Revisiting the physiology of nausea and vomiting—challenging the paradigm
- 283 Downloads
The predominant neurotransmitters and receptors for acute and delayed chemotherapy-induced nausea and vomiting (CINV) are represented in the current paradigm, which reflects successful control of emesis. However, control of nausea (N) lags behind management of vomiting (V). This review aims to re-examine and incorporate new information about the mechanisms of V and N.
The initial literature search focused on CINV. Keywords in articles led to subsequent discovery of publications focused on N&V in other medical and scientific fields (e.g., gastroenterology, neurology, cannabinoid science, neuropharmacology, and motion sickness). Using keywords to identify other sources continued until no further recent, meaningful publications were found.
More than 86% of references were from recent non-oncology journals and books, suggesting there are many areas for cross-fertilization research into mechanisms and management of N&V—particularly of N, which involves overlapping and dissimilar CNS areas from V. Information from cited articles was incorporated into visual representation of N&V, which is certainly not exhaustive but supports highly complex processes in the stomach and gut, the vagus nerve and spinal cord neurons, the nucleus tractus solitarii, and the anterior insular cortex and anterior cingulate cortex with input from the amygdala.
These data support the idea that mechanisms for N, whatever the cause, must be highly similar. Continued research into nausea, including patient-reported evaluation and outcomes, is important; interventions for nausea could be considered adjuvants to current standard of care antiemetics and be individualized, depending on patient-reported efficacy and adverse effects and preferences.
KeywordsNausea Vomiting Gut-brain axis Insular cortex Interoception
Compliance with ethical standards
Conflict of interest
Rita J. Wickham has received speaker’s honoraria from Insys Therapeutics and advisory board compensation from Helsinn Healthcare SA. There is no primary data associated with this manuscript.
- 4.Donovan HS, Hagan TL, Campbell GB, Boisen MM, Rosenblum LM, Edwards RP, Bovbjerg DH, Horn CC (2016) Nausea as a sentinel symptom for cytotoxic chemotherapy effects on the gut-brain axis among women receiving treatment for recurrent ovarian cancer: an exploratory analysis. Support Care Cancer 24:2635–2642. https://doi.org/10.1007/s00520-015-3071-4 CrossRefPubMedPubMedCentralGoogle Scholar
- 15.Hiura Y, Takiguchi S, Yamamoto K, Kurokawa Y, Yamasaki M, Nakajima K, Miyata H, Fujiwara Y, Mori M, Doki Y (2012) Fall in plasma ghrelin concentrations after cisplatin-based chemotherapy in esophageal cancer patients. Int J Clin Oncol 17:316–323. https://doi.org/10.1007/s10147-011-0289-0 CrossRefPubMedGoogle Scholar
- 16.Wo JM, Ejskjaer N, Hellstrom PM et al (2011) Randomised clinical trial: ghrelin agonist TZP-101 relieves gastroparesis associated with severe nausea and vomiting – randomised clinical study subset data. Aliment Pharmacol Ther 33:679–688. https://doi.org/10.1111/j.1365-2036.2010.04567.x CrossRefPubMedGoogle Scholar
- 17.Rudd JA, Chan SW, Ngan MP, Tu L, Lu Z, Giuliano C, Lovati E, Pietra C (2018) Anti-emetic action of the brain-penetrating new ghrelin agonist, HM01, alone and in combination with the 5-HT3 antagonist, palonosetron and with the NK1 antagonist, netupitant, against cisplatin- and motion-induced emesis in Suncus murinus (house musk shrew). Front Pharmacol 9:869. https://doi.org/10.3389/fphar.2018.00869 CrossRefPubMedPubMedCentralGoogle Scholar
- 18.Cabezos PA, Vera G, Martin-Fontelles MI et al (2010) Cisplatin-induced gastrointestinal dysmotility is aggravated after chronic administration in the rat. Comparison with pica. Neurogastroenterol Motil 22:797–805, 797-e225. https://doi.org/10.1111/j.1365-2982.2010.01483.x CrossRefPubMedGoogle Scholar
- 28.Alcaino C, Knutson KR, Treichel AJ, Yildiz G, Strege PR, Linden DR, Li JH, Leiter AB, Szurszewski JH, Farrugia G, Beyder A (2018) A population of gut epithelial enterochromaffin cells is mechanosensitive and requires Piezo2 to convert force into serotonin release. Proc Natl Acad Sci U S A 115(32):E7632–E7641. https://doi.org/10.1073/pnas.1804938115 CrossRefPubMedPubMedCentralGoogle Scholar
- 32.Ju C, Hamaue N, Machida T, Liu Y, Iizuka K, Wang Y, Minami M, Hirafuji M (2008) Anti-inflammatory drugs ameliorate opposite enzymatic changes in ileal 5-hydroxytryptamine metabolism in the delayed phase after cisplatin administration to rats. Eur J Pharmacol 589:281–287. https://doi.org/10.1016/j.ejphar.2008.04.050 CrossRefPubMedGoogle Scholar
- 41.Miyata S (2015) New aspects in fenestrated capillary and tissue dynamics in the sensory circumventricular organs of adult brains. Front Neurosci 9:–390. https://doi.org/10.3389/fnins.2015.00390
- 43.Chin C-L, Fox GB, Hradil VP et al (2006) Pharmacological MRI in awake rats reveals neural activity in area postrema and nucleus tractus solitarius: relevance as a potential biomarker for detecting drug-induced emesis. NeuroImage 33:1152–1160. https://doi.org/10.1124/jpet.111.188797 CrossRefPubMedGoogle Scholar
- 44.Craig AD (2015) How do you feel? (pp 130–181). Princeton University PressGoogle Scholar
- 45.Sun X, Xu L, Guo F, Luo W, Gao S, Luan X (2017) Neurokinin-1 receptor blocker CP-99 94 improved emesis induced by cisplatin via regulating the activity of gastric distention responsive neurons in the dorsal motor nucleus of vagus and enhancing gastric motility in rats. Neurogastroenterol Motil 29(10):1–11. https://doi.org/10.1111/nmo.13096 CrossRefPubMedGoogle Scholar
- 47.Farmer AD, Ban VF, Coen SJ, Sanger GJ, Barker GJ, Gresty MA, Giampietro VP, Williams SC, Webb DL, Hellström PM, Andrews PLR, Aziz Q (2015) Visually induced nausea causes characteristic changes in cerebral, autonomic and endocrine function in humans. J Physiol 593(5):1183–1196. https://doi.org/10.1113/jphysiol.2014.284240 CrossRefPubMedPubMedCentralGoogle Scholar
- 55.Pirri C, Bayliss E, Trotter J, Olver IN, Katris P, Drummond P, Bennett R (2013) Nausea still the poor relation in antiemetic therapy? The impact on cancer patients’ quality of life and psychological adjustment of nausea, vomiting and appetite loss, individually and concurrently as part of a symptom cluster. Support Care Cancer 21:735–748. https://doi.org/10.1007/s00520-012-1574-9 CrossRefPubMedGoogle Scholar
- 57.Mechoulam R, Parker LA (2013) The endocannabinoid system and the brain. Annu Rev Psychol 64:21–47. https://doi.org/10.1146/annurev-psych-113011-143739 CrossRefPubMedGoogle Scholar
- 60.Smith LA, Azariah F, Lavender VTC, et al (2015). Cannabinoids for nausea and vomiting in adults with cancer receiving chemotherapy. Cochrane Database of Systematic Reviews Issue 11. Art. No.: CD009464. https://doi.org/10.1002/14651858.CD009464.pub2