The motor, modulatory, and sensory neurotransmitters that mediate the peristaltic reflex in the mouse colon were identified by direct measurement, and their involvement in various pathways was determined by selective receptor antagonists. Mucosal stimulation in the central compartment of a three-compartment flat sheet preparation of mouse colon elicited ascending contraction and descending relaxation in the orad and caudad compartments, respectively. Ascending contraction was accompanied by substance P release, a marker for excitatory neurotransmitter release, into the orad compartment and was partly inhibited by atropine and spantide, and abolished by a combination of the two antagonists. Descending relaxation was accompanied by vasoactive intestinal peptide (VIP) release, a marker for inhibitory neurotransmitter release, into the caudad compartment, and was partly inhibited by VIP10-28 and NG-nitro-L-arginine, and abolished by a combination of the two agents. Somatostatin release increased during descending relaxation: immunoneutralization of somatostatin or blockade of its effect with a selective somatostatin type 2 receptor antagonist inhibited descending relaxation. The delta-opioid receptor antagonist naltrindole augmented descending relaxation and ascending contraction. Calcitonin gene-related peptide (CGRP) release increased in the central compartment and was mediated by concurrent release of 5-hydroxytryptamine (5-HT) because its release was blocked by a 5-HT4 receptor antagonist. Both the latter and the CGRP antagonist CGRP8-37, inhibited ascending contraction and descending relaxation. Thus, the reflex in mouse like that in rat and human intestine is initiated by mucosal release of 5-HT and activation of 5-HT4 receptors on CGRP sensory neurons and is relayed via somatostatin and opioid interneurons to VIP/nitric-oxide synthase inhibitory motor neurons and via cholinergic interneurons to acetylcholine/tachykinin excitatory motor neurons.
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