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

了解 OEF/OIF 女性胃肠道疼痛

• 批准号: 8142489
• 负责人: Beverley Greenwood-Van Meerveld
• 金额: --
• 依托单位: OKLAHOMA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8142489
• 关键词: Abdominal Pain; Address; Adult; Adverse effects; Affect; Afghanistan; Age; Amygdaloid structure; Animals; Anxiety; Anxiety Disorders; Awareness; Behavior; Behavior assessment; Behavioral; Biological Models; Brain; Caring; Cell Nucleus; Child Abuse; Childhood; Chronic; Chronic Disease; Chronic stress; Cognitive; Colon; Corticosterone; Data; Development; Diarrhea; Disease; Down-Regulation; Early-life trauma; Elderly; Employee Strikes; Estradiol; Estrous Cycle; Etiology; Event; Exhibits; Exposure to; Fatigue; Female; Fright; Functional disorder; Gender; Glucocorticoid Receptor; Glucocorticoids; Goals; Grant; Gulf War; Health; High Prevalence; Home environment; Hormones; Hydrocortisone; Hypersensitivity; Incidence; Individual; Individual Differences; Intestines; Iraq; Laboratories; Lead; Life; Life Experience; Life Stress; Link; Long-Term Effects; Longevity; Longitudinal Studies; Luteal Phase; Mediating; Medical center; Military Personnel; Mineralocorticoid Receptor; Modeling; Neonatal; Neuraxis; Neurons; Oklahoma; Outcome; Ovarian hormone; Pain; Pathology; Pathway interactions; Patients; Perception; Peripheral; Physiology; Post-Traumatic Stress Disorders; Predisposition; Progesterone; Psychopathology; Quality of life; Rat Strains; Rattus; Recording of previous events; Recruitment Activity; Reporting; Research; Research Support; Risk; Risk Factors; Rodent Model; Separation Anxiety; Soldier; Steroid Receptors; Stimulus; Stress; Symptoms; Testing; Therapeutic Intervention; Time; United States; Veterans; Visceral; Visceral pain; War; Woman; Work; arm; biological adaptation to stress; chronic abdominal pain; chronic widespread pain; colon distension; colorectal distension; combat; conditioning; coping; design; early childhood; early experience; experience; gastrointestinal; gastrointestinal symptom; high risk; improved; indexing; innovation; insight; interest; male; men; neonatal exposure; novel; operation; psychological stressor; receptor; receptor expression; relating to nervous system; research study; response; sex; showing emotion

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.

描述（由申请人提供）： 过去 30 年，军队各部门的女性人数增加了一倍，预计未来 10 年将再增加一倍，超过 23 万名女性——约占美军人数的 11%——曾在伊拉克和阿富汗服役。尽管退伍军人管理局专注于为女性退伍军人提供专门护理，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，她们忍受着与男性退伍军人相同的恶劣条件，并返回家乡患有不明原因的慢性疾病。最近的研究结果表明，与男性退伍军人相比，女性退伍军人患有创伤后应激障碍（PTSD）和慢性胃肠道症状的比例较高。该提案特别感兴趣的是，患有创伤后应激障碍（PTSD）等焦虑相关疾病的退伍军人，童年时期的不良经历和虐待发生率较高。虽然在 OEF/OIF 服役的女性退伍军人的数据有限，但研究表明，腹痛症状是由于内脏过敏引起的，其特征是海湾战争退伍军人 (GWV) 对内脏刺激的意识增强，而且症状会因压力而恶化，这表明认知与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过敏之间的联系，方法是表明，由于不可预测的早期生活压力而导致焦虑水平升高的老鼠在成年后表现出过敏性结肠。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）的刺激，通过糖皮质激素受体（GR）和盐皮质激素受体（MR）介导的机制增强了大鼠的焦虑样行为和结肠过敏。当前提案的关键是PI最近的研究表明，在自由活动的啮齿动物模型中，结肠对管腔扩张的敏感性根据发情周期而变化，黄体期与内脏过敏有关，并且杏仁核上黄体酮和/或雌二醇水平升高会导致对结直肠扩张的反应性增强。结合她之前的研究，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相关差异的机制是什么？” AIM 1a 将检验以下假设：成年大鼠在应对不可预测的 ELS 时，焦虑和腹痛报告存在性别相关差异。该设计将涉及对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进行行为评估。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 将调查对 ELS 的反应是否会在个体的一生中发生变化。在此目标下，PI将调查ELS在新生啮齿动物模型中产生的童年经历是否会导致成年大鼠的焦虑样行为和结肠过敏，并在动物的整个生命周期中持续存在。AIM 2将直接确定糖皮质激素对杏仁核的刺激是否会驱动ELS对成年大鼠焦虑样行为和结肠过敏的影响。由于皮质酮 (CORT) 的作用是由 GR 和 MR 介导的，并且 GR 与 MR 的不平衡被认为是造成应激相关病理的原因，因此该目标将直接检验 ELS 后成年大鼠杏仁核中 MR/GR 表达异常的假设。我们还将确定使用反义寡脱氧核苷酸 (ODN) 下调 CeA 中 GR 或 MR 是否会影响焦虑和焦虑。 结肠过敏。此外，我们将研究与年龄匹配的对照组相比，暴露于 ELS 的大鼠在成年后对慢性压力的行为反应是否有所改变 公共卫生相关性： 我们的工作假设是，早期生活压力的历史可能会增加士兵，尤其是女士兵，对战斗相关压力的不利影响以及随后的成人病症发展的敏感性。成功完成本申请中提出的目标将为了解可能导致慢性腹痛的女性生理学相关的脑肠功能障碍的机制提供新的见解。更重要的是，我们的研究结果可能会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。