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），都与应激反应的改变有关。由于慢性持续应激通常先于肠道功能性疾病和炎症性疾病的恶化，因此了解这一现象背后的机制对治疗干预具有重要意义。急性心理或生理压力会激活自主神经系统（ANS）的交感神经和副交感神经分支以及下丘脑垂体肾上腺轴（HPA）。这些系统调节疼痛通路，但也影响外周免疫功能。外周作用的HPA轴的产物（糖皮质激素）和ANS的两个分支（儿茶酚胺和乙酰胆碱）抑制外周免疫功能，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抑制作用在慢性应激期间被中央应激回路的变化所削弱，包括I-IPA轴反应的钝化、某些肾上腺素能受体的下调和迷走神经张力的降低。目前的建议是基于一种普遍的假设，即慢性应激期间糖皮质激素分泌减少可能是肠道相关免疫系统上调、炎症细胞因子产生和细胞因子介导的内脏传入神经通路敏化的重要因素。