Emetic action of the prostanoid TP receptor agonist, U46619, in Suncus murinus (house musk shrew)

The emetic action of the prostanoid TP receptor agonist, 11α,9α-epoxymethano-15S-hydroxyprosta-5Z,13E-dienoic acid (U46619; 300 μg/kg, i.p.), was investigated in Suncus murinus. The emetic response was reduced by 76% following bilateral abdominal vagotomy (P<0.001) and by reserpine (5 mg/kg, i.p., 24 h pretreatment; P<0.05) but U46619 administered i.c.v. (30–300 ng) was not emetic, suggesting a peripheral mechanism involving monoamines. However, fenfluramine (5 mg/kg, repeated treatment) and para-chlorophenylalanine (100–400 mg/kg) and ondansetron (0.3–3 mg/kg) were inactive (P>0.05) to reduce U46619-induced emesis precluding a role of 5-HT and 5-HT3 receptors in the mechanism. Similarly, phentolamine (0.3–3 mg/kg), propranolol (3 mg/kg), and their combination, and metoclopramide (0.3–3 mg/kg), domperidone (0.3–3 mg/kg), droperidol (0.3–3 mg/kg), scopolamine (0.3–3 mg/kg) and promethazine (0.3–3 mg/kg) were inactive (P>0.05) to reduce the retching and vomiting response. However, the tachykinin NK1 receptor antagonist, (+)-2S,3S(-3-(2-methoxy-5-trifluoromethoxybenzyl)amino-2-phenylpiperidine) (CP-122,721; 1–10 mg/kg) antagonized emesis (P<0.01). In conclusion, U46619-induced emesis appears to be mediated via a predominant peripheral mechanism sensitive to reserpine and is not likely to involve adrenoceptors, dopamine, 5-HT3, muscarinic or histamine (H1) receptors. The action of CP-122,721 to reduce U46619-induced emesis extends the spectrum of anti-emetic action tachykinin NK1 receptor antagonists to mechanisms involving TP receptors.