AFFERENT DYSFUNCTION & GAS RETENTION: ROLE OF SEROTONIN

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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.