Revisiting the physiology of nausea and vomiting—challenging the paradigm

Mechanisms of Nausea and Vomiting: Current Knowledge and Recent Advances in Intracellular Emetic Signaling Systems

“…Nausea and vomiting can be generated by diverse stimuli and are mediated by the bidirectional interaction between brain and gut. In brief: (1) The brainstem area postrema in the floor of the fourth ventricle lacks blood brain barrier and thus serves as direct central receptor sites for circulating and systemic emetic stimuli in the cerebrospinal fluid and the blood [11]. (2) Systemically administered drugs can activate corresponding receptors present on vagal afferents, which project sensory signals to the nucleus of the solitary tract [11,12].…”

“…In brief: (1) The brainstem area postrema in the floor of the fourth ventricle lacks blood brain barrier and thus serves as direct central receptor sites for circulating and systemic emetic stimuli in the cerebrospinal fluid and the blood [11]. (2) Systemically administered drugs can activate corresponding receptors present on vagal afferents, which project sensory signals to the nucleus of the solitary tract [11,12]. (3) Peripheral stimuli such as toxic drugs and microbials (e.g., bacteria, viruses, fungi) that enter the lumen of the gastrointestinal tract (GIT) and pathologies in the GIT cause release of local emetic neurotransmitters/modulators, which subsequently act on the corresponding receptors present on vagal afferents and/or stimulate the brainstem area postrema via circulating blood [9,10].…”

Nausea and Vomiting Not Related to Cancer Therapy: Intractable Problem or Clinical Challenge?

“…Nausea and vomiting can have one or more causes involving neurotransmitters and receptors in afferent peripheral and central nervous system (CNS) pathways. The gastrointestinal (GI) system and the vagus nerve are the major components of a bidirectional peripheral pathway: the gut-brain axis ( Wickham, 2020 ). Central nervous system pathways include the brainstem area postrema (chemoreceptor trigger zone [CTZ]) and nucleus tractus solitarius (NTS) in the medulla, and the cortex and other higher regions.…”

“…The endocannabinoid system (ECS) includes endogenous cannabinoids (endocannabinoids) synthesized on demand to bind at ECS receptors (CB 1 or CB 2 ) and act largely as neuromodulators, and are then rapidly metabolized to constituent molecules ( Lu & Anderson, 2017 ; Sharkey, Darmani, & Parker, 2014 ). The ECS has essential roles in virtually every homeostatic physiologic process in all organ systems ( Hendren et al, 2015 ; Wickham, 2020 ). In the 1970s, a few small studies found delta-9-tetrahydrocannabinol (THC) synthesized in dronabinol or nabilone was as or more effective for CINV than chlorpromazine, metoclopramide, and other antiemetics ( Cangemi & Kuo, 2019 ).…”

Metoclopramide, Dexamethasone, or Palonosetron for Prevention of Delayed Chemotherapy-Induced Nausea and Vomiting After Moderately Emetogenic Chemotherapy (MEDEA): A Randomized, Phase III, Noninferiority Trial

“…Another DEX-sparing option to improve CINV outcomes in MEC-treated patients is the addition of a third prophylactic drug to the antiemetic backbone containing a 5-HT 3 RA plus single-dose DEX. Receptors other than serotonergic, such as dopaminergic, histaminic, and muscarinic, may be the dominant receptors in the control of nausea [21][22][23]. Therefore, dopamine 2 (D 2 )-receptor antagonists with prokinetic effects like metoclopramide, currently recommended only for the treatment of breakthrough emesis, could be useful in improving delayed nausea control.…”