The anti-emetic 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-related (0.1-1.0 mg kg-1, s.c.) inhibition of vomiting and retching in ferrets challenged with central (loperamide and apomorphine), peripheral (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, indicated that it was without significant effect against CuSO4, loperamide, cisplatin and apomorphine-induced emesis. Against ipecac, it inhibited both retching and vomiting, expressing approximately 1/10th the potency 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 vagus without affecting the cardiovascular response, the apnoeic response to central vagal stimulation or the guarding and hypertensive response to stimulation of the greater splanchnic nerves. CP-99,994 (1 mg kg-1, i.v.) did not alter baseline cardiovascular and respiratory parameters and it failed to block the characteristic heart rate, blood pressure and respiratory rate/depth changes in response to i.v. 2-methyl-5-HT challenge (von Bezold-Jarisch reflex). 5. Using in vitro autoradiography, [3H]-substance P was shown to bind to several regions of the ferret brainstem with the density of binding in the nucleus tractus solitarius being much greater than in the area postrema. This binding was displaced by CP-99,994 in a concentration-related manner. 6. In dogs, CP-99,994 (40 micrograms kg-1 bolus and 300 micrograms kg-1 h-1, i.v.) produced statistically significant reductions in vomiting to CuSO4 and apomorphine as well as retching to CuSO4. 7. Together, these studies support 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 within the nucleus tractus solitarius although the involvement of the area postrema could not be excluded.
Watson
J W
JW
Department of Immunology, Pfizer Inc, Groton, CT 06340, USA.
Gonsalves
S F
SF
Fossa
A A
AA
McLean
S
S
Seeger
T
T
Obach
S
S
Andrews
P L
PL
D000818:Animals; D000932:Antiemetics / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D001933:Brain Stem / Q000378:metabolism; D004285:Dogs; D005289:Ferrets; D005683:Gagging / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology; D008297:Male; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D013373:Substance P / Q000378:metabolism; D000077526:Tropisetron; D014630:Vagus Nerve / Q000502:physiology
D000932:Antiemetics; D007211:Indoles; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D018040:Receptors, Neurokinin-1; C080755:3-(2-methoxybenzylamino)-2-phenylpiperidine; D013373:Substance P; D000077526:Tropisetron