Many chemotherapeutic agents activate multiple signaling systems, including potentially emetogenic arachidonic acid metabolites. Of these messengers, the emetic role of the leukotriene family has been neglected. The aims of this study were to test the emetic potential of key leukotrienes (LTA(4), LTB(4), LTF(4), and the cysteinyl leukotrienes LTC(4), LTD(4) and LTE(4)), and to investigate whether the leukotriene CysLT(1) receptor antagonist pranlukast or mixed leukotriene CysLT(1/2) receptor antagonist Bay u9773 can prevent the LTC(4)-induced emesis. Least shrews were injected with varying doses of one of the six tested leukotrienes and vomiting parameters were measured for 30min. LTC(4) and LTD(4) were most efficacious, and significantly increased both the frequency and percentage of animals vomiting at doses from 0.1 and 0.05mg/kg, respectively. The other tested leukotrienes were either weakly emetic or ineffective at doses up to 4mg/kg. The relative emetogenic activities of the cysteinyl leukotrienes (LTC(4)=LTD(4)>LTE(4)) suggest that leukotriene CysLT(2) receptors have a key role in emesis. However, pranlukast dose-dependently, and at 10mg/kg completely, blocked LTC(4)-induced vomiting, implicating a leukotriene CysLT(1) receptor-mediated emetic effect. Bay u9773 dose-dependently reduced the percentage of animals vomiting, but did not significantly reduce vomiting frequency. Fos immunoreactivity, measured subsequent to LTC(4)-induced vomiting to define its putative anatomical substrates, was significantly increased in the enteric nervous system and medullary dorsal vagal complex following LTC(4) (P<0.05) versus vehicle injections. This study is the first to show that some leukotrienes induce emesis, possibly involving both central and peripheral leukotriene CysLT(1) and/or leukotriene CysLT(2) receptors.