Ca²⁺ signaling and emesis: Recent progress and new perspectives

Area of Science:

• Neuroscience
• Pharmacology
• Gastroenterology

Background:

• Chemotherapeutics like cisplatin induce vomiting through calcium (Ca2+)-dependent neurotransmitter release from gastrointestinal cells and the brainstem.
• Emetic receptors (NK1, 5-HT3, D2, M1, H1) activation triggers intracellular Ca2+ signaling, leading to emesis.
• Existing antiemetics like netupitant/palonosetron target specific receptors, but broad-spectrum control remains a challenge.

Purpose of the Study:

• To investigate the role of calcium signaling in the emetic process.
• To evaluate the antiemetic potential of L-type calcium channel blockers (LTCC blockers).
• To explore the synergistic effects of LTCC blockers with existing antiemetic drugs.

Main Methods:

• Utilized the least shrew as an animal model for emesis.
• Administered L-type Ca2+ channel agonists (FPL 64176) and intracellular Ca2+ mobilizers (thapsigargin) to induce vomiting.
• Tested the effects of LTCC antagonists (nifedipine, amlodipine) alone and in combination with palonosetron against various emetogens.

Main Results:

• LTCC agonists and intracellular Ca2+ mobilizers successfully induced vomiting in the least shrew.
• LTCC blockers demonstrated broad-spectrum antiemetic efficacy against receptor-specific emetic agents (5-HT3, NK1, D2, M1).
• LTCC blockers potentiated the antiemetic effect of palonosetron against cisplatin-induced emesis.

Conclusions:

• Intracellular calcium signaling is a critical pathway in mediating emesis.
• LTCC blockers represent a promising therapeutic strategy for broad-spectrum antiemesis.
• Combining LTCC blockers with existing antiemetics may enhance treatment efficacy for chemotherapy-induced nausea and vomiting (CINV).