GONADAL STEROID HORMONAL REGULATION OF PESISTENT PAIN

慢性或持续性疼痛每年影响数百万成年人，损失的工作日，医疗和生活质量降低的成本在数十亿美元的范围内。 其中许多情况与性别有关。 女性颞下颌关节紊乱病、神经性疼痛、纤维肌痛、偏头痛和某些形式的关节炎的患病率较高。此外，与月经周期、更年期、怀孕和哺乳相关的激素水平的变化影响疼痛水平。 本研究的目的是评估孕酮和孕酮与雌激素联合对持续性疼痛和炎症大鼠模型相关的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抑制持续性疼痛的影响，在脊髓水平的分子，生化和生理事件级联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。 具体目标1将描述哺乳期女性、激素替代的卵巢切除女性和去势男性中孕酮产生的行为炎症性痛觉过敏的变化。 具体目标2将确定孕酮对行为痛觉过敏的发展和维持的影响，以及外周组织、脊髓和大脑中抗痛觉过敏作用的可能靶点。 具体目标3将确定孕酮的抗痛觉过敏作用部分是通过调节GABAA受体活化来介导的。 具体目标4将测试的假设，孕酮的抗痛觉过敏的影响是阿片类药物介导的，部分，在脊髓的水平。具体目标5将检查孕酮对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，我们建议阐明生殖激素对大鼠模型持续性疼痛机制的影响，该模型模拟已知表现出周期性或妊娠相关变化的人类慢性疼痛状况。 研究结果将是重要的新方法来管理这些条件的发展。

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.