AFFERENT DYSFUNCTION & GAS RETENTION: ROLE OF SEROTONIN

胃肠病医生常见的主诉是胃气和腹胀，但这些症状的发病机制尚不清楚。研究集中在内脏疼痛的原因上，确定了痛觉过敏对内脏疼痛的作用，定义了痛觉过敏对内脏和机械感受器刺激的作用。夸张的感觉被注意到治愈了同时的化学和机械刺激，显示了传入信息的总和。5-羟色胺(5-HT)通过作用于神经H-HT和H-HT4受体来调节肠道感觉运动功能。我们假设，胃气和腹胀患者对小肠化学和机械感受器刺激的内脏传入反应表现出主要缺陷，这些反应受不同的5-羟色胺途径的不同调节。我们进一步假设，这些传入功能障碍引起中枢神经系统(CNS)对感觉信息的异常处理，从而引起肠道运动模式的次级反射改变，从而促进病理性气体滞留。我们建议进行全面的研究，包括内脏传入活动、中枢神经系统对肠道感觉信息的处理、肠道运动以及健康志愿者中有气体和腹胀反应的患者的气体滞留。将评估十二指肠营养灌流和肠胀的感觉，以确定有胃气和腹胀的患者是否表现出痛敏，并测试痛敏是否针对个别营养亚类或肠道区域是全身性的还是特异性的。同时营养灌流和肠扩张期间的症状报告将揭示患者是否对双重传入刺激表现出更显著的总和。在选择性5-HT3和5-HT4拮抗剂存在的情况下，将重复知觉研究，以确定每个受试组内脏知觉的5-羟色胺调节。在有或没有5-羟色胺拮抗剂的情况下，将进行对肠道刺激反应的诱发电位的测量，以表征脊髓传入功能，而脑PET激活模式将定义有气体和腹胀的中枢神经系统对肠道感觉功能的处理异常。最后，化学和机械感受器刺激对肠道运动活动的影响将被量化，并与对注入小肠的气体滞留的影响相关联。我们预计，胃气和腹胀患者将分别通过激活5-HT3和5-HT4受体通路表现出对化学和机械感受器刺激的痛敏，以及增强的总和反应，这将产生夸大的脊髓和脑诱发电位。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，导致气体滞留。这项提案中的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.