Chronic Stress and Visceral Nociception

慢性压力和内脏伤害感受

• 批准号: 6849224
• 负责人: JAMES A MCROBERTS
• 金额: $ 12.6万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-01 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6849224
• 关键词: adrenocorticotropic hormone; behavioral /social science research tag; colon; corticotropin releasing factor; cortisol; cytokine; enteric nervous system; hyperalgesia; hypothalamic pituitary adrenal axis; immunocytochemistry; laboratory rat; messenger RNA; mucosal immunity; neuroendocrine system; pain; psychological stressor; psychoneuroimmunology; secretory immune system; visceral afferent nerve

DESCRIPTION (provided by applicant): Many functional disorders, including irritable bowel syndrome (IBS), are associated with alterations in the stress response. Since chronic sustained stress often precedes exacerbations of both functional and inflammatory diseases of the intestine, understanding the mechanisms underlying this phenomenon have important implications for therapeutic intervention. Acute psychological or physical stress activates both the sympathetic and parasympathetic branches of the autonomic nervous system (ANS) and the hypothalamic pituitary adrenal (HPA) axis. These systems modulate pain pathways, but also influence the peripheral immune function. Peripherally acting products of the HPA axis (glucocorticoids) and both branches of the ANS (catecholamines and acetylcholine) inhibit peripheral immune function, principally by blocking the action of pro-inflammatory cytokines that stimulate cellular immunity. However, the normal restraining effect of acute stress on immune cell proliferation and activation is compromised during chronic stress by changes in the central stress circuits, including a blunting of the I-IPA axis response, down regulation of certain adrenergic receptors, and decreased vagal tone. The current proposal is based on the general hypothesis that development of hypocortisolism (reduced glucocorticoid secretion) during chronic stress may be an important factor in the up-regulation of the gut-associated immune system, production of inflammatory cytokines and cytokine-mediated sensitization of visceral afferent nerve pathways. In a rat model, we have found that chronic psychological stress leads to profound, long lasting visceral hyperalgesia to mechanical distension of the colon and rectum, associated with mast cell hyperplasia and up-regulation of the pro-inflammatory cytokines, tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6). By exposing rats to a chronic psychological stressor and assessing HPA axis, mucosal immune function and visceral nociceptive responses, we will test this general hypothesis in 3 specific aims. In aim 1, we measure changes HPA axis during and after chronic stress and determine the underlying mechanisms involved in modulating this response. In aim 2 we will correlate these endocrine changes with changes in mucosal immune cell infiltration and activation by enzyme assays, immunohistoehemistry, and quantification of mucosal cytokine mRNA levels. In aim 3, we evaluate 2 specific therapeutic interventions aimed at blocking the central stress response or mucosal immune activation for reduction of visceral hyperalgesia. These proposed experiments should also establish whether chronic psychological stress in rats is a reasonable model of chronic stress mediated symptom exacerbations in IBS patients.

描述（由申请人提供）：许多功能障碍，包括肠易激综合征（IBS），都与压力反应的改变有关。由于慢性持续压力通常在肠道功能和炎症性疾病的加剧之前，因此了解这种现象的机制对治疗干预具有重要意义。急性心理或身体压力激活了自主神经系统（ANS）和下丘脑垂体肾上腺（HPA）轴的交感神经和副交感分支。这些系统调节疼痛途径，但也会影响周围免疫功能。 HPA轴（糖皮质激素）和ANS（儿茶酚胺和乙酰胆碱）的两个分支的外周作用产物抑制外周种免疫功能，主要是通过阻断刺激细胞免疫的促炎细胞因子的作用。然而，急性应激对免疫细胞增殖和激活的正常限制作用在慢性应激过程中因中央应力电路的变化而受到损害，包括i-IPA轴响应的钝化，某些肾上腺素能受体的调节调节和降低阴性。当前的建议基于一般假设，即慢性应激期间低皮质醇（减少糖皮质激素分泌）的发展可能是肠道肠相关免疫系统上调，炎症细胞因子的产生和细胞因子介导的亲和力nerve nerve nerve nerve Pathways的敏化的重要因素。 在大鼠模型中，我们发现，慢性心理压力导致结肠和直肠机械延伸的深刻，持久的内脏痛觉过敏，与肥大细胞增生以及促炎细胞因子的上调有关，肿瘤坏死因子alpha（TNF-Alpha）（TNF-Alpha）和Interleueukin-6（Irthleukin-6（Ill-6））。通过将大鼠暴露于慢性心理压力源并评估HPA轴，粘膜免疫功能和内脏伤害反应，我们将以3个特定目标检验这一普遍假设。在AIM 1中，我们在慢性应力期间和之后测量更改HPA轴，并确定调节此响应所涉及的潜在机制。在AIM 2中，我们将通过酶测定，免疫霍斯化学以及粘膜细胞因子mRNA水平的量化与粘膜免疫细胞浸润和激活的变化相关。在AIM 3中，我们评估了2种特定的治疗干预措施，旨在阻止中央应力反应或粘膜免疫激活，以减少内脏痛觉过敏。这些提出的实验还应确定大鼠的慢性心理压力是否是IBS患者加剧慢性应激介导的症状的合理模型。