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: 9033203
• 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 2019-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9033203
• 关键词: Abdominal Cramps; Abdominal Pain; Acetylation; Address; Adult; Adverse effects; Afghanistan; Amygdaloid structure; Anxiety; Brain; Caring; Cell Nucleus; Child Abuse; Chronic; Chronic stress; Communication; Corticotropin; Crossover Design; DNA Methylation; Data; Development; Diarrhea; Disease; Disease susceptibility; Elderly; Epigenetic Process; Experimental Models; Exposure to; Fatigue; Feedback; Female; Functional disorder; Gene Expression; Genes; Health; Healthcare; Hippocampus (Brain); Histone Acetylation; Hour; Hypersensitivity; Incidence; Individual; Infusion procedures; Iraq; Irritable Bowel Syndrome; Lead; Life; Life Experience; Life Stress; Link; Measures; Mediating; Military Personnel; Mission; Modeling; Molecular; Neonatal; Neurologic; Odors; Organ; Outcome; Output; Pain; Pain Disorder; Pain management; Pathology; Pathway interactions; Patient Care; Patients; Pattern; Perception; Physiology; Population; Post-Traumatic Stress Disorders; Predisposing Factor; Predisposition; Psychological Stress; Psychopathology; Rattus; Recording of previous events; Recruitment Activity; Reporting; Research; Risk; Risk Factors; Role; Series; Shock; Soldier; Stress; Symptoms; Testing; Therapeutic Intervention; United States; Veterans; Visceral; Visceral pain; Water; Woman; Work; anxiety-related disorders; arm; biological adaptation to stress; chronic abdominal pain; chronic widespread pain; combat; conditioning; coping; design; early experience; expectation; experience; gastrointestinal; high risk; histone acetyltransferase; hypothalamic-pituitary-adrenal axis; improved; insight; knock-down; male; maternal separation; new therapeutic target; novel; novel strategies; operation; pain behavior; public health relevance; pup; research study; response; sex; stressor; targeted treatment

 DESCRIPTION (provided by applicant): The objective of our study is to elucidate the mechanisms underlying the sexually dimorphic effects of early life stress (ELS) on pain perception in female veterans. Our overarching hypothesis is that exposure to adversity in early life predisposes female veterans to heightened visceral pain via a central mechanism involving abnormalities in brain-gut communication. RESEARCH PLAN: Under Specific Aim 1, we will test the hypothesis that stress in early life serves as a risk factor for heightened pain in adulthood produced by chronic stress. Having identified in preliminary experiments increases in stress-responsive genes within the central nucleus of the amygdala (CeA) of female rats exposed to ELS, in Specific Aim 2 we will test the hypothesis that heightened pain perception in adulthood following ELS is mediated by central increases in stress-responsive genes. Specific Aim 3 will explore the hypothesis that centrally driven epigenetic changes make an individual more susceptible to chronic stress and contribute to the sexually dimorphic effects of ELS on pain perception in adult female rats. METHODOLOGY: We will employ validated rats models that recapitulate visceral pain in patients. Specifically, we will measure colonic sensitivity by quantifying the number of abdominal cramps in response to colonic distension. Stress in early life will be induced by odor shock conditioning in neonatal rat pups. Stress in adulthood will result from repeated exposure for 1 hour each day to a water avoidance stressor (WAS). We will investigate whether ELS serves as a predisposing risk factor for heightened visceral pain in response to chronic WAS in adulthood. We also will investigate whether knockdown of amygdaloid gene expression using specific antisense oligodeoxynucleotides (ODNs) inhibits the development of pain following ELS. Finally we will use an array of epigenetic approaches targeting histone acetyltransferases within the CeA to gain further mechanistic insight into stress-induced visceral pain. ANTICIPATED RESULTS: For Specific Aim 1 we expect to show that rats experiencing adult stress will have visceral hypersensitivity compared to controls. However, we anticipate that that there will be a greater visceral sensitivity to the adult stress following ELS. We also expect an exaggerated activation of the HPA axis indicated by an elevated systemic CORT and ACTH, as well as increased fecal pellet output (FPO) in response to WAS in all experimental groups, however the magnitude of the change will be greater in response to ELS. For Specific Aim 2, we anticipate that imbalances of stress responsive genes contribute to abnormal visceral pain perception in adulthood following ELS. In experiments proposed under specific aim 3 we expect to show that heightened visceral pain following ELS may be modulated through epigenetically mediated mechanisms within the CeA. RELEVANCE TO VETERANS HEALTH: The VA provides specialized health care for female veterans, however limited research has focused on illnesses experienced by female Veterans. Of importance to this proposal, female veterans with anxiety-related disorders have higher rates of childhood abuse. Our findings may identify novel approaches to improve the treatment of pain in female Veterans.

 描述（由申请人提供）： 本研究的目的是阐明早期生活压力（ELS）对女性退伍军人疼痛感知的性二态性影响的机制。我们的总体假设是，在早期生活中暴露于逆境使女性退伍军人通过涉及脑肠通信异常的中枢机制容易产生内脏疼痛。研究报告：在具体目标1中，我们将检验以下假设：早期生活中的压力是慢性压力导致成年期疼痛加剧的风险因素。在初步实验中发现，暴露于ELS的雌性大鼠杏仁核（CeA）中央核内的应激反应基因增加，在具体目标2中，我们将检验以下假设：ELS后成年期疼痛感知增强是由应激反应基因的中枢增加介导的。具体目标3将探讨这一假设，即中枢驱动的表观遗传变化使个体更容易受到慢性应激的影响，并有助于ELS对成年雌性大鼠疼痛感知的性二态效应。方法学：我们将采用经过验证的大鼠模型，重现患者的内脏疼痛。具体来说，我们将通过量化结肠扩张引起的腹部绞痛次数来测量结肠敏感性。气味休克条件反射可诱导新生大鼠幼鼠早期的应激反应。成年期的压力来自于每天重复暴露于避水应激源（WAS）1小时。我们将调查ELS是否作为一个诱发危险因素，在成年期慢性WAS的内脏疼痛加剧。我们还将研究是否敲低杏仁核基因表达使用特定的反义寡脱氧核苷酸（ODNs）抑制疼痛的发展ELS。最后，我们将使用一系列针对CeA内组蛋白乙酰转移酶的表观遗传方法，以进一步了解应激诱导的内脏痛的机制。预期结果：对于具体目标1，我们期望表明，与对照组相比，经历成年应激的大鼠将具有内脏高敏感性。然而，我们预计，将有一个更大的内脏敏感性成人压力后ELS。我们还预计，在所有实验组中，响应于WAS，HPA轴的过度激活（由全身CORT和ACTH升高以及粪粒排出量（FPO）增加指示），但是响应于ELS，变化的幅度将更大。对于具体目标2，我们预计，压力反应基因的不平衡有助于异常内脏疼痛感知成年后ELS。在特定目标3下提出的实验中，我们希望表明ELS后内脏疼痛加剧可能通过CeA内的表观遗传介导机制进行调节。与兽医健康的相关性：退伍军人事务部为女性退伍军人提供专门的医疗保健，但有限的研究集中在女性退伍军人经历的疾病上。对这项建议很重要的是，患有焦虑相关疾病的女性退伍军人有更高的儿童虐待率。我们的研究结果可能会发现新的方法来改善女性退伍军人的疼痛治疗。