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

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. (C) 2012 Elsevier B.V. All rights reserved.