ESTROGEN MODULATION OF HUMAN NOCICEPTORS

描述（由申请人提供）：多种疼痛疾病的临床研究表明，患者的生理性别是疼痛的常见危险因素，许多研究表明，在许多急性和慢性疾病中，女性的疼痛风险增加。这项转化临床研究直接验证了雌二醇（172-E2）增加人类急性疼痛患者外周伤害感受器活性以及雌激素受体多态性与伤害感受器活性增加和术后疼痛相关的假设。为了解决这一假设，我们开发了一种方法来评估雌二醇对支配健康组织手术活检的外周人类伤害感受器的胞外活性的增强（评估从拔出的第三磨牙中支配牙髓的神经元末梢释放P物质（SP））。我们的初步研究在手术活检中发现了雌激素受体1 （ER1）和ER1在人类三叉神经节神经元和周围神经元中都存在，并发现雌二醇显著增加了缓激肽/前列腺素E2 （BK/PGE2）诱发的iSP，从女性的人体组织活检中发现，但从男性中没有。此外，在这次A1修订中，我们报告了新的发现，ER1和ER2的某些多态性与这些患者术后疼痛强度增加呈正相关。因此，我们已经提出了一个工作假设，雌激素使人类三叉神经伤害感受器的外周末梢敏感。为了评估这一假设，我们提出了以下目标：具体目标1：确定在BK/PGE2或辣椒素刺激后，雌性与雄性在SP释放增加方面是否不同。特异性目标2：确定循环雌二醇水平升高是否与BK/PGE2或辣椒素刺激后SP释放增加有关。特异性目标3：确定雌激素受体α (ER1)或β (ER2)的特异性多态性是否与暴露于雌二醇的手术活检中BK/PGE2或辣椒素引起的SP释放增加有关。具体目标4：建立数据和基因库，以促进未来的遗传流行病学和药物遗传学研究。该数据库将用于三个拟议的二次分析，包括评估内质网多态性与术后疼痛之间的关系，并将提供给其他研究人员，以促进NIH数据共享政策。这些综合研究将在药理学、生化和遗传水平上评估雌激素对人类外周伤害感受器的调节作用。总的来说，这些研究为雌激素受体的激活增强女性伤害感受器功能的假设提供了一个全面的评估。

DESCRIPTION (provided by applicant): Clinical studies of multiple pain disorders indicate that a patient's biological sex is a common risk factor for pain, with many studies demonstrating that women are at increased risk for pain in many acute and chronic conditions. The proposed translational clinical study directly tests the hypotheses that estradiol (172-E2) increases peripheral nociceptor activity in human acute pain patients and that polymorphisms of the estrogen receptors are associated with increased nociceptor activity and post-operative pain. To address this hypothesis, we have developed a method for evaluating estradiol enhancement of the exocytotic activity of peripheral human nociceptors innervating surgical biopsies of healthy tissue (evaluating substance P (SP) release from neuron terminals innervating dental pulp from extracted third molar teeth). Our preliminary studies identified estrogen receptor 1 (ER1) and ER1 in both human trigeminal ganglia neurons and in peripheral neurons in surgical biopsies, and discovered that estradiol significantly increases bradykinin/prostaglandin E2 (BK/PGE2)-evoked iSP from human tissue biopsies collected from women, but not from men. Moreover, in this A1 revision, we report new findings that certain polymorphisms of ER1 and ER2 are positively correlated with increased intensity of post-operative pain in these patients. Thus, we have developed a working hypothesis that estrogen sensitizes peripheral terminals of human trigeminal nociceptors. To evaluate this hypothesis, we propose the following aims: Specific Aim 1: Determine whether females differ from males for increased release of SP following stimulation with either BK/PGE2 or with capsaicin. Specific Aim 2: Determine whether elevated circulating estradiol levels are associated with increased release of SP following stimulation with either BK/PGE2 or with capsaicin Specific Aim 3: Determine whether specific polymorphisms of the estrogen receptor alpha (ER1) or beta (ER2) are associated with increased BK/PGE2- or capsaicin-evoked release of SP from surgical biopsies exposed to estradiol. Specific Aim 4: Establish a data and gene bank to facilitate future genetic epidemiological and pharmacogenetic studies. This database will be used for three proposed secondary analyses including an evaluation of the association between ER polymorphisms and post-surgical pain and will be also available to other investigators to foster the NIH policy for data sharing. These integrated studies will evaluate estrogen modulation of peripheral human nociceptors at the pharmacological, biochemical and genetic levels. Collectively, these studies provide a comprehensive evaluation of the hypothesis that activation of estrogen receptors enhances nociceptor function in women. PUBLIC HEALTH RELEVANCE: Although women are at greater risk for pain in many acute and chronic pain conditions, comparatively little is known about the mechanisms mediating this effect. In this study, we will test whether estrogens enhance pain nerve activity from surgical biopsies collected from female versus male patients and study whether certain natural mutations of the gene for the estrogen receptors are correlated with increased levels of post- operative pain. Understanding estrogen activity on pain nerves will not only increase our understanding of why women are at risk for pain, but offers the potential for developing new types of selective estrogen receptor modulators capable of reducing this effect.