Central Mechanisms Modulating Visceral Sensitivity

项目目标：重新提交退伍军人事务部续签奖助金，继续提供资金 自2005年以来，专注于了解慢性疼痛的基本机制并将其 为男性和女性退伍军人提供新的治疗选择。这一点在当前情况下很重要 我们的退伍军人慢性疼痛的治疗方法很大程度上是无效的，因为缺乏 了解导致慢性疼痛的机制。 研究计划和方法：本次续订申请将基于以下新发现 父母拨款，并利用尖端发现方法来描绘神经通路 以及导致压力诱导的慢性疼痛的分子机制。有证据表明疼痛加剧 在女性退伍军人中进行报道，因此，特定目标1将利用最先进的方法来检验假设 杏仁中央核(CEA)的性二型性表观遗传失调是基因的基础 表达的变化介导了应激对内脏伤害性信息处理的持续影响。在特定项下 目的2我们将利用临床证据表明，患者的慢性疼痛可以通过以下方式减轻 心理疗法，如生物反馈、放松训练和瑜伽；然而， 这样的心理疗法改善临床疼痛是未知的。我们将根据我们的初步数据显示 环境浓缩通过修复来逆转应激诱导的内脏疼痛的治疗潜力 促肾上腺皮质激素释放激素(CRH)、糖皮质激素受体(GR)和盐皮质激素受体(MR)在CEA中的表达。这 AIM还将研究CEA中的表观遗传机制是否是EE对慢性前列腺癌影响的基础 压力引起的内脏疼痛。 预期结果：在本申请中，我们提出了一种方法，提供了一种新的方式 用表观遗传学技术结合经典行为学对慢性疼痛的思考 结果测量以确定将增强我们对慢性疼痛的基本理解的机制。在……下面 具体目标1我们预计，有独特的中枢机制驱动女性对疼痛的脆弱性。我们 希望能证明，成人慢性应激后的高度疼痛是通过表观遗传调节的 CEA内部的调节机制，男性和女性之间将有显著差异。 在特定目标2下，我们预计在#年逆转CEA内发生的异常分子事件 利用环境富集法应对慢性应激，并研究组蛋白的重要性 调整以调节环境浓缩的影响。 与退伍军人健康的相关性：将退伍军人奖励计划中提议的工作放在一起 大大提高了我们对导致慢性疼痛的神经和分子水平事件的理解 与我们之前的数据结合在一起，为压力如何导致慢性疾病提供了一个统一的中心假说 疼痛。退伍军人管理局为患有慢性疼痛的退伍军人提供专门的医疗保健，但治疗方案 止痛是非常有限的，而且充满副作用。从科学上讲，这个项目的结果将确定 一种新的与压力相关的大脑回路，以及调节慢性疼痛的特定神经递质。 识别慢性应激诱导疼痛的机制和回路可能导致新的 治疗经历慢性疼痛的退伍军人的治疗目标，这是一项重大的未实现的医疗保健 负担。此外，由于患有焦虑相关障碍的女性退伍军人有更高的疼痛发生率，我们的 研究将比较雄性和雌性大鼠的数据，试图确定可能是 这是女退伍军人独有的。

OBJECTIVES OF THE PROJECT: This resubmission of a VA Merit grant renewal continuously funded since 2005 focusing on understanding the basic mechanisms that underlie chronic pain and translating those findings into new therapeutic options for both male and female Veterans. This is important as current therapeutic approaches for treating our Veterans with chronic pain are largely ineffective due to a paucity of understanding of the mechanisms leading to chronic pain. RESEARCH PLAN & METHODOLOGY: This renewal application will build upon the novel findings from the parent grant and also takes advantage of cutting edge discovery approaches to delineate neural pathways and molecular mechanisms leading to stress-induced chronic pain. There is evidence of increased pain reporting in female veterans, thus specific Aim 1 will utilize state of the art approaches to test the hypothesis that sexually dimorphic epigenetic dysregulation in the central nucleus of the amygdala (CeA) underlies gene expression changes mediating the persistent effects of stress on visceral nociceptive processing. Under Specific Aim 2 we will take advantage of clinical evidence suggesting that chronic pain in patients can be reduced by psychological therapies such as biofeedback, relaxation training and yoga; however, the mechanisms by which such psychotherapies improve clinical pain are unknown. We will build upon our preliminary data showing the therapeutic potential of environmental enrichment to reverse stress-induced visceral pain by restoring corticotropin-releasing hormone (CRH), GR and mineralocorticoid receptor (MR) expression in the CeA. This aim will also investigate whether epigenetic mechanisms in the CeA underlie the effects of EE on chronic stress-induced visceral pain. ANTICIPATED OUTCOMES: In this application, we propose an approach that offers a novel way of thinking about chronic pain by using state of the art epigenetic techniques combined with classical behavioral outcome measures to identify mechanisms that will enhance our basic understanding of chronic pain. Under Specific Aim 1 we anticipate that there are unique central mechanisms driving female vulnerability for pain. We expect to show that heightened pain following chronic adult stress is modulated through epigenetically mediated mechanisms within the CeA, and that there will be significant differences between males and females. Under Specific Aim 2 we anticipate reversing the abnormal molecular events occurring within the CeA in response to chronic stress using environmental enrichment and investigate the importance of histone modifications to mediate the effects of environmental enrichment. RELEVANCE TO VETERANS HEALTH: Taken together the work proposed in this VA Merit grant will substantially advance our understanding of the neural and molecular level events responsible for chronic pain and taken together with our previous data provide a unifying central hypothesis for how stress leads to chronic pain. The VA provides specialized health care for veterans with chronic pain, however therapeutic options for pain relief are very limited and fraught with side effects. Scientifically, the results from this project will identify a novel stress-associated brain circuit, along with the specific neurotransmitters, that modulates chronic pain. Identification of the mechanisms and circuitry involved in chronic stress-induced pain could lead to new targets for therapies to treat veterans experiencing chronic pain, which is a significant unmet healthcare burden. Furthermore, since female veterans with anxiety-related disorders have higher rates of pain, our research will compare data from male and female rats in an attempt to identify novel mechanisms that may be unique to female veterans.