Ca^{2 +} signaling and emesis: Recent progress and new perspectives

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• 作者：Weixia Zhong ; Andrew J. Picca ; Albert S. Lee ; Nissar A. Darmani ; ^{ndarmani@westernu.edu}
• 关键词：Cancer ; Cisplatin ; Vomiting ; Emesis ; Antiemesis ; Ca2  ; + ;   ; L-type Ca2  ; + channel ; Palonosetron ; Netupitant ; CB1 receptor
• 刊名：Autonomic Neuroscience
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：202
• 期：Complete
• 页码：18-27
• 全文大小：722 K
• 卷排序：202

文摘

Cisplatin-like chemotherapeutics cause vomiting via calcium (Ca2 +)-dependent release of multiple neurotransmitters (dopamine, serotonin, substance P, etc.) from the gastrointestinal enterochromaffin cells and/or the brainstem. Intracellular Ca2 + signaling is triggered by activation of diverse emetic receptors (including tachykininergic NK1, serotonergic 5-HT3, dopaminergic D2, cholinergic M1, or histaminergic H1), whose activation in vomit-competent species can evoke emesis. Other emetogens such as cisplatin, rotavirus NSP4 protein and bacterial toxins can also induce intracellular Ca2 + elevation. Netupitant is a highly selective neurokinin NK1 receptor (NK1R) antagonist and palonosetron is a selective second-generation serotonin 5-HT3 receptor (5-HT3R) antagonist with a distinct pharmacological profile. An oral fixed combination of netupitant/palonosetron (NEPA; Akynzeo(®)) with > 85% antiemetic efficacy is available for use in the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV). Cannabinoid CB1 receptor agonists possess broad-spectrum antiemetic activity since they prevent vomiting caused by a variety of emetic stimuli including the chemotherapeutic agent cisplatin, 5-HT3R agonists, and D2R agonists. Our findings demonstrate that application of the L-type Ca2 + channel (LTCC) agonist FPL 64176 and the intracellular Ca2 + mobilizing agent thapsigargin (a sarco/endoplasmic reticulum Ca2 +-ATPase inhibitor) cause vomiting in the least shrew. On the other hand, blockade of LTCCs by corresponding antagonists (nifedipine or amlodipine) not only provide broad-spectrum antiemetic efficacy against diverse agents that specifically activate emetogenic receptors such as 5-HT3, NK1, D2, and M1 receptors, but can also potentiate the antiemetic efficacy of palonosetron against the non-specific emetogen, cisplatin. In this review, we will provide an overview of Ca2 + involvement in the emetic process; discuss the relationship between Ca2 + signaling and the prevailing therapeutics in control of vomiting; highlight the evidence for Ca2 +-signaling blockers/inhibitors in suppressing emetic behavior in the least shrew model of emesis as well as in the clinical setting; and also draw attention to the clinical benefits of Ca2 +-signaling blockers/inhibitors in the treatment of nausea and vomiting.