Central Mechanisms Modulating Visceral Sensitivity

该项目的优点：这一重新提交的VA优异奖助学金续期不断资助 自2005年以来，专注于了解慢性疼痛的基本机制，并将其转化为 为男性和女性退伍军人提供新的治疗选择。这一点很重要， 治疗我们的退伍军人慢性疼痛的治疗方法在很大程度上是无效的，因为缺乏 了解导致慢性疼痛的机制。 研究方法和方法：这一更新申请将建立在新的发现， 并利用尖端的发现方法来描绘神经通路 以及导致应激性慢性疼痛的分子机制。有证据表明疼痛加剧 报告女性退伍军人，因此具体目标1将利用最先进的方法来检验假设 杏仁核中央核（CeA）的性二态表观遗传失调是基因 表达变化介导的持续影响的压力对内脏伤害性加工。根据具体 目的2：我们将利用临床证据表明， 心理疗法，如生物反馈，放松训练和瑜伽;然而， 这种改善临床疼痛的心理疗法是未知的。我们将根据初步数据， 环境丰富通过恢复来逆转应激诱导的内脏痛的治疗潜力 促肾上腺皮质激素释放激素（CRH）、GR和盐皮质激素受体（MR）在CeA中的表达。这 目的还将调查是否在CeA的表观遗传机制的基础EE的影响，慢性 压力引起的内脏疼痛 预期结果：在这个应用程序中，我们提出了一种方法，提供了一种新的方式， 通过使用最先进的表观遗传技术结合经典的行为学方法来思考慢性疼痛， 结果测量，以确定机制，这将提高我们对慢性疼痛的基本理解。下 具体目标1我们预计，有独特的中央机制驱动女性疼痛的脆弱性。我们 我希望表明，慢性成人压力后的疼痛加剧是通过表观遗传学调节的， CeA内的介导机制，男性和女性之间将有显着差异。 在特定目标2下，我们预期逆转CeA内发生的异常分子事件， 使用环境富集对慢性应激的反应，并研究组蛋白的重要性 修饰介导环境富集的影响。 与兽医健康的相关性：综合考虑，在VA Merit补助金中提出的工作将 大大推进我们对慢性疼痛的神经和分子水平事件的理解 结合我们以前的数据，我们为压力如何导致慢性疾病提供了一个统一的中心假设。 痛苦VA为患有慢性疼痛的退伍军人提供专门的医疗保健，然而， 疼痛缓解是非常有限的并且充满了副作用。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，沿着特定的神经递质，调节慢性疼痛。 识别慢性应激引起的疼痛的机制和电路可能会导致新的 治疗经历慢性疼痛的退伍军人的治疗目标，这是一个重大的未满足的医疗保健 负担此外，由于患有焦虑相关疾病的女性退伍军人有更高的疼痛率， 研究将比较雄性和雌性大鼠的数据，试图确定可能是 只有女性退伍军人才有

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.