性别差异的机械基础将有助于制定针对性类型肌肉疼痛类型的性别特定的管理策略。公共卫生相关性该项目研究了新型的机械性，这些机制可能是在炎症性msucle疼痛条件下的外周外阿片受体（POR）效应中的性二态性的基础。在炎症性疼痛条件下，鲍勃（即MU，Delta和Kappa ORS）在炎症性疼痛条件下介导了抗伤害感受和/或抗Hyperlagesia，而越来越多地被认为是重要的治疗靶标，而不会产生中央介导的副作用。许多类型的慢性疼痛疾病，例如颞下颌关节肌肉（TMJMD）表现出性二态疼痛和镇痛反应。因此，该项目的结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围阿片类药物受体系统，以减轻持续的持续性口腔肌肉疼痛。