Participation of serotonin and substance P in the action of cholecystokinin on colonic motility.

Cholecystokinin (CCK) has a potent stimulatory effect on gastrointestinal motility. The mechanism of CCK-generated contractions in the colon is unknown. We explored the possibility that CCK-mediated contractions in the guinea pig colon occur via a serotonin and/or substance P pathway. In the circular layer, octapeptide of CCK (CCK-8) had no effect under basal conditions, but after treatment with tetrodotoxin the peptide generated dose-dependent contractions (ED50 6 X 10(-8) M). In the longitudinal layer, CCK-8 produced dose-related contractions (ED50 6 X 10(-9) M) blocked by tetrodotoxin and markedly inhibited by the substance P antagonist, Spantide. The effect of substance P was not significantly antagonized by tetrodotoxin but was markedly attenuated by Spantide. Serotonin produced dose-dependent contractions in the longitudinal layer (ED50 4 X 10(-8) M). Desensitization to serotonin antagonized the action of CCK-8 but had no effect on substance P-mediated contractions. Pretreatment with the serotonin antagonist mianserin inhibited CCK-8- but not substance P-generated contractions. In contrast, the stimulatory effect of serotonin was antagonized by Spantide. These studies suggest that in the circular layer of the guinea pig colon CCK-8 has no effect under basal conditions, but after removal of tonic inhibition, the peptide produced a direct stimulatory effect. In contrast, CCK-8 generated contractions in guinea pig colon longitudinal layer, mediated by a pathway involving serotonin and substance P.