Pranlukast prevents cysteinyl leukotriene‐induced emesis in the least shrew (Cryptotis parva)

Abstract

Chemotherapeutic agents activate multiple signaling systems, including the cascade of arachidonic acid metabolites, of which some have emetic potential (e.g. PG F2α). The aims of this study were to test the emetic potential of one family of the neglected metabolites, the leukotrienes (LTA4, LTB4, LTF4, and the cysteinyl leukotrienes LTC4, LTD4 and LTE4), and to investigate whether the cysteinyl leukotriene CysLT1 receptor antagonist pranlukast can prevent the LTC4 induced emesis. Least shrews were injected with varying doses of one of the six tested leukotrienes and vomiting parameters were measured for 30 minutes. LTC4 and LTD4 were most efficacious, and significantly increased both the frequency and percentage of animals vomiting at doses from 0.1 and 0.05 mg/kg, respectively. The emetic profile of the cysteinyl leukotrienes (LTC4=LTD4>LTE4) suggests CysLT2 receptors have a key role in emesis whereas pranlukast which dose‐dependently, and at 10 mg/kg completely blocked LTC4‐induced vomiting, implicates a leukotriene CysLT1 receptor‐mediated emetic effect. Fos immunoreactivity, measured subsequent to LTC4‐induced vomiting, was significantly increased in the enteric nervous system and medullary dorsal vagal complex following LTC4 (P < 0.05) versus vehicle administration. This study is the first to show that some leukotrienes induce emesis, possibly involving both central and peripheral leukotriene CysLT1 and/or leukotriene CysLT2 receptors. This work was supported by NIH grant # R01CA115331 from the National Cancer Institute to Dr. Darmani.