Pharmacological mechanisms of 5-HT₃ and tachykinin NK₁ receptor antagonism to prevent chemotherapy-induced nausea and vomiting

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• 作者：Camilo Rojas^a ; Barbara S. Slusher^a ; ^b ; ^c ; ^{bslusher@jhmi.edu}
• 关键词：Palonosetron ; Ondansetron ; Granisetron ; Netupitant ; 5-HT3 receptor ; NK1 receptor
• 刊名：European Journal of Pharmacology
• 出版年：2012
• 期刊代码：24_00142999
• 类别：neu
• 出版时间：5 June, 2012
• 卷：684
• 期：1-3
• 页码：1-7
• 文件大小：907 K

摘要

Nausea and vomiting are among the most common and distressing consequences of cytotoxic chemotherapies. Nausea and vomiting can be acute (0-24 h) or delayed (24-72 h) after chemotherapy administration. The introduction of 5-HT₃ receptor antagonists in the 90s was a major advance in the prevention of acute emesis. These receptor antagonists exhibited similar control on acute emesis but had no effect on delayed emesis. These findings led to the hypothesis that serotonin plays a central role in the mechanism of acute emesis but a lesser role in the pathogenesis of delayed emesis. In contrast, delayed emesis has been largely associated with the activation of neurokinin 1 (NK₁) receptors by substance P. However, in 2003, a new 5-HT₃ receptor antagonist was introduced into the market; unlike first generation 5-HT₃ receptor antagonists, palonosetron was found to be effective in preventing both acute and delayed chemotherapy induced nausea and vomiting. Recent mechanistic studies have shown that palonosetron, in contrast to first generation receptor antagonists, exhibits allosteric binding to the 5-HT₃ receptor, positive cooperativity, persistent inhibition of receptor function after the drug is removed and triggers 5-HT₃ receptor internalization. Further, in vitro and in vivo experiments have shown that palonosetron can inhibit substance P-mediated responses, presumably through its unique interactions with the 5-HT₃ receptor. It appears that the crossroads of acute and delayed emeses include interactions among the 5-HT₃ and NK₁ receptor neurotransmitter pathways and that inhibitions of these interactions lend the possibility of improved treatment that encompasses both acute and delayed emeses.