Amygdala Mediated Mechanisms Regulating Visceral Pain

慢性内脏疼痛在美国是一个严重的问题，目前的治疗方法基本上无效。为什么 内脏疼痛是如此糟糕的管理是未知的，但我们已经证明成年雄性和雌性大鼠 慢性心理应激后出现内脏对结肠扩张的过敏反应，显著 女性的反应夸张。此外，我们发现，暴露在不可预测的早期生命中的雌性大鼠 成年后，应激(ELs)表现出内脏过敏，而男性没有证据表明结肠增加。 敏感度。综上所述，这些证据表明，女性对压力诱导的结肠具有性二态易感性。 过敏症。我们的初步数据还表明，表观遗传修饰有助于应激诱导 糖皮质激素受体和促肾上腺皮质激素释放激素变化引起的内脏痛 在杏仁中央核(CEA)有表达。然而，三个重要的问题仍然存在：1) CEA内GR和CRH表达的性别差异是否解释了为什么女性 对慢性应激引起的内脏疼痛更敏感？2)CEA中有特定的表观遗传机制 解释为什么暴露在不可预测的ELS中会使雌性大鼠内脏疼痛易感性，而雄性大鼠 弹性？3)CEA是应激性内脏疼痛发展的支点吗？提供答案 目标1将利用最先进的方法专注于CEA中的表观遗传失调，该失调调节 成人应激对过敏性的持久的性二态效应。目标2我们将利用Pivotal 初步数据用于检验CEA内存在性别二态表观遗传机制的假设 在不可预测的ELS之后，成年女性的内脏疼痛易感性。目标3将决定是否 应激引起的内脏伤害性信息处理的改变是杏仁核特有的。我们合在一起就是 提出了一种新的方法，使用最先进的表观遗传技术结合行为外... 来确定增强我们对慢性内脏疼痛的基本理解的机制。具体目标1将 表明慢性成人应激后的高度内脏疼痛是通过表观遗传机制调节的 在CEA内部。特定目标2将表明，成年后，暴露在不可预测的ELs中的雌性大鼠有 不同于雄性大鼠的CEA的表观遗传学特征和Aim 3将研究杏仁核的特异性 我们的发现。这个应用程序将建立在我们新颖的初步发现的基础上，并充分利用切割- EDGE方法描绘导致应激诱导的慢性内脏疼痛的中央分子机制。 与人类健康的相关性：NIH R01的这项拨款将极大地促进我们对 神经和分子水平的事件对慢性疼痛负责，与我们之前的数据提供了统一的 关于压力如何导致慢性疼痛的假说。从科学上讲，结果将确定新的性二型性 女性易患慢性应激性疼痛的机制和回路，导致 治疗慢性疼痛的新目标，这是一个重大的未得到满足的医疗负担。

Chronic visceral pain is a significant problem in the US and current treatments are largely ineffective. Why visceral pain is so poorly managed is unknown, but we have demonstrated that adult male and female rats develop visceral hypersensitivity to colonic distension after chronic psychological stress, with a significantly exaggerated response in females. Moreover, we found that female rats exposed to unpredictable early life stress (ELS) exhibit visceral hypersensitivity as adults, whereas males have no evidence of increased colonic sensitivity. Together, this evidence points to a sexually dimorphic female vulnerability to stress-induced colonic hypersensitivity. Our preliminary data also indicates that epigenetic modifications contribute to stress-induced visceral pain through alterations in glucocorticoid receptor (GR) and corticotropin-releasing hormone (CRH) expression in the central nucleus of the amygdala (CeA). However, three important questions still remain: 1) Do sexually dimorphic differences in the expression of GR and CRH within the CeA explain why females are more susceptible to chronic stress-induced visceral pain? 2) Do specific epigenetic mechanisms in the CeA explain why exposure to unpredictable ELS confers visceral pain vulnerability in female rats while male rats are resilient? 3) Is the CeA the fulcrum for the development of stress-induced visceral pain. To provide answers Aim 1 will utilize state-of-the-art approaches to focus on epigenetic dysregulation in the CeA that mediate the persistent sexually dimorphic effects of adult stress on hypersensitivity. Aim 2 we will take advantage of pivotal preliminary data to test the hypothesis that there are sexually dimorphic epigenetic mechanisms within the CeA conferring visceral pain vulnerability in adult females following unpredictable ELS. Aim 3 will determine whether stress-induced changes in visceral nociceptive processing are specific to the amygdala. Taken together we are proposing a novel approach by using state-of-the-art epigenetic techniques combined with behavioral out- comes to identify mechanisms to enhance our basic understanding of chronic visceral pain. Specific Aim 1 will show that heightened visceral pain following chronic adult stress is modulated through epigenetic mechanisms within the CeA. Specific Aim 2 will show that as adults, female rats exposed in unpredictable ELS have an epigenetic signature in the CeA that differs from male rats and aim 3 will investigate the amygdala specificity of our findings. This application will build upon our novel preliminary findings and take full advantage of cutting- edge approaches to delineate central molecular mechanisms leading to stress-induced chronic visceral pain. RELEVANCE TO HUMAN HEALTH: This NIH R01 grant will substantially advance our knowledge of the neural and molecular level events responsible for chronic pain, and with our previous data provide a unifying hypothesis for how stress leads to chronic pain. Scientifically, the results will identify novel sexually dimorphic mechanisms and circuitry involved in female vulnerability to develop chronic stress-induced pain, leading to new targets for therapies to treat chronic pain, which is a significant unmet healthcare burden.