5-HT RELEASED BY MUCOSAL STIMULI INITIATES PERISTALSIS BY ACTIVATING 5-HT4 5-HT1P RECEPTORS ON SENSORY CGRP NEURONS/

The intestinal peristaltic reflex can be elicited by mucosal stimulati on or circular muscle stretch. Muscle stretch activates extrinsic, whe reas mucosal stimulation activates intrinsic calcitonin gene-related p eptide (CGRP)-containing sensory neurons. The present study examined t he role of 5-hydroxytryptamine (5-HT) in sensory transmission. A three -compartment preparation of rat colon was used that enables separate m easurement of sensory transmitters and modulators. Mucosal stimuli (2- 8 brush strokes) caused concurrent increase in 5-HT and CGRP release i n proportion to the intensity of stimulation. Release of both 5-HT and CGRP occurred exclusively into the central compartment where the stim uli were applied. Exogenous 5-HT caused a concentration-dependent rele ase of CGRP. Release of CGRP induced by exogenous 5-HT or mucosal stim ulation was inhibited by selective 5-HT4 and 5-HT1p antagonists but wa s not affected by 5-HT1A, 5-HT2, and 5-HT3 antagonists. Ascending cont raction and descending relaxation of circular muscle measured in the p eripheral orad and caudad compartments, respectively, were also select ively inhibited by 5-HT4 and 5-HT1p antagonists added to the central b ut not peripheral compartments. In contrast, muscle stretch elicited C GRP but not 5-HT release; the ascending contraction and descending rel axation components of the peristaltic reflex induced by muscle stretch were not affected by 5-HT antagonists. We conclude that 5-HT released by mucosal stimulation initiates the peristaltic reflex by activating 5-HT4/5-HT1p receptors on sensory CGRP-containing neurons.