THE ANTIEMETIC EFFECTS OF CP-99,994 IN THE FERRET AND THE DOG - ROLE OF THE NK1 RECEPTOR

1 The selective NK1 receptor antagonist, CP-99,994, produced dose-rela ted (0.1-1.0 mg kg(-1), s.c.) inhibition of vomiting and retching in f errets challenged with central (loperamide and apomorphine), periphera l (CuSO4) and mixed central and peripheral (ipecac, cisplatin) emetic stimuli. 2 Parallel studies with the enantiomer, CP-100,263 (1 mg kg(- 1), s.c.), which is > 1 000 fold less potent as a NK1 antagonist, indi cated that it was without significant effect against CuSO4, loperamide , cisplatin and apomorphine-induced emesis. Against ipecac, it inhibit ed both retching and vomiting, expressing approximately 1/10th the pot ency of CP-99,994. 3 The 5-HT3 receptor antagonist, tropisetron (1 mg kg(-1), s.c.) inhibited retching and vomiting to cisplatin and ipecac, but not CuSO4 or loperamide. 4 CP-99,994 (1 mg kg(-1), i.v.) blocked retching induced by electrical stimulation of the ventral abdominal va gus without affecting the cardiovascular response, the apnoeic respons e to central vagal stimulation or the guarding and hypertensive respon se to stimulation of the greater splanchnic nerves. CP-99,994 (1 mg kg (-1), i.v.) did not alter baseline cardiovascular and respiratory para meters and it failed to block the characteristic heart rate, blood pre ssure and respiratory rate/depth changes in response to i.v. 2-methyl- 5-HT challenge (von Bezold-Jarisch reflex). 5 Using in vitro autoradio graphy, [H-3]-substance P was shown to bind to several regions of the ferret brainstem with the density of binding in the nucleus tractus so litarius being much greater than in the area postrema. This binding wa s displaced by CP-99,994 in a concentration-related manner. 6 In dogs, CP-99,994 (40 mu g kg(-1) bolus and 300 mu g kg(-1) h(-1), i.v.) prod uced statistically significant reductions in vomiting to CuSO4 and apo morphine as well as retching to CuSO4. 7 Together, these studies suppo rt the hypothesis that the NK1 receptor antagonist properties of CP-99 ,994 are responsible for its broad spectrum anti-emetic effects. They also suggest that CP-99,994 acts within the brainstem, most probably w ithin the nucleus tractus solitarius although the involvement of the a rea postrema could not be excluded.