Understanding Pain of Gastrointestinal Origin in Women that Serve in OEF/OIF

描述（由申请人提供）： 在过去30年里，军队各部门的女性人数翻了一番，预计在未来十年内还将翻一番，超过23万名女性-约占美国军队的11%-曾在伊拉克和阿富汗服役。虽然退伍军人事务部专注于为女性退伍军人提供专业护理，但很少有研究专门关注女性退伍军人所经历的疾病，但很明显，她们与男性退伍军人一样忍受着同样的恶劣条件，并返回家中患有病因不明的慢性疾病。最近的研究结果表明，与男性相比，女性退伍军人的创伤后应激障碍（PTSD）和慢性胃肠道症状的患病率很高。这项建议特别令人感兴趣的是，患有焦虑相关疾病（如PTSD）的退伍军人有更高的不良童年经历和虐待率。虽然在OEF/OIF服役的女性退伍军人的数据有限，但研究表明，腹痛症状是由于海湾战争退伍军人（GWV）对内脏刺激的意识增加而引起的内脏超敏反应，并且症状因压力而恶化，这表明认知和外周自主活动之间存在联系。当前提案的PI在她的实验室中建立了焦虑和内脏高敏感性之间的联系，通过显示由于不可预测的早期生活压力而易患高度焦虑的大鼠在成年后表现出高敏感性结肠。此外，皮质酮诱导的杏仁核（参与恐惧和焦虑情绪表达的关键中枢核团）刺激通过糖皮质激素受体（GR）和盐皮质激素受体（MR）介导的机制增强大鼠的焦虑样行为和结肠超敏反应。当前提案的关键是PI最近的研究表明，在自由移动的啮齿动物模型中，结肠对管腔扩张的敏感性取决于发情周期，黄体期与内脏高敏感性相关，杏仁核上孕酮和/或雌二醇水平升高导致对结肠直肠扩张的反应性升高。结合她以前的研究，PI寻求以下问题的答案：“导致女性退伍军人焦虑和慢性腹痛的内脏敏感性性别差异的机制是什么？”“AIM 1a将测试这样一个假设，即成年大鼠在对不可预测的ELS做出反应时，焦虑和腹痛报告存在性别相关的差异。该设计将涉及在骑自行车的雌性大鼠和卵巢切除（OVX）大鼠的焦虑和结肠过敏的行为评估。然后将这些观察结果与同龄成年雄性大鼠的观察结果进行比较。AIM 1b将研究对ELS的反应是否会在个体的整个生命周期中发生变化。在此目的下，PI将研究ELS在新生啮齿动物模型中产生的童年经历是否导致成年大鼠的焦虑样行为和结肠超敏反应，这些行为和结肠超敏反应在动物的整个生命周期内持续存在。AIM 2将直接确定糖皮质激素刺激杏仁核是否驱动ELS对成年大鼠的焦虑样行为和结肠超敏反应的影响。由于皮质酮（CORT）的作用是由GR和MR介导的，GR与MR的不平衡被认为是与应激相关的病理学，这个目的将直接测试的假设，即MR/GR表达在成年大鼠ELS后异常，我们还将确定是否下调GR或MR在CeA使用反义寡脱氧核苷酸（ODNs）影响焦虑和结肠超敏反应。此外，我们将研究暴露于ELS的大鼠与年龄匹配的对照组相比，是否在成年后对慢性应激表现出改变的行为反应 公共卫生相关性： 我们的工作假设是，早期生活压力史可能会增加士兵，特别是女兵对战斗相关压力的不利影响以及随后的成年病理学发展的易感性。本申请中提出的目标的成功完成将为可能导致慢性腹痛的与女性生理学相关的脑肠功能障碍机制提供新的见解。更重要的是，我们的研究结果可以确定针对大脑的新疗法的新靶点，以改善治疗，甚至降低部署在OEF/OIF的女性退伍军人发生内脏疼痛的风险。

DESCRIPTION (provided by applicant): The number of women in all branches of the military has doubled in the last 30 years and it is expected to double again in the next decade, and more than 230,000 women - about 11% of the U.S. military have served in Iraq and Afghanistan. Although the VA is focused on providing specialized care for female veterans, very few research studies have focused specifically on illnesses experienced by female veterans but it is very clear that they endured the same harsh conditions as male veterans, and return home to suffer chronic illnesses of unknown etiology. Recent findings have shown that female veterans have a high prevalence of posttraumatic stress disorder (PTSD) and chronic gastrointestinal symptoms compared to their male counterparts. Of particular interest to this proposal, veterans suffering from anxiety-related disorders such as PTSD have higher rates of adverse childhood experiences and abuse. Although limited data is available for female veterans that serve in OEF/OIF, studies have shown that symptoms of abdominal pain are due to visceral hypersensitivity characterized by increased awareness of visceral stimuli in Gulf War Veterans (GWV) and that symptoms are worsened by stress, suggesting a link between cognitive and peripheral autonomic activity. The PI of the current proposal has in her laboratory established a link between anxiety and visceral hypersensitivity by showing that rats predisposed to heightened levels of anxiety due to unpredictable early life stress exhibit a hypersensitive colon in adulthood. Furthermore, corticosterone-induced stimulation of the amygdala, a key central nuclei involved in the emotional expression of fear and anxiety, enhances anxiety-like behavior and colonic hypersensitivity in rats through both glucocorticoid receptor (GR) and mineralocorticoid receptor (MR)- mediated mechanisms. Key to the current proposal is the PI's recent research showing that in a freely moving rodent model, colonic sensitivity to luminal distension varies depending on the estrous cycle with the luteal phase being associated with visceral hypersensitivity and that elevated levels of progesterone and/or estradiol on the amygdala lead to heightened responsiveness to colorectal distension. Taken together with her previous research has led the PI to seek an answer to the following question "What are the mechanisms responsible for the gender-related differences in visceral sensitivity that lead to anxiety and chronic abdominal pain in female veterans?" AIM 1a will test the hypothesis that there are sex-related differences in anxiety and abdominal pain reporting in adult rats in response to unpredictable ELS. The design will involve the behavioral assessment of anxiety and colonic hypersensitivity in cycling female rats and ovariectomized (OVX) rats. These observations will then be compared to that in adult male rats of the same age. AIM 1b will investigate whether the responses to ELS change across the lifespan of an individual. Under this aim the PI will investigate whether childhood experiences produced by ELS in a neonatal rodent model leads to anxiety-like behavior and colonic hypersensitivity in adult rats that persists throughout the life time of the animal AIM 2 will determine directly whether glucocorticoid stimulation of the amygdala drives the effects of ELS on anxiety-like behavior and colonic hypersensitivity in adult rats. Since the action of corticosterone (CORT) is mediated by GR and MR and an imbalance of GR versus MR is thought to be responsible for stress-related pathologies, this aim will directly test the hypothesis that MR/GR expression in the amygdala is abnormal in adult rats following ELS, We will also determine whether down regulation of GR or MR in the CeA using antisense oligodeoxynucleotides (ODNs) affects anxiety and colonic hypersensitivity. Moreover, we will examine whether rats exposed to ELS show altered behavioral responses to chronic stress in adulthood compared to age-matched controls PUBLIC HEALTH RELEVANCE: It is our working hypothesis that a history of early life stress may increase the susceptibility of a soldier, especially a female soldier, to the adverse effects of combat-related stress and the subsequent development of adult pathologies. Successful completion of the aims proposed within this application will offer new insights into the mechanisms of brain-gut dysfunction in relation to female physiology that likely lead to chronic abdominal pain. More importantly our findings may identify novel targets for new therapies directed at the brain to improve the treatment or even reduce the risk for the development of visceral pain in female veterans deployed in OEF/OIF.