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

 描述(由申请人提供)： 本研究的目的是阐明早期生活压力(ELS)对女性退伍军人痛觉的性二态效应的潜在机制。我们的主要假设是，在早期生活中暴露在逆境中，通过涉及大脑-肠道通信异常的中枢机制，使女性退伍军人容易出现内脏疼痛加剧。研究计划：在特定目标1下，我们将检验这一假设，即早期生活压力是由慢性压力导致的成年后疼痛加剧的危险因素。在初步实验中发现暴露于ELS的雌性大鼠杏仁中央核(CEA)内的应激反应基因增加后，在特定的目标2中，我们将测试这一假说，即ELS后成年后痛觉的增强是由应激反应基因的中枢增加所介导的。具体目标3将探索这一假说，即中央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对成年雌性大鼠痛觉的性二态效应。方法：我们将使用经过验证的大鼠模型来概括患者的内脏疼痛。具体地说，我们将通过量化腹部痉挛对结肠扩张的反应来测量结肠敏感性。气味休克条件反射可诱导新生大鼠早期应激。成年期的压力是由于每天重复暴露在一种避免饮水的应激源下1小时而产生的。我们将调查ELS是否是成年后慢性内脏疼痛加剧的易感危险因素。我们还将研究使用特定的反义寡核苷酸(ODN)抑制杏仁核基因表达是否抑制ELS后疼痛的发展。最后，我们将使用一系列针对CEA中的组蛋白乙酰转移酶的表观遗传学方法，以进一步深入了解应激诱导的内脏疼痛。预期结果：对于特定的目标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ELS后对成人应激有更大的内脏敏感性。我们还预计，在所有试验组中，由于全身皮质醇和ACTH的升高，HPA轴被夸大地激活，以及粪便颗粒产量(FPO)的增加，但在ELS的反应中，变化的幅度将更大。对于特定的目标2，我们预计应激反应基因的失衡导致ELS后成年期的异常内脏痛觉。在特定目标3下提出的实验中，我们希望证明ELS后内脏疼痛的加剧可能是通过CEA内的表观遗传机制调节的。与退伍军人健康的相关性：退伍军人管理局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。对这项提议来说，重要的是，患有焦虑相关障碍的女性退伍军人儿童期虐待的比率更高。我们的发现可能会确定新的方法来改善女性退伍军人的疼痛治疗。

 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.