u-50488 and Intestinal-Obstruction

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.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Acetates; Acetic Acid; Animals; Benzyl Compounds; Capsaicin; Corticotropin-Releasing Hormone; Gastric Emptying; Gastrointestinal Motility; Intestinal Obstruction; Male; Neurons, Afferent; Peptide Fragments; Peritoneal Cavity; Propylamines; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Corticotropin-Releasing Hormone

Fedotozine is a peripheral opioid agonist. Its effects were assessed in experimental ileus in rats.. Ileus was induced by abdominal surgery (laparotomy and cecum palpation) or peritonitis (acetic acid, intraperitoneally). Digestive motility was recorded by electromyography and gastrointestinal transit estimated using a 51Cr-labeled test meal.. Surgery or peritonitis inhibited motility and migrating myoelectrical complexes for 2-3 hours. In both models, fedotozine (3 mg/kg, intravenously; 10 mg/kg, subcutaneously) restored a normal motility pattern. This action was reproduced by the kappa-agonist, U-50, and 488H and was blocked by subcutaneous naloxone, naloxone-methiodide, or nor-binaltorphimine, a selective kappa-antagonist. Peritonitis induced a 57% inhibition of gastric emptying and intestinal transit that was reversed by fedotozine (1-10 mg/kg, subcutaneously) or kappa-agonists (U-50, 488H, bremazocine) but not delta-agonists (DPDPE, [D-Ala2]-deltorphin-II), whereas mu-agonists (morphine, fentanyl) potentiated ileus. Fedotozine restoration of transit was blocked by subcutaneous naloxone, naloxone-methiodide, or norbinaltorphimine but not by intracerebroventricular naloxone. Fedotozine was inactive up to 300 micrograms/rat when given intracerebroventrically or intrathecally.. Fedotozine reverses experimental ileus via an action at peripheral kappa-opioid receptors.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Abdomen; Animals; Benzyl Compounds; Gastric Emptying; Gastrointestinal Motility; Intestinal Obstruction; Male; Naloxone; Peritonitis; Propylamines; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa