Possible involvement of 5-HT4 receptors, in addition to 5-HT3 receptors, in the emesis induced by high-dose cisplatin in Suncus murinus.
To clarify the mechanism for the severe emesis concomitant with intensive chemotherapy, we investigated the effects of 5-HT3- and 5-HT4-receptor antagonists on the emesis induced by the high-dose of cisplatin in Suncus murinus. The emesis induced by 50 mg/kg of cisplatin was reduced by the oral pretreatment with tropisetron, which is known as a 5-HT3- and 5-HT4-receptor dual antagonist in vitro, with the ID50 value of 0.52 mg/kg. On the contrary, granisetron, a selective 5-HT3-receptor antagonist, did not markedly inhibit the emesis at up to 30 mg/kg. Moreover, GR125487, a selective 5-HT4-receptor antagonist, did not inhibit the emesis. However, co-administration of GR125487 and granisetron significantly reduced the number of emetic episodes. The study of the co-administration of GR125487 with tropisetron showed that GR125487 did not further enhance the inhibitory effect of tropisetron alone, suggesting that the anti-emetic effect of tropisetron is mediated via the blockade of both 5-HT3 and 5-HT4 receptors. These results suggest that both the 5-HT3 and 5-HT4 receptors are involved in the emesis induced by the high-dose of cisplatin in Suncus murinus.
Horikoshi
K
K
Drug Development Research Laboratories, Pharmaceutical Research Institute, Kyowa Hakko Kogyo Co., Ltd., Sunto-gun, Shizuoka, Japan. akira.karasawa@kyowa.co.jp
Yokoyama
T
T
Kishibayashi
N
N
Ohmori
K
K
Ishii
A
A
Karasawa
A
A
D000818:Animals; D000932:Antiemetics / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000009:adverse effects*; D002945:Cisplatin / Q000009:adverse effects*; D017829:Granisetron / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008297:Male; D017294:Ondansetron / Q000494:pharmacology; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000502:physiology; D044406:Receptors, Serotonin, 5-HT3; D044422:Receptors, Serotonin, 5-HT4; D012702:Serotonin Antagonists / Q000494:pharmacology*; D012788:Shrews; D013449:Sulfonamides / Q000494:pharmacology; D000077526:Tropisetron; D014839:Vomiting / Q000139:chemically induced / Q000503:physiopathology* / Q000517:prevention & control
D000932:Antiemetics; D000970:Antineoplastic Agents; D002945:Cisplatin; D017829:Granisetron; D007211:Indoles; D017294:Ondansetron; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D044422:Receptors, Serotonin, 5-HT4; D012702:Serotonin Antagonists; D013449:Sulfonamides; D000077526:Tropisetron; C082871:GR 113808