GONADAL STEROID HORMONAL REGULATION OF PESISTENT PAIN

慢性或持续性疼痛每年影响数以百万计的成年人，损失工作日、医疗和生活质量下降的成本高达数十亿美元。这些情况中有许多与性别有关。女性表现出更高的患病率，患有颞下颌关节紊乱病、神经性疼痛、纤维肌痛、偏头痛和某些形式的关节炎。此外，与月经周期、更年期、怀孕和哺乳期相关的激素水平的变化也会影响疼痛程度。本研究的目的是评价孕酮和孕酮联合雌激素对持续性疼痛和炎症模型大鼠痛觉过敏和神经元过度兴奋的影响。我们的主要假设是，内源性生殖激素可以通过影响脊髓水平的一系列分子、生化和生理事件来抑制持续性疼痛，这些事件涉及抑制性和兴奋性氨基酸及其受体，以及阿片肽及其受体。我们将研究这些激素对行为痛敏、脊髓神经元、GABA受体的调节、阿片受体和阿片肽的表达以及NMDA受体功能的影响。具体目标1将描述孕酮在哺乳期女性、荷尔蒙替代卵巢切除女性和去势男性中产生的行为炎性痛敏的变化。具体目标2将确定黄体酮在行为痛敏发生和维持中的作用，以及外周组织、脊髓和脑中可能的抗痛觉过敏效应的靶点。具体目标3将确定黄体酮的抗痛觉过敏作用部分是通过调节GABAA受体的激活来实现的。特定目标4将检验黄体酮的止痛作用是阿片类药物介导的假说，部分是在脊髓水平。具体目标5将检测孕酮对NMDA受体功能的影响，以及炎症和痛觉过敏后NMDA受体亚单位基因表达的变化。总之，我们建议在模拟人类慢性疼痛条件的大鼠模型中阐明生殖激素对持续性疼痛机制的影响，该模型具有周期性或妊娠相关的变化。这些发现对于开发管理这些疾病的新方法将是重要的。

Chronic or persistent pain affects millions of adults each year with costs in lost work days, medical treatment and the reduction in the quality of life in the range of billions of dollars. Many of these conditions are gender-related. Women exhibit a higher prevalence of temporomandibular disorders, neuropathic pain, fibromyalgia, migraine headaches and some forms of arthritis. Furthermore, variations in hormonal levels associated with menstrual cycle, menopause, pregnancy and lactation influence pain levels. The purpose of this study is to evaluate the effects of progesterone and progesterone in combination with estrogen on the hyperalgesia and neuronal hyperexcitability associated with a rat model of persistent pain and inflammation. Our major hypothesis is that endogenous reproductive hormones can suppress persistent pain by their influence on a cascade of molecular, biochemical and physiological events at the spinal level involving inhibitory and excitatory amino acids and their receptors, and opioid peptides and their receptors. We will investigate the effects of these hormones on behavioral hyperalgesia, spinal cord neurons, modulation of GABA receptors, expression of opioid receptors and opioid peptides, and NMDA receptor function. Specific Aim 1 will characterize the changes in behavioral inflammatory hyperalgesia produced by progesterone, in lactating females, ovariectomized females with hormone replacement, and castrated males. Specific Aim 2 will determine the effects of progesterone on the development and maintenance of behavioral hyperalgesia, as well as the possible target sites of the antihyperalgesic effects in peripheral tissue, the spinal cord and the brain. Specific Aim 3 will determine that progesterone's antihyperalgesic effects are mediated, in part, via modulation of GABAA receptor activation. Specific Aim 4 will test the hypothesis that progesterone's antihyperalgesic effects are opioid-mediated, in part, at the level of the spinal cord. Specific Aim 5 will examine progesterone effects on NMDA receptor function and changes in NMDA receptor subunit gene expression following inflammation and hyperalgesia. In summary, we propose to elucidate the influence of reproductive hormones on mechanisms of persistent pain in a rat model that mimics human chronic pain conditions known to exhibit cyclical or pregnancy-related variations. The findings will be important for the development of new approaches to the management of these conditions.