Role of androgens in age-related changes in pain and analgesia

雄激素在与年龄相关的疼痛和镇痛变化中的作用

• 批准号: 9336776
• 负责人: JIN Y Ro
• 金额: $ 19.31万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9336776
• 关键词: Absence of pain sensation; Achievement; Adverse effects; Affect; Afferent Neurons; Age; Aging; Agonist; Analgesics; Androgen Receptor; Androgens; Arthritis; Attenuated; Binding Sites; Clinical; Clinical Data; Clinical Research; Custom; Data; Degenerative polyarthritis; Development; Dose; Drowsiness; Drug Kinetics; Effectiveness; Elderly; Estrogens; Female; Foundations; Gene Expression; Goals; Gonadal Hormones; Hormone Receptor; Hyperalgesia; Impairment; Inflammation; Interleukin-1 beta; Investigation; Knee joint; Knowledge; Link; Maintenance; Mediating; Modeling; Molecular; Morphine; Nature; Nausea; Older Population; Opioid; Opioid Analgesics; Opioid Receptor; Pain; Pain management; Patients; Peripheral; Persistent pain; Persons; Pharmaceutical Preparations; Pharmacodynamics; Phenotype; Play; Population; Pre-Clinical Model; Process; Promoter Regions; Rattus; Regulation; Reporting; Rodent Model; Role; Running; Safety; Site; Spinal Ganglia; Testing; Testosterone; Tissues; Transcription Coactivator; Up-Regulation; Ursidae Family; Ventilatory Depression; Woman; addiction; age effect; age related; aged; aging population; attenuation; base; chronic pain; cytokine; high risk; injured; insight; juvenile animal; male; men; middle age; multidisciplinary; older patient; patient population; pre-clinical; preclinical study; receptor; receptor expression; receptor function; response; therapeutic development; treatment strategy

ABSTRACT AND PROJECT SUMMARY This project explores the effects of age and testosterone in determining the extent and nature of age-dependent phenotypes of peripheral µ-opioid receptor (MOR) expression and function. Preclinical and clinical studies continue to report effective pain management with opioids delivered to local sites. In the elderly, age-related changes can affect responses to peripheral opioid treatments. To develop rational strategies of pain management in the elderly, it is crucial to understand the effects and mechanisms of these age-related changes. Peripheral inflammation regulates MOR expression in sensory neurons in a testosterone-dependent manner, which bears important implications for older populations since testosterone levels naturally decline with aging. We hypothesize that declining testosterone levels during aging result in attenuation of peripheral MOR efficacy and impairment of MOR regulation in sensory neurons following inflammation. This hypothesis will be tested in two specific aims. In Aim 1, using our model of osteoarthritis, we will compare anti-hyperalgesic effects of DAMGO, a MOR agonist, administered at the injured site in young, middle-aged, and aged rats. We will quantify MOR expression levels in dorsal root ganglia (DRG) and determine the anti-hyperalgesic response. We predict that MOR efficacy will decrease with age since inflammation-induced upregulation of MOR expression in DRG declines with age. In Aim 2, we will investigate (1) whether testosterone supplement in middle-aged and aged rats modulates peripheral MOR expression and function, and (2) whether testosterone effects are mediated by androgen receptor (AR) in DRG. We predict that testosterone is a key modulator for peripheral MOR expression and function, and that AR functions as a transcriptional activator for MOR in DRG. Successful achievement of these aims will enhance our understanding on age-dependent changes in peripheral analgesic mechanisms and lay a foundation for the development of therapeutic strategies that can be optimally customized for the elderly as well as testosterone-compromised patient populations.

摘要及项目总结