Emetic action of the prostanoid TP receptor agonist, U46619, in Suncus murinus (house musk shrew).
The emetic action of the prostanoid TP receptor agonist, 11alpha,9alpha-epoxymethano-15S-hydroxyprosta-5Z,13E-dienoic acid (U46619; 300 microg/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, (+)-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-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.
Kan
Kelvin K W
KK
Department of Pharmacology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China.
Jones
Robert L
RL
Ngan
Man-P
MP
Rudd
John A
JA
Wai
Man-K
MK
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000633:toxicity*; D000818:Animals; D004639:Emetics / Q000633:toxicity*; D005260:Female; D008297:Male; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use; D017482:Receptors, Thromboxane / Q000819:agonists* / Q000502:physiology; D012788:Shrews / Q000502:physiology; D014628:Vagotomy / Q000379:methods; D014630:Vagus Nerve / Q000187:drug effects / Q000502:physiology; D014839:Vomiting / Q000139:chemically induced* / Q000503:physiopathology / Q000517:prevention & control
D004639:Emetics; D010880:Piperidines; D017482:Receptors, Thromboxane; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C099414:(2S,3S)-2-phenyl-3-((5-trifluoromethoxy-2-methoxy)benzylamino)piperidine