Pathophysiology of nausea and vomiting. Vomiting is caused by noxious stimulation of the vomiting center directly or indirectly via 1 or more of 4 additional sites: the gastrointestinal (GI) tract, the vestibular system, the chemoreceptor trigger zone, and higher centers in the cortex and thalamus. Once receptors are activated, neural pathways lead to the vomiting center, where emesis is initiated. Neural traffic originating in the GI tract travels along afferent fibers of cranial nerves IX (glossopharyngeal) and X (vagal). Antiemetic targets for drug interventions are predicated on their ability to block the illustrated receptor sites. Receptors illustrated along with their conventional ligands are as follows: H₁ histamine, M₁ acetylcholine, 5-HT₃ serotonin, DA₂ dopamine, NK₁ (neurokinin) substance P, and mu/kappa opioids. Transmitter mediators in the cerebral cortex and thalamus are poorly understood, although cortical cannabinoid (CB₁) pathways have been characterized.