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，造成损失工作日、医疗费用和生活质量下降的费用达数十亿美元。许多这些情况都与性别有关。女性在颞下颌紊乱、神经性疼痛、纤维肌痛、偏头痛和某些关节炎方面的患病率更高。此外，与月经周期、更年期、怀孕和哺乳期相关的激素水平变化也会影响疼痛程度。本研究的目的是评估黄体酮和黄体酮联合雌激素对持续疼痛和炎症大鼠模型相关的痛觉过敏和神经元高兴奋性的影响。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疼痛，这些事件涉及抑制性和兴奋性氨基酸及其受体、阿片肽及其受体。我们将研究这些激素对行为痛觉过敏、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。特异性目的1将描述孕酮引起的行为炎性痛觉过敏的变化，在哺乳期雌性，卵巢切除的雌性激素替代，和阉割的雄性。特异性目的2将确定黄体酮对行为性痛觉过敏的发展和维持的影响，以及在外周组织、脊髓和大脑中抗痛觉过敏作用的可能靶点。特异性目的3将确定黄体酮的抗痛觉作用是介导的，部分是通过GABAA受体激活的调节。特异性目的4将检验黄体酮的抗痛觉作用是阿片介导的，部分是在脊髓水平上。特异性目的5将研究黄体酮对NMDA受体功能的影响以及炎症和痛觉过敏后NMDA受体亚基基因表达的变化。总之，我们建议阐明生殖激素对大鼠模型中持续疼痛机制的影响，该模型模仿已知表现出周期性或妊娠相关变化的人类慢性疼痛状况。这些发现对于发展新的方法来管理这些条件将是重要的。

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.