Sex-Differences in Peripheral Opioid Receptor Mechanisms

外周阿片受体机制的性别差异

基本信息

批准号：
8284212
负责人：
JIN Y Ro
金额：
$ 34.92万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-30 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8284212
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 Health 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 receptor function research study response sex sexual dimorphism therapeutic target

项目摘要

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.

描述（由适用提供）：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和受伤或炎症中以多种水平表达对性别之间的POR信号的影响不同。研究将确定在（1）ORS，μ，δ和κORS的三个亚型的表达水平中是否存在性别差异；（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蛋白耦合和依赖性ATP的钾通道（Girk和Katp）的表达。这些研究中的每一个都将通过行为测试来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证据的增加和临床前证据，这些证据表明鲍尔作为治疗多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的管理策略。