Amygdala Mediated Mechanisms Regulating Visceral Pain

慢性内脏痛在美国是一个严重的问题，目前的治疗方法在很大程度上无效。为什么 内脏疼痛是如此管理不善是未知的，但我们已经证明，成年雄性和雌性大鼠， 在慢性心理应激后，结肠扩张会产生内脏高敏感性， 女性反应过度。此外，我们发现，雌性大鼠暴露于不可预测的早期生活， 应激（ELS）在成年时表现出内脏高敏感性，而男性没有证据表明结肠 灵敏度总之，这一证据表明，性二态女性易受应激诱导的结肠炎的影响。 超敏反应我们的初步数据还表明，表观遗传修饰有助于应激诱导的 内脏痛通过糖皮质激素受体（GR）和促肾上腺皮质激素释放激素（CRH）的改变 在杏仁核中央核（CeA）的表达。然而，仍然存在三个重要问题：1） CeA内GR和CRH表达的性二态性差异是否解释了为什么女性 更容易受到慢性压力引起的内脏疼痛的影响2)CeA中特定的表观遗传机制 解释为什么暴露于不可预测的ELS赋予雌性大鼠内脏疼痛的脆弱性，而雄性大鼠 有弹性的？3)CeA是否是压力诱发内脏痛的支点？提供答案 目的1将利用最先进的方法，集中在CeA的表观遗传失调，介导 成人应激对超敏反应的持续性二态性影响。目标2我们将利用关键的 初步数据，以测试的假设，有性别二型表观遗传机制内的CeA 赋予成年女性在不可预测的ELS后内脏疼痛的脆弱性。目标3将决定是否 内脏伤害感受处理中的应激诱导的变化是杏仁核特有的。综合起来， 提出了一种新的方法，通过使用最先进的表观遗传技术结合行为外， 来确定机制，以加强我们对慢性内脏疼痛的基本理解。具体目标1将 表明成年人慢性压力后内脏疼痛加剧是通过表观遗传机制调节的， 在CeA。具体目标2将表明，作为成年大鼠，暴露在不可预测的ELS中的雌性大鼠具有 CeA中不同于雄性大鼠的表观遗传特征，目的3将研究 我们的发现这项应用将建立在我们新的初步发现，并充分利用切割- 边缘的方法来描绘中央分子机制，导致压力引起的慢性内脏痛。 与人类健康的相关性：这项NIH R 01资助将大大提高我们对人类健康的认识。 神经和分子水平的事件负责慢性疼痛，并与我们以前的数据提供了一个统一的 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态 机制和电路参与女性脆弱性发展慢性压力引起的疼痛，导致 治疗慢性疼痛的新目标，这是一个重大的未满足的医疗保健负担。

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.