AFFERENT DYSFUNCTION & GAS RETENTION: ROLE OF SEROTONIN

胃肠病学家常抱怨胀气和腹胀，但这些症状的发病机制尚不清楚。研究集中在内脏痛的原因，定义痛觉过敏对内脏痛的作用，定义痛觉过敏对内脏和机械感受器刺激的作用。注意到夸大的感知，同时固化化学和机械刺激，显示传入信息的总和。5-羟色胺（5-HT）通过作用于神经H-HT和H-HT 4受体调节肠道感觉运动功能。我们假设，气体和腹胀患者表现出原发性缺陷内脏传入反应小肠化学和mechanoreceptor刺激不同的5-HT途径调节。我们进一步假设，这些传入功能障碍引起异常的中枢神经系统（CNS）处理的感觉信息，引起继发性反射改变肠运动模式，从而促进病理性气体潴留。我们提出了全面的研究，包括内脏传入活动，中枢神经系统处理的肠道感觉信息，肠动力，气体潴留患者的气体和腹胀与健康志愿者的反应。将评估十二指肠营养灌注和肠扩张的感知，以确定胀气和腹胀患者是否表现出痛觉过敏，并测试痛觉过敏是否是全身性的或特定于单个营养亚类或肠区域。同时营养灌注和肠扩张期间的症状报告将揭示患者是否对双传入刺激表现出更显著的总和。将在存在选择性5-HT 3和5-HT 4拮抗剂的情况下重复感知研究，以确定每个受试者组中内脏感知的5-HT调节。将在有和没有5-HT拮抗剂的情况下测量对肠刺激的诱发电位，以表征脊髓传入功能，而脑PET激活模式将定义肠感觉功能的CNS处理异常（含气体和腹胀）。最后，将量化化学感受器和机械感受器刺激对肠运动活性的影响，并将其与对输注到小肠中的气体的保留的影响相关联。我们预计，患有气体和腹胀的患者将分别通过激活5-HT 3和5-HT 4受体途径对化学感受器和机械感受器刺激表现出痛觉过敏，以及将产生夸大的脊髓和大脑诱发电位的增强的总和反应。这可能会产生异常的中枢神经系统活动，引起肠道运动的继发性障碍，导致气体潴留。这项研究将为气体和腹胀的发展机制提供新的和重要的见解。

Gas and bloating are common complaints to gastroenterologists, but the pathogenesis of these symptoms is unknown. Research has focused on causes of visceral pain, defining roles for hyperalgesia to visceral pain, defining roles for hyperalgesia to visceral - and mechanoreceptor stimulation. Exaggerated perception is noted curing concurrent chemical and mechanical stimulation showing summation of afferent information. Serotonin (5-HT) modulates gut sensorimotor function via action on neural H-HT and H-HT4 receptors. We hypothesize that patients with gas and bloating exhibit primary defects in visceral afferent responses to small intestinal chemo- and mechanoreceptor stimulation which are differentially regulated by distinct 5-HT pathways. We further hypothesize that these afferent dysfunctions evoke abnormal central nervous system (CNS) processing of sensory information which elicit secondary reflex alterations in intestinal motor patterns thereby promoting pathologic gas retention. We propose comprehensive studies comprising visceral afferent activity, CNS processing of gut sensory information, intestinal motility, and gas retention in patients with gas and bloating with responses in health volunteers. Perception of duodenal nutrient perfusion and intestinal distention will be assessed to determine if patients with gas and bloating exhibit hyperalgesia and to test if hyperalgesia is generalized or specific for individual nutrient subclasses or intestinal regions. Symptoms reports during simultaneous nutrient perfusion and intestinal distention will reveal if patients exhibit more prominent summation to dual afferent stimulation. Perceptual studies will be repeated in the presence of selective 5-HT3 and 5-HT4 antagonists to define 5-HT regulation of visceral perception in each subject groups. Measurement of evoke potentials in response to intestinal stimulation will be performed with and without 5-HT antagonists to characterize spinal afferent function, while brain PET activation patterns will define abnormalities of CNS processing of gut sensory function with gas and bloating. Finally, effects of chemo- and mechanoreceptor stimulation on intestinal motor activity will be quantified and correlated with effects on retention of gas infused into the small intestine We expect that patients with gas and bloating will exhibit hyperalgesia to chemo- and mechanoreceptor stimulation via activation of 5-HT3 and 5-HT4 receptor pathways, respectively, as well as enhanced summation responses which will produce exaggerated spinal and cerebral evoked potentials. This may produce abnormal central nervous system activity which evokes secondary disturbances in intestinal motility resulting in gas retention. The investigation in this proposal will provide novel and significant insight into the mechanisms underlying development of gas and bloating.