Role of Calcium in Vomiting

Cisplatin-like chemotherapeutics cause vomiting via calcium (Ca 2+ )-dependent release of multiple neurotransmitters/mediators (dopamine, serotonin, substance P, prosta - glandins and leukotrienes) from the gastrointestinal enterochromaffin cells and/or the brainstem. Intracellular Ca 2+ signaling is triggered by activation of diverse emetic recep tors (including neurokininergic NK 1 , serotonergic 5-HT 3 , dopaminergic D 2 , cholinergic M 1 , or histaminergic H 1 ) , whose stimulation in vomit-competent species evokes emesis. Other emetogens such as cisplatin, rotavirus NSP4 protein, and bacterial toxins can also induce intracellular Ca 2+ elevation. Our findings demonstrate that application of the L-type Ca 2+ channel (LTCC) agonist FPL 64176 and the intracellular Ca 2+ mobilizing agent thapsigargin (a sarco/endoplasmic reticulum Ca 2+ -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-HT 3 , NK 1 , D 2 , and M 1 receptors, but can also potentiate the antiemetic efficacy of palonosetron against the nonspecific emetogen, cisplatin. In this review, we will provide an overview of Ca 2+ involvement in the emetic process; discuss the relationship between Ca 2+ signaling and the prevailing therapeutics in control of vomiting; highlight the current evidence for Ca 2+ signaling blockers/inhibitors in suppressing emetic behavior and also draw attention to the clinical benefits of Ca 2+ -signaling blockers/inhibitors for the treatment of nausea and vomiting. (10 mg/kg, i.p.), the and non-selective 5-HT agonist 5-HT (5 mg/kg, i.p.), the peripherally/centrally-acting and more selective 5-HT 3 R agonist (5 mg/kg, i.p.), the D 2 R-preferring agonist quinpirole (2 mg/kg, i.p.), the non-selective dopamine D 2 R agonist apomorphine (2 mg/kg, i.p.), the nonselective cho linergic agonist pilocarpine (2 mg/kg, i.p.), the M 1 -preferring cholinergic agonist McN-A343 (2 mg/kg, i.p.), and the selective neurokinin NK 1 R agonist GR73632 (5 mg/kg, i.p.). The vomiting behavior was recorded for 30 min. Our results suggest that both amlodipine and nifedipine act by suppressing the influx of extracellular Ca 2+ , thereby delay the onset as well as protect ing least shrews from vomiting, further supporting our proposed Ca 2+ hypothesis of emesis. totally dependent upon G i/o [144]. These signaling effects were totally inhibited by various specific CysLT1-receptor antagonists, and CysLT1 antago nists the P2Y agonist-induced activation of phospholipase C and intracellular