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，患者的生物性别是疼痛的常见风险因素，许多研究表明，女性在许多急性和慢性疾病中的疼痛风险增加。拟议的转化临床研究直接测试的假设，雌二醇（172-E2）增加外周伤害性感受器活动在人类急性疼痛患者和雌激素受体的多态性与伤害性感受器活动和术后疼痛增加。为了解决这一假设，我们已经开发了一种方法，用于评估雌二醇增强外周人类伤害感受器的外吞活性的支配手术活检的健康组织（评估P物质（SP）释放神经元末梢支配牙髓提取第三磨牙）。我们的初步研究确定了雌激素受体1（ER 1）和ER 1在人类三叉神经节神经元和周围神经元的手术活检，并发现雌二醇显着增加缓激肽/前列腺素E2（BK/PGE 2）诱发的iSP从人体组织活检收集的妇女，但不是从男人。此外，在本A1修订版中，我们报告了新的发现，即ER 1和ER 2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，我们提出了一个工作假说，即雌激素敏感的外周终端的人三叉神经伤害感受器。为了评估这一假设，我们提出了以下目标：具体目标1：确定女性是否不同于男性的增加释放SP刺激后BK/PGE 2或辣椒素。具体目标二：确定升高的循环雌二醇水平是否与BK/PGE 2或辣椒素刺激后SP释放增加相关具体目标3：确定雌激素受体α（ER 1）或β（ER 2）的特定多态性是否与暴露于雌二醇的手术活检中BK/PGE 2或辣椒素诱发的SP释放增加相关。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。该数据库将用于三项拟议的二次分析，包括ER多态性与术后疼痛之间的相关性评价，并将提供给其他研究人员，以促进NIH的数据共享政策。这些综合研究将在药理学、生物化学和遗传学水平上评价雌激素对外周人类伤害感受器的调节。总的来说，这些研究提供了一个全面的评估的假设，激活雌激素受体增强女性的伤害感受器功能。 公共卫生相关性：虽然女性在许多急性和慢性疼痛条件下疼痛的风险更大，但对介导这种效应的机制知之甚少。在这项研究中，我们将测试雌激素是否会增强来自女性与男性患者的手术活检组织的疼痛神经活动，并研究雌激素受体基因的某些自然突变是否与术后疼痛水平的增加相关。了解雌激素对疼痛神经的活性不仅会增加我们对女性疼痛风险的理解，而且还可能开发出能够减少这种影响的新型选择性雌激素受体调节剂。

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.