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

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• 作者：Seetha Chebolu ; Yaozhi Wang ; Andrew P. Ray ; Nissar A. Darmani
• 关键词：Leukotriene A₄ ; Leukotriene B₄ ; Fos ; Dorsal vagal complex ; Enteric nervous system
• 刊名：European Journal of Pharmacology
• 出版年：2010
• 出版时间：25 February 2010
• 年：2010
• 卷：628
• 期：1-3
• 页码：195-201
• 全文大小：705 K

文摘

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 (LTA₄, LTB₄, LTF₄, and the cysteinyl leukotrienes LTC₄, LTD₄ and LTE₄), and to investigate whether the leukotriene CysLT₁ receptor antagonist pranlukast or mixed leukotriene CysLT_1/2 receptor antagonist Bay u9773 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 min. 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 other tested leukotrienes were either weakly emetic or ineffective at doses up to 4 mg/kg. The relative emetogenic activities of the cysteinyl leukotrienes (LTC₄ = LTD₄ > LTE₄) suggest that leukotriene CysLT₂ receptors have a key role in emesis. However, pranlukast dose-dependently, and at 10 mg/kg completely, blocked LTC₄-induced vomiting, implicating a leukotriene CysLT₁ 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 LTC₄-induced vomiting to define its putative anatomical substrates, was significantly increased in the enteric nervous system and medullary dorsal vagal complex following LTC₄ (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 CysLT₁ and/or leukotriene CysLT₂ receptors.