Chronic Stress and Visceral Nociception

描述(申请人提供)：许多功能障碍，包括肠易激综合征(IBS)，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，了解这种现象的机制对于治疗干预具有重要的意义。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(HPA)轴。这些系统调节疼痛通路，但也影响外周免疫功能。HPA轴的外周作用产物(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过程中会受到中枢应激回路的影响，包括I-IPA轴反应减弱，某些肾上腺素能受体下调，迷走神经张力下降。目前的建议是基于一个普遍的假设，即慢性应激期间皮质醇减少(糖皮质激素分泌减少)的发展可能是肠道相关免疫系统上调、炎性细胞因子的产生以及细胞因子介导的内脏传入神经通路敏化的重要因素。 在一种大鼠模型中，我们发现慢性心理应激导致严重、持久的内脏痛敏，导致结肠和直肠的机械性扩张，伴随着肥大细胞的增殖和促炎细胞因子肿瘤坏死因子-α(TNF-α)和白介素6(IL-6)的上调。通过将大鼠暴露于慢性心理应激源，并评估HPA轴、粘膜免疫功能和内脏伤害性反应，我们将在3个具体目标上检验这一普遍假设。在目标1中，我们测量了慢性应激期间和之后HPA轴的变化，并确定了参与调节这种反应的潜在机制。在目标2中，我们将通过酶分析、免疫组织化学和粘膜细胞因子mRNA水平的定量，将这些内分泌变化与粘膜免疫细胞浸润和激活的变化相关联。在目标3中，我们评估了两种特定的治疗措施，旨在阻断中枢应激反应或粘膜免疫激活，以减少内脏痛觉过敏。这些拟议的实验还应该确定大鼠的慢性心理应激是否是IBS患者慢性应激介导的症状恶化的合理模型。

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.