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.
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Aapro M (2018) CINV: still troubling patients after all these years. Support Care Cancer 26(suppl 1):S5–S9. https://doi.org/10.1007/s00520-018-4131-3
Childs DS, Looker S, Le-Rademacher J et al (2019) What occurs in the other 20% of cancer patients with chemotherapy-induced nausea and vomiting (CINV)? A single-institution qualitative study. Support Care Cancer 27:249–255. https://doi.org/10.1007/s00520-018-4323-x
Singh P, Yoon SS, Kuo B (2016) Nausea: a review of pathophysiology and therapeutics. Ther Adv Gastroenterol 9:98–112. https://doi.org/10.1177/1756283X15618131
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
Ng TL, Hutton B, Clemons M (2015) Chemotherapy-induced nausea and vomiting: time for more emphasis on nausea? Oncologist 20:576–583. https://doi.org/10.1634/theoncologist.2014-0438
Harder SL, Groenvold M, Herrstedt J, Johnsen AT (2019) Nausea in advanced cancer: relationships between intensity, burden, and the need for help. Support Care Cancer 27:265–273. https://doi.org/10.1007/s00520-018-4326-7
Horn CC (2014) The medical implications of gastrointestinal vagal afferent pathways in nausea and vomiting. Curr Pharm Des 20:2703–2712. https://doi.org/10.2174/13816128113199990568
Torres CH, Mazzarello S, Ng T et al (2015) Defining optimal control of chemotherapy-induced nausea and vomiting—based on patients’ experience. Support Care Cancer 23:3341–3359. https://doi.org/10.1007/s00520-015-2801-y
Limebeer CL, Rock EM, Sharkey KA, Parker LA (2018) Nausea-induced 5-HT release in the interoceptive insular cortex and regulation by monoacylglycerol lipase (MAGL) inhibition and cannabidiol. eNeuro 5(4). https://doi.org/10.1523/ENEURO.0256-18.2018
Sanger GJ, Andrews PLR (2018) A history of drug discovery for treatment of nausea and vomiting and the implications for future research. Front Pharmacol 9:913. Published online Sept 4, 2018. https://doi.org/10.3389/fphar.2018.00913
Balaban CD, Yates BJ (2017) What is nausea? A historical analysis of changing views. Auton Neurosci 202:5–17. https://doi.org/10.1016/j.autneu.2016.07.003
Napadow V, Sheehan JD, Kim J, LaCount LT, Park K, Kaptchuk TJ, Rosen BR, Kuo B (2013) The brain circuitry underlying the temporal evolution of nausea in humans. Cereb Cortex 23:806–813. https://doi.org/10.1093/cercor/bhs073
Koch KL (2014) Gastric dysrhythmias: a potential objective measure of nausea. Exp Brain Res 232:2553–2561. https://doi.org/10.1007/s00221-014-4007-9
Müller TD, Nogueiras R, Andermann ML (2015) Ghrelin. Molecular Metabolism 4:437–460. https://doi.org/10.1016/j.molmet.2015.03.005
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
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
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
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
Rock EM, Sticht MA, Limebeer CL, Parker LA (2016) Cannabinoid regulation of acute and anticipatory nausea. Cannabis Cannabinoid Res 1:113–121. https://doi.org/10.1089/can.2016.0006
Weltens N, Iven J, Van Oudenhove L, Kano M (2018) The gut–brain axis in health neuroscience: implications for functional gastrointestinal disorders and appetite regulation. Ann N Y Acad Sci 1428:129–150. https://doi.org/10.1111/nyas.13969
Schemann M (2005) Control of gastrointestinal motility by the “gut brain” — the enteric nervous system. J Pediatr Gastroenterol Nutr 41:S4–S6
Critchley HD, Harrison NA (2013) Visceral influences on brain and behavior. Neuron 77:624–638. https://doi.org/10.1016/j.neuron.2013.02.008
Ahlman H, Nilsson O (2001) The gut as the largest endocrine organ in the body. Ann Oncol 12(Suppl 2):S63–S68
Nezami BG, Srinivasan S (2010) Enteric nervous system in the small intestine: pathophysiology and clinical implications. Curr Gastroenterol Rep 12:358–365. https://doi.org/10.1007/s11894-010-0129-9
Bellono NW, Bayrer JR, Leitch DB, Castro J, Zhang C, O’Donnell TA, Brierley SM, Ingraham HA, Julius D (2017) Enterochromaffin cells are gut chemosensors that couple to sensory neural pathways. Cell 170:185–198. https://doi.org/10.1016/j.cell.2017.05.034
Diwakarla S, Fothergill LJ, Fakhry J, Callaghan B, Furness JB (2017) Heterogeneity of enterochromaffin cells within the gastrointestinal tract. Neurogastroenterol Motil 29:e13101–ee1315. https://doi.org/10.1111/nmo.13101
Obara Y, Machida T, Takano Y, Shiga S, Suzuki A, Hamaue N, Iizuka K, Hirafuji M (2018) Cisplatin increases the number of enterochromaffin cells containing substance P in rat intestine. Naunyn Schmiedeberg's Arch Pharmacol 391:847–858. https://doi.org/10.1007/s00210-018-1493-5
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
Babic T, Browning KN (2014) The role of vagal neurocircuits in the regulation of nausea and vomiting. Eur J Pharmacol 722:38–47. https://doi.org/10.1016/j.ejphar.2013.08.047
Zhong W, Picca AJ, Lee AS, Darmani NA (2017) Ca2+ signaling and emesis: recent progress and new perspectives. Auton Neurosci 202:18–27. https://doi.org/10.1016/j.autneu.2016.07.006
Yamamoto K, Asano K, Tasaka A, Ogura Y, Kim S, Ito Y, Yamatodani A (2014) Involvement of substance P in the development of cisplatin-induced acute and delayed pica in rats. Brit J Pharmacol 171:2888–2899. https://doi.org/10.1111/bph.12629
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
Machida T, Takano Y, Iizuka K, Machida M, Hirafuji M (2017) Methotrexate causes acute hyperplasia of enterochromaffin cells containing substance P in the intestinal mucosa of rats. J Pharmacol Sci 133:190–193. https://doi.org/10.1016/j.jphs.2017.02.009
Travagli RA, Anselmi L (2016) Vagal neurocircuitry and its influence on gastric motility. Nat Rev Gastroenterol Hepatol 13:389–401. https://doi.org/10.1038/nrgastro.2016.76
Muth ER (2006) Motion and space sickness: intestinal and autonomic correlates. Auton Neurosci 129(1-2):58–66. https://doi.org/10.1016/j.autneu.2006.07.020
Lackner JR (2014) Motion sickness: more than nausea and vomiting. Exp Brain Res 232:2493–2510. https://doi.org/10.1007/s00221-014-4008-8
Toschi N, Kim J, Sclocco R, Duggento A, Barbieri R, Kuo B, Napadow V (2017) Motion sickness increases functional connectivity between visual motion and nausea-associated brain regions. Auton Neurosci 202:108–113. https://doi.org/10.1016/j.autneu.2016.10.003
Cutsforth-Gregory JK, Benarroch EE (2017) Nucleus of the solitary tract, medullary reflexes, and clinical implications. Neurology 88:1187–1196. https://doi.org/10.1212/WNL.0000000000003751
Kaur C, Ling E-A (2017) The circumventricular organs. Histol Histopathol 32:879–892. https://doi.org/10.14670/HH-11-881
Price CJ, Hoyda TD, Ferguson AV (2008) The area postrema: a brain monitor and integrator of systemic autonomic state. Neuroscientist 14:182–194. https://doi.org/10.1177/1073858407311100
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
Wang Q-P, Guan J-L, Pan W, Kastin AJ, Shioda S (2008) A diffusion barrier between the area postrema and nucleus tractus solitarius. Neurochem Res 33:2035–2043. https://doi.org/10.1007/s11064-008-9676-y
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
Craig AD (2015) How do you feel? (pp 130–181). Princeton University Press
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
Stich MA, Limebeer CL, Rafla BR et al (2016) Endocannabinoid regulation of nausea is mediated by 2-arachidonoylglycerol (2-AG) in the rat visceral insular cortex. Neuropharmacol 102:92–102. https://doi.org/10.1016/j.neuropharm.2015.10.039
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
Sclocco R, Kim J, Garcia RG, Sheehan JD, Beissner F, Bianchi AM, Cerutti S, Kuo B, Barbieri R, Napadow V (2016) Brain circuitry supporting multi-organ autonomic outflow in response to nausea. Cereb Cortex 26:485–497. https://doi.org/10.1093/cercor/bhu172
Uddin LQ, Nomi JS, Hebert-Seropian B et al (2017) Structure and function of the human insula. J Clin Neurophysiol 34:300–306. https://doi.org/10.1097/WNP.0000000000000377
Namkung H, Kim S-H, Sawa A (2017) The insula: an underestimated brain area in clinical neuroscience, psychiatry, and neurology. Trends Neurosci 40:200–207. https://doi.org/10.1016/j.tins.2017.02.002
Gogolla N (2017) The insular cortex. Curr Biol 27:R573–R591. https://doi.org/10.1016/j.cub.2017.05.010
Craig AD (2009) How do you feel — now? The anterior insula and human awareness. Nat Rev Neurosci 10:59–70. https://doi.org/10.1038/nrn2555
Janak PH, Tye KM (2015) From circuits to behaviour in the amygdala. Nature 517(7534):284–292. https://doi.org/10.1038/nature14188
Benarroch EE (2016) Parabrachial nuclear complex: multiple functions and potential clinical implications. Neurology 86:676–683. https://doi.org/10.1212/WNL.0000000000002393
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
Lu Y, Anderson HD (2017) Cannabinoid signaling in health and disease. Can J Physiol Pharmacol 95:311–327. https://doi.org/10.1139/cjpp-2016-0346
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
Sharkey KA, Darmani NA, Parker LA (2014) Regulation of nausea and vomiting by cannabinoids and the endocannabinoid system. Eur J Pharmacol 722:134–146. https://doi.org/10.1016/j.ejphar.2013.09.068
Zheng Y, Wang X-L, Moa F-F, Li M (2014) Dexamethasone alleviates motion sickness in rats in part by enhancing the endocannabinoid system. Eur J Pharmacol 727:99–105. https://doi.org/10.1016/j.ejphar.2014.01.047
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
Abrams DI (2018) The therapeutic effects of Cannabis and cannabinoids: an update from the National Academies of Sciences, Engineering and Medicine report. Eur J Intern Med 49:7–11. https://doi.org/10.1016/j.ejim.2018.01.003
Farrell C, Brearley SG, Pilling M, Molassiotis A (2013) The impact of chemotherapy-related nausea on patients’ nutritional status, psychological distress and quality of life. Support Care Cancer 21:59–66. https://doi.org/10.1007/s00520-012-1493-9
Andrews PLR, Sanger GJ (2014) Nausea and the quest for the perfect anti-emetic. Eur J Pharmacol 722:108–121. https://doi.org/10.1016/j.ejphar.2013.09.072
Malamood M, Roberts A, Kataria R, Parkman H, Schey R (2017) Mirtazapine for symptom control in refractory gastroparesis. Drug Des Devel Ther 11:1035–1041. https://doi.org/10.2147/DDDT.S125743
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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.
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Wickham, R.J. Revisiting the physiology of nausea and vomiting—challenging the paradigm. Support Care Cancer 28, 13–21 (2020). https://doi.org/10.1007/s00520-019-05012-8
- Gut-brain axis
- Insular cortex