Fedotozine Reversal of Peritoneal-irritation-induced Ileus in Rats: Possible Peripheral Action on Sensory Afferents

Two kappa agonists, fedotozine and trans-(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolydinyl)-cyclohexyl ]- benzeneacetamide methanesulfonate [(+/-)U-50,488H] were used to reverse the gastrointestinal transit inhibition induced by either peritoneal irritation (PI) or intracisternal (i.c.) administration of corticotropin releasing factor (CRF). PI was induced by acetic acid given i.p. Gastric emptying and intestinal transit were estimated with a 51Cr-labeled test meal. PI inhibited both gastric emptying (-50.9%) and intestinal transit (-48.8%). These inhibitions were prevented in a dose-dependent manner by the CRF antagonist, alpha-helical-CRF9-41 at doses (1-10 nmol/rat i.c.) that had no effect in control animals. CRF (300 pmol/rat i.c.) reproduced the gastrointestinal transit inhibitions seen under PI. The CRF effects were blocked by alpha-helical-CRF9-41 (10 nmol/rat) given i.c. but not i.v. Fedotozine (1-10 mg/kg s.c. but not 300 micrograms/rat i.c.v. or intrathecally) and (+/-)U-50,488H (0.3-3 mg/kg s.c. but not 100 micrograms/kg i.c.v.) reversed PI- but not CRF-induced ileus. Neither PI-induced ileus nor the fedotozine response was affected by perivagal capsaicin treatment. It was concluded that the PI-induced ileus depends on central CRF receptors. This result is consistent with the activation of an extrinsic inhibitory reflex. The reversal by kappa agonists of PI- but not CRF-induced ileus suggests that kappa agonists do not act after but before the CRF receptors. A possible peripheral action on nonvagal sensory afferents is suggested.