LAUSR

ABSTRACT Ca2+ plays a major role in maintaining cellular homeostasis and regulates processes including apoptotic cell death and side‐effects of cancer chemotherapy including vomiting. Currently we explored the emetic mechanisms of FPL64176, an L‐type Ca2+ channel (LTCC) agonist with maximal emetogenic effect at its 10mg/kg dose. FPL64176 evoked c‐Fos immunoreactivity in shrew brainstem sections containing the vomit‐associated nuclei, nucleus tractus solitarius (NTS) and dorsal motor nucleus of the vagus. FPL64176 also increased phosphorylation of proteins ERK1/2, PKC&agr;/&bgr;II and Akt in the brainstem. Moreover, their corresponding inhibitors (PD98059, GF 109203X and LY294002, respectively) reduced FPL64176‐evoked vomiting. A 30min subcutaneous (s.c.) pretreatment with the LTCC antagonist nifedipine (10mg/kg) abolished FPL64176‐elicited vomiting, c‐Fos expression, and emetic effector phosphorylation. Ryanodine receptors (RyRs) and inositol trisphosphate receptors (IP3Rs) mediate intracellular Ca2+ release from the sarcoplasmic/endoplasmic reticulum. The RyR antagonist dantrolene (i.p.), or a combination of low doses of nifedipine and dantrolene, but not the IP3R antagonist 2‐APB, significantly attenuated FPL64176‐induced vomiting. The serotonin type 3 receptor (5‐HT3R) antagonist palonosetron (s.c.), the neurokinin 1 receptor (NK1R) antagonist netupitant (i.p.) or a combination of non‐effective doses of netupitant and palonosetron showed antiemetic potential against FPL64176‐evoked vomiting. Serotonin (5‐HT) and substance P immunostaining revealed FPL64176‐induced emesis was accompanied by an increase in 5‐HT but not SP‐immunoreactivity in the dorsomedial subdivision of the NTS. These findings demonstrate that Ca2+ mobilization through LTCCs and RyRs, and subsequent emetic effector phosphorylation and 5‐HT release play important roles in FPL64176‐induced emesis which can be prevented by 5‐HT3R and NK1R antagonists.