AFFERENT DYSFUNCTION & GAS RETENTION: ROLE OF SEROTONIN

气和腹胀是胃肠病学家常见的主诉，但这些症状的发病机制尚不清楚。研究主要集中在内脏疼痛的原因，定义痛觉过敏对内脏疼痛的作用，定义痛觉过敏对内脏和机械受体刺激的作用。在化学刺激和机械刺激同时发生的情况下，表现为传入信息的汇总，从而引起知觉的夸大。5-羟色胺（5-HT）通过作用于神经H-HT和H-HT4受体调节肠道感觉运动功能。我们假设，气胀患者对小肠化疗和机械受体刺激的内脏传入反应表现出原发性缺陷，这是由不同的5-羟色胺途径不同地调节的。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，引起肠道运动模式的二次反射改变，从而促进病理性气体潴留。我们建议综合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、肠道运动和气胀患者的气体潴留以及健康志愿者的反应。评估十二指肠营养物质灌注和肠道膨胀的感觉，以确定气胀患者是否表现出痛觉过敏，并测试痛觉过敏是普遍的还是特定于单个营养亚类或肠道区域。营养物质同时灌注和肠道扩张时的症状报告将揭示患者对双重传入刺激是否表现出更突出的汇总。知觉研究将在选择性5-HT3和5-HT4拮抗剂存在的情况下重复进行，以确定每个受试者组中5-HT对内脏知觉的调节。在使用或不使用5-HT拮抗剂的情况下，对肠刺激反应的诱发电位进行测量，以表征脊髓传入功能，而脑PET激活模式将定义CNS处理肠道感觉功能的异常，包括气体和腹胀。最后，化学和机械受体刺激对肠道运动活动的影响将被量化，并与注入小肠的气体潴留的影响相关。我们预计，气体和腹胀患者将分别通过激活5-HT3和5-HT4受体途径对化学和机械受体刺激表现出痛觉过敏，以及增强的汇总反应，从而产生夸大的脊髓和大脑诱发电位。这可能导致中枢神经系统活动异常，引起肠道运动的继发性紊乱，导致气体潴留。本提案中的研究将为气体和腹胀的发展机制提供新颖而重要的见解。

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.