The effects of a novel tachykinin NK1-receptor antagonist HSP-117 [(2S,3S)-3-[(5-isopropyl-2,3-dihydrobenzofuran-7-yl)methyl]amino-2-phenylpiperidine dihydrochloride] on cisplatin-induced pica, i.e., the eating of nonnutritive substances such as kaolin were examined in rats. HSP-117 inhibited kaolin intake in a dose-dependent manner for 2 days. The 5-HT3-receptor antagonist ondansetron inhibited only on the first day, but not on the second day. These results indicate that the cisplatin-induced kaolin intake on the first day is related to both 5-HT3- and NK1 receptors, while only the NK1 receptor is involved on the second day. Thus, cisplatin-induced continuous pica in rats represents a useful model of not only acute but also delayed emesis.

01 Jun 2000·Neuroscience LettersQ4 · MEDICINE

The role of tachykinin NK-1 receptors in the area postrema of ferrets in emesis

Q4 · MEDICINE

Article

Author: Yukio Takano ; Misako Hyakusoku ; Sachiko Nago ; Hideto Ariumi ; Hiro-o Kamiya ; Ryo Saito

The role of tachykinin NK-1 receptors in the area postrema (AP) in emesis was examined in ferrets. Strong c-fos-like immunoreactivity was observed in the AP and nucleus tractus solitalius (NTS) in cisplatin (10 mg/kg, i.p.)-treated animals, but not in control animals. The number of the central emetogen morphine-induced vomits and retches was remarkably reduced (95%) and that of the peripheral emetogen copper sulphate-induced vomits was significantly (54%) reduced by AP lesion. Pretreatment with the tachykinin NK-1 receptor antagonists HSP-117 (1.0 microg) and CP-99,994 (7.5 microg) into the AP decreased the numbers of vomits and retches induced by morphine and copper sulphate. These results suggest that NK-1 receptors in the AP are involved in the mechanism of emesis induced by morphine and copper sulphate.

01 Jan 1999·Folia Pharmacologica Japonica

The role of tachykinin NK-1 receptors in emetic action in the area postrema of ferrets

Article

Author: Ariumi, H ; Takano, Y ; Kamiya, H ; Saito, R ; Kubota, H ; Nago, S ; Honda, K

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.

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Indication	Highest Phase	Country/Location	Organization	Date
Nausea and vomiting	Preclinical	Japan	Hisamitsu Pharmaceutical Co., Inc.	-

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