Pathways by which chemotherapeutic agents may produce an emetic response

Chemotherapy-induced emesis results from stimulation of a multistep reflex pathway that is controlled by the brain and triggered by afferent impulses to the CPG (previously called the "vomiting center") from the AP and NTS (previously referred to as the "chemoreceptor trigger zone")), gastrointestinal tract (by way of vagal afferent fibers), and possibly, the cerebral cortex. The mechanism that is best supported by research involves an effect of chemotherapy on the upper small intestine. Local generation of free radicals leads to localized exocytotic release of serotonin (5-hydroxytryptamine [5-HT]) from the enterochromaffin cells; 5-HT then interacts with 5-HT3 receptors on vagal afferent terminals in the wall of the bowel. This stimulates vagal afferent fibers, which project to the NTS and AP in the dorsal brain stem. This peripheral mechanism of emesis is believed to be 5-HT3 receptor dominant and plays a key role in acute emesis. Afferent stimulation from the vagus also results in the release of Substance P in the NTS and AP. This central mechanism of emesis is believed to be NK1 receptor dominant and plays an important role in delayed emesis.

Neural fibers project from the NTS and AP to the final effector of the emetic reflex, the CPG, which is an anatomically indistinct area occupying a more ventral location in the medulla. Antineoplastic agents may also induce emesis through a direct interaction with the AP. Other potential sources of afferent input to the CPG that result in emesis after chemotherapy include a number of structures in the temporal lobe, such as the amygdala. Evidence for this pathway is less well established than for other proposed sites of chemotherapeutic action.