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

Authors
Publisher
Elsevier B.V.
Publication Date
Volume
482
Identifiers
DOI: 10.1016/j.ejphar.2003.09.069
Keywords
  • U46619
  • Prostanoid Tp Receptor
  • Tachykinin Nk1Receptor
  • Emetic
  • Anti-Emetic
  • Prostanoid
  • (Suncus Murinus)

Abstract

Abstract The emetic action of the prostanoid TP receptor agonist, 11α,9α-epoxymethano-15 S-hydroxyprosta-5 Z,13 E-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-HT 3 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 NK 1 receptor antagonist, (+)-2 S,3 S(-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-HT 3, muscarinic or histamine (H 1) receptors. The action of CP-122,721 to reduce U46619-induced emesis extends the spectrum of anti-emetic action tachykinin NK 1 receptor antagonists to mechanisms involving TP receptors.

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