A re-consideration of neural/receptor mechanisms in chemotherapy-induced nausea and vomiting: current scenario and future perspective

Abstract

The neural mechanisms and the receptors behind the course of chemotherapy-induced nausea and vomiting (CINV) are well described and considered mechanistically multifactorial, whereas the neurobiology of nausea is not completely understood yet. Some of the anti-neoplastic medications like cisplatin result in biphasic vomiting response. The acute phase of vomiting is triggered mainly via the release of serotonin from the enterochromaffin (EC) cells in the gastrointestinal tract (GIT) and results in stimulation of dorsal vagal complex (DVC) of the vomiting center and the vomiting is initiated by downward communication to the gut via vagal efferents. Agonism of 5HT₃ receptors is majorly involved in the mediation of the acute phase. Therefore, antagonists at 5HT₃ receptors are effective in the management of acute-phase vomiting episodes. Likewise, Dopamine type 2 (D₂) receptors, dopamine neurotransmitter, Muscarinic receptors (M₃), GLP₁ receptors, and histaminergic receptors (H₁) are also implicated in the vomiting act as well. In continuation, Cannabinoid type 1 (CB₁) receptors are also recommended and included in the guidelines as agonism of presynaptically located CB₁ receptors inhibits the release of excitatory neurotransmitters responsible for vomiting initiation. The delayed phase involves the release of "Substance P" in the gut and results in the stimulation of neurokinin-1 (NK₁) receptors centrally in the area postrema (AP) and nucleus tractus solitarius (NTS), subsequently the vomiting response. The current understanding is the existence of overlapping mechanisms of neurotransmitters, serotonin, dopamine, and substance P throughout the time course of CINV. Furthermore, the emetic neurotransmitters are released via calcium ion (Ca⁺⁺)-dependent mechanisms, implicating the molecular targets of intracellular Ca⁺⁺ signaling in emetic circuitry. The current review entails the neurobiology of nausea and vomiting induced by cancer chemotherapeutic agents and the recent approaches in the management.

Keywords: Chemotherapy; Emetic circuits; Nausea and vomiting; Neurotransmitters; Receptors.