Fedotozine reverses ileus induced by surgery or peritonitis: action at peripheral kappa-opioid receptors.

Abstract

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.