[The role of tachykinin NK-1 receptors in emetic action in the area postrema of ferrets].
Substance P (SP) is a member of the tachykinin family of bioactive peptides and has highest affinity for the NK-1 receptor. We have developed the non-peptide compound HSP-117 as a selective antagonist of the NK-1 receptor. Binding of 3H-SP to the membranes of IM-9 cells was inhibited by the antagonists HSP-117 and CP-99,994, the inhibitory activity of HSP-117 being 50-fold that of CP-99,994. The SP-induced firing responses of single neuron activity in slices of the nucleus tractus solitarius of ferrets were inhibited by 10 microM HSP-117. Intracerebroventricular injection of HSP-117 significantly inhibited retching and vomiting induced by copper sulphate and morphine and the inhibitory effect of HSP-117 on emesis was greater than that of CP-99,994. Moreover, emesis induced by copper sulphate and morphine were inhibited by the microinjection of HSP-117 and CP-99,994 into the area postrema and by lesion of the area postrema. These results indicate that HSP-117 is a potent anti-emetic agent, blocking NK-1 receptors in the area postrema and that NK-1 receptors in the area postrema play an important role in emesis induced by broad-spectrum emetic stimuli.
Saito
R
R
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Japan.
Ariumi
H
H
Kubota
H
H
Nago
S
S
Honda
K
K
Takano
Y
Y
Kamiya
H
H
D000818:Animals; D000932:Antiemetics / Q000494:pharmacology*; D001572:Benzofurans / Q000494:pharmacology*; D019327:Copper Sulfate; D005289:Ferrets; D008526:Medulla Oblongata / Q000737:chemistry*; D009020:Morphine; D010880:Piperidines / Q000494:pharmacology*; D018040:Receptors, Neurokinin-1 / Q000032:analysis / Q000502:physiology*; D017552:Solitary Nucleus / Q000187:drug effects; D013237:Stereoisomerism; D014839:Vomiting / Q000139:chemically induced / Q000503:physiopathology*
D000932:Antiemetics; D001572:Benzofurans; D010880:Piperidines; D018040:Receptors, Neurokinin-1; C080755:3-(2-methoxybenzylamino)-2-phenylpiperidine; D009020:Morphine; C119466:HSP 117; D019327:Copper Sulfate