Mechanism of the prostanoid TP receptor agonist U46619 for inducing emesis in the ferret

Abstract

U46619 is a potent thromboxane A(2) mimetic with emesis-inducing actions that are mediated via prostanoid TP receptors. We investigated its emetic mechanism of action in more detail using the ferret as model animal. The emesis induced by U46619 (30 microg/kg, intraperitoneal) was antagonized significantly by (+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine hydrochloride (CP-99,994; 1 and 10 mg/kg; P < 0.05) and metoclopramide (0.3 and 3 mg/kg), but not by domperidone (3 mg/kg), sulpiride (0.1 mg/kg), ondansetron (0.1 and 1 mg/kg) alone or combined with droperidol (3 mg/kg), GR125487 (1 mg/kg), promethazine (3 mg/kg), or scopolamine (3 mg/kg); GR 125487 (1 mg/kg) prevented the anti-emetic action of metoclopramide (3 mg/kg). U46619 0.3 microg administered into the fourth ventricle rapidly induced emesis. However, bilateral abdominal vagotomy was ineffective in reducing the emetic response (P > 0.05). Our data suggests that U46619 induces emesis via an extra-abdominal mechanism, probably within the brain. Metoclopramide probably has a mechanism of action to prevent U46619-induced emesis via 5-HT(4) receptor activation and NK(1) tachykinin receptor antagonists could be useful to prevent emesis induced by TP receptor activation in man.