Central Mechanisms Modulating Visceral Sensitivity

调节内脏敏感性的中枢机制

• 批准号: 8543970
• 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: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8543970
• 关键词: Abdominal Cramps; Abdominal Pain; Acute; Address; Adrenal Cortex Hormones; Adult; Affect; Amygdaloid structure; Anxiety; Area; Awareness; Behavior; Behavioral; Brain; Brain region; CRF receptor type 1; CRF receptor type 2; Caring; Cell Nucleus; Chronic; Chronic stress; Cognitive; Corticosterone; Corticotropin Receptors; Data; Development; Diarrhea; Disease; Emotional; Emotions; Endocrine; Event; Exhibits; Experimental Models; Foundations; Functional Gastrointestinal Disorders; Functional disorder; Gastrointestinal tract structure; Gene Expression; Generations; Genomics; Glucocorticoid Receptor; Goals; Gulf War; Habits; Healthcare; Hippocampus (Brain); Home environment; Hyperalgesia; Hypersensitivity; Image; Implant; Insula of Reil; Intestines; Irritable Bowel Syndrome; Lead; Life; Link; Mediating; Mineralocorticoid Receptor; Mission; Monitor; Nociception; Pain; Pathway interactions; Patient Care; Patients; Peripheral; Phenotype; Play; Population; Prefrontal Cortex; Productivity; Rattus; Receptor Signaling; Relative (related person); Reporting; Risk; Rodent Model; Role; Sensory Process; Series; Signal Transduction; Stimulus; Stress; Structure; Structure of terminal stria nuclei of preoptic region; Symptoms; Testing; Tissues; Treatment Efficacy; Veterans; Visceral; Visceral pain; Water; Work; behavior measurement; chronic abdominal pain; direct application; experience; gastrointestinal; gastrointestinal symptom; improved; insight; neural circuit; neuromechanism; neuronal circuitry; novel; novel therapeutics; pain behavior; parent grant; primary outcome; protein expression; public health relevance; receptor; receptor expression; research study; response; stressor

DESCRIPTION (provided by applicant): Chronic gastrointestinal (GI) symptoms, such as severe abdominal pain and diarrhea are among the most frequently reported symptoms in Veterans returning from active duty. Although little data is available for Veterans that serve in OEF/OIF, recent findings have shown that Gulf War Veterans (GWV) who develop symptoms of abdominal pain and diarrhea exhibit visceral hypersensitivity characterized by increased awareness of visceral stimuli, similar to patients with functional GI disorders such as irritable bowel syndrome (IBS). Moreover, GWV and IBS patients have higher levels of anxiety and report symptoms are worsened by stress and anxiety, suggesting a link between cognitive and peripheral autonomic activity. The objective of our study is to elucidate the specific receptor-mediated mechanism(s) by which the emotional brain communicates with the GI tract to amplify visceral pain signals. The hypothesis of this application is that specific genomic responses within the amygdala underlie the induction of anxiety and abnormal pain behaviors. The application is divided in three Specific Aims:- Under Specific Aim 1, we will attempt to identify the relative importance of amygdala glucocorticoid receptors (GR) and mineralocorticoid receptors (MR) in anxiety and visceral pain. Employing validated rodent models, that exhibit the cardinal aspects of IBS, namely anxiety accompanied by colonic hypersensitivity induced by either i) direct application of corticosterone micropellets onto the central nucleus of the amygala (CeA) or ii) repeated water avoidance stress (WAS), we will investigate whether knockdown of amygdaloid gene expression using specific antisense oligodeoxynucleotides (ODNs) inhibits the development of anxiety and pain induced by stress. For this aim the primary outcome of treatment efficacy will be changes in the behavioral measurements of anxiety and colonic hypersensitivity accompanied by decreases in gene and protein expression. Specific Aim 2. To specifically answer the question: "What are the mechanisms responsible for the IBS-like phenotypes in rodent models of stress?" we will determine if CRF is the common downstream target of GR and MR signaling in the amygdala. To identify whether i) GR and MR regulate anxiety and hypersensitivity through a common pathway and whether ii) amygdala implants of CORT and repeated WAS use the same corticoid regulated pathway, CRF ODN will be continuously infused into the CeA of adult rats. The level of anxiety will be tested in the elevated plus maze and open field, and colonic sensitivity in response to luminal distension will be monitor a visceromotor behavioral response quantified as the number of abdominal cramps during a colonic distension Behavioral measurements will be conducted following administration of CRF OND to the CeA in the two experimental models. Under this aim we will provide novel evidence for the genomic mechanisms in the central neural circuit responsible for IBS-like phenotypes. Specific Aim 3, we will explore the hypothesis that the bed nucleus of the stria terminalis (BNST) is part of the neuronal circuitry from the amygdala that induces anxiety and amplified visceral pain responses. The experiment proposed under this aim will provide the foundation to answer the question - do CRF2 receptors the BNSTAL play a role in the induction of anxiety and pain behaviors in response to elevated amygdala CORT. Impact on Veterans Health Care: This proposal is highly relevant to the patient-care mission of the VA since the VA cares for a population that has been exposed to severe stress, often leading to anxiety-related disorders. Successful completion of the aims proposed within this application will offer insights into the mechanisms of brain-gut dysfunction that lead to chronic abdominal pain. Our findings may identify targets for the development of novel therapeutic strategies directed at the brain, to improve the treatment or even reduce the risk for the development of anxiety-linked visceral pain in Veterans.

描述（由申请人提供）： 慢性胃肠道（GI）症状，例如严重腹痛和腹泻，是退伍军人最常报告的症状之一。虽然在 OEF/OIF 服役的退伍军人的数据很少，但最近的研究结果表明，出现腹痛和腹泻症状的海湾战争退伍军人 (GWV) 表现出内脏过敏，其特征是对内脏刺激的意识增强，类似于患有腹痛和腹泻的患者 功能性胃肠道疾病，例如肠易激综合症（IBS）。此外，GWV 和 IBS 患者的焦虑程度较高，并且报告症状因压力和焦虑而恶化，这表明认知和外周自主活动之间存在联系。我们研究的目的是阐明情绪脑与胃肠道沟通以放大内脏疼痛信号的特定受体介导机制。该应用的假设是杏仁核内的特定基因组反应是诱发焦虑和异常疼痛行为的基础。该应用程序分为三个具体目标：- 在具体目标 1 下，我们将尝试确定杏仁核糖皮质激素受体 (GR) 和盐皮质激素受体 (MR) 在焦虑和内脏疼痛中的相对重要性。采用经过验证的啮齿动物模型，该模型展示了 IBS 的主要方面，即伴随着结肠过敏的焦虑，这些过敏是由 i) 直接将皮质酮微丸施用到杏仁核 (CeA) 中央核上或 ii) 反复回避水应激 (WAS) 引起的，我们将研究使用特定反义寡脱氧核苷酸（ODN）敲低杏仁基因表达是否可以抑制压力引起的焦虑和疼痛的发展。为此，治疗效果的主要结果将是焦虑和结肠过敏的行为测量的变化，并伴随着基因和蛋白质表达的减少。具体目标 2. 具体回答以下问题：“在啮齿动物应激模型中，导致 IBS 样表型的机制是什么？”我们将确定 CRF 是否是杏仁核中 GR 和 MR 信号传导的共同下游目标。为了确定 i) GR 和 MR 是否通过共同途径调节焦虑和超敏反应，以及 ii) CORT 和重复 WAS 的杏仁核植入物是否使用相同的皮质激素调节途径，CRF ODN 将持续注入成年大鼠的 CeA 中。将在高架十字迷宫和开放视野中测试焦虑水平，并监测结肠对管腔扩张的敏感性，将内脏运动行为反应量化为结肠扩张期间腹部痉挛的次数。 CRF OND 到 CeA 的两个实验模型。在这个目标下，我们将为负责IBS样表型的中枢神经回路的基因组机制提供新的证据。具体目标 3，我们将探讨这样的假设：终纹床核 (BNST) 是杏仁核神经元回路的一部分，可引起焦虑并放大内脏疼痛反应。在此目的下提出的实验将为回答以下问题提供基础：CRF2 受体 BNSTAL 是否在响应杏仁核 CORT 升高而诱导焦虑和疼痛行为中发挥作用。对退伍军人医疗保健的影响：该提案与退伍军人管理局的患者护理使命高度相关，因为退伍军人管理局照顾的是承受严重压力的人群，通常会导致焦虑相关疾病。成功完成本申请中提出的目标将为了解导致慢性腹痛的脑肠功能障碍的机制提供见解。我们的研究结果可能会确定开发针对大脑的新型治疗策略的目标，以改善退伍军人的治疗，甚至降低发生与焦虑相关的内脏疼痛的风险。