Effects of CP-99, 994, a tachykinin NK(1) receptor antagonist, on abdominal afferent vagal activity in ferrets: evidence for involvement of NK(1) and 5-HT(3) receptors.
The effect of CP-99, 994, a tachykinin NK(1) receptor antagonist, on abdominal vagal afferent nerve activity in the ferret was investigated. Substance P (1 microg/kg, i.v.) increased vagal afferent activity by 449.0+/-51.9% and this was reduced to 145.9+/-5.7% (p<0.01) by pre-treatment with CP-99, 994 (1 mg/kg, i.v.), and to 149.5+/-1.5% (p<0.001) by granisetron (1 mg/kg, i.v.), a 5-HT(3) receptor antagonist. In addition, the increase in vagal nerve activity induced by 5-HT (25 microg/kg, i.v., 552.0+/-57.0% increase from pre-injection level) was significantly reduced (401.3+/-10.6% increase from pre-injection level, p<0.05) by CP-99, 994 (100 microg/kg, i.v.). These results provide evidence for an involvement of peripheral NK(1) and 5-HT(3) receptors in substance P-induced vagal afferent activation. While the functional consequences (if any) of such peripheral effects were not investigated, they could contribute either directly (e.g. by blockade of receptors on vagal afferents) or indirectly (e.g. modulation of 5-HT release or reduction of local inflammatory response) to the antiemetic effects of CP-99, 994 against cisplatin and other emetic agents acting primarily via the vagus.
Minami
M
M
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, 1757 Kanazawa, Ishikari-Tobetsu, Hokkaido 061-0293, Japan. minami@hoku-iryo-u.ac.jp
Endo
T
T
Yokota
H
H
Ogawa
T
T
Nemoto
M
M
Hamaue
N
N
Hirafuji
M
M
Yoshioka
M
M
Nagahisa
A
A
Andrews
P L
PL
D000005:Abdomen / Q000294:innervation*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005289:Ferrets; D017829:Granisetron / Q000494:pharmacology; D007275:Injections, Intravenous; D008297:Male; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D018040:Receptors, Neurokinin-1 / Q000502:physiology; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology; D044406:Receptors, Serotonin, 5-HT3; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D013237:Stereoisomerism; D013373:Substance P / Q000494:pharmacology; D014630:Vagus Nerve / Q000187:drug effects* / Q000502:physiology
D017829:Granisetron; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D018040:Receptors, Neurokinin-1; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D012701:Serotonin; D012702:Serotonin Antagonists; D013373:Substance P; C080755:3-(2-methoxybenzylamino)-2-phenylpiperidine