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

摘要和项目总结 该项目探讨了年龄和睾酮在确定年龄依赖性的程度和性质的影响。 外周μ-阿片受体（莫尔）表达和功能的表型。临床前和临床研究 继续报告使用阿片类药物对当地站点进行有效的疼痛管理。在老年人中，与年龄有关的 这些变化会影响对外周阿片类药物治疗的反应。发展理性的疼痛策略 在老年人的管理中，了解这些与年龄有关的变化的影响和机制至关重要。 外周炎症以睾酮依赖性方式调节感觉神经元中的莫尔表达， 这对老年人具有重要意义，因为睾丸激素水平随着年龄的增长而自然下降。 我们推测，衰老过程中睾酮水平下降导致外周莫尔疗效减弱 以及炎症后感觉神经元中莫尔调节的损害。这一假设将在 两个具体目标。在目的1中，使用我们的骨关节炎模型，我们将比较 DAMGO，一种莫尔激动剂，在年轻、中年和老年大鼠的损伤部位给药。我们将量化 莫尔在背根神经节（DRG）的表达水平，并确定抗痛觉过敏反应。我们预测 莫尔功效将随着年龄而降低，因为炎症诱导的DRG中莫尔表达的上调 随着年龄的增长而下降。目的二：（1）中老年人群是否需要补充睾酮 大鼠调节外周莫尔表达和功能，以及（2）睾酮效应是否由 DRG雄激素受体（AR）。我们预测睾酮是外周莫尔表达的关键调节因子 和功能，并且AR在DRG中作为莫尔的转录激活因子发挥作用。成功实现 这些目标将增强我们对外周镇痛机制年龄依赖性变化的理解 并为治疗策略的开发奠定基础，这些策略可以最佳地为患者定制。 老年人以及睾酮受损的患者人群。

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.