SUBSTANCE-P AS A MEDIATOR OF COLONIC SECRETORY REFLEXES

The role of substance P in neural reflex pathways activated by strokin g was investigated in muscle-stripped segments of distal colon from gu inea pigs. Stroking the mucosal surface with a brush at 1 stroke/s evo ked an increase in short-circuit current (I-sc) indicative of chloride secretion. The response to mucosal stroking was maximally reduced by 69-75% by the antagonist GR-82334. The agonist [Sar(9),Met(O-2)(11)] s ubstance P caused a bumetanide-sensitive increase in I-sc when added t o the mucosal or serosal bath. Ablation of extrinsic afferents with ac ute or chronic administration of capsaicin did not alter the mucosal s troking response. Reverse transcription-polymerase chain reaction and in situ hybridization revealed the presence of neurokinin(1) (NK1) rec eptor messenger RNA in isolated colonocytes or crypt glands. Ligand bi nding of I-125-Bolton-Hunter-labeled substance P was inhibited by GR-8 2334. The 50% inhibitory concentration was 0.84 nM. The results demons trate a role for substance P released from capsaicin-insensitive submu cosal neurons and in mucosal stroking reflexes. The presence of NK1 re ceptors on isolated colonocytes suggest that appropriate elements are present for axon reflex activation of intestinal epithelial cells.