The Physiology and Pharmacology of Nausea and Vomiting Induced by Anticancer Chemotherapy in Humans

  • Paul L. R. AndrewsEmail author
  • John A. Rudd


The basic pathways inducing vomiting, the brainstem sites of integration and the main motor components had all been described by the early 1950s but relatively little was known about how cancer chemotherapeutic agents induced emesis until research was prompted by the clinical use of cisplatin thirty years later. The acute phase of cisplatin-induced emesis is predominantly driven by 5-hydroxytryptamine released from enterochromaffin cells in the small intestine activating 5-HT3 receptors located on vagal afferent terminals. Other substances such as prostanoids and substance P also interact with receptors on the afferents and are proposed to be involved in local inflammatory responses. Although for the delayed phase of cisplatin-induced emesis a contribution of the vagal afferents driven by an inflammatory response in the gut cannot be excluded, the evidence supports release of an endocrine mediator (unidentified) from the gut but acting on the area postrema to activate central pathways. The potential mechanisms by which cisplatin and other chemotherapeutic agents act on the gut epithelium and enteric neurones are reviewed. The sites and mechanisms of action of 5-HT3 and NK1 receptor antagonists are discussed in relation to the emetic pathways. The biologically significant, aversive, unpleasant sensation of nausea is a focus of the chapter because it impacts on the patient’s quality of life. The potential roles of vasopressin secretion, disturbance of gastric myoelectric activity and central pathways implicated in the genesis of the sensation are discussed in the wider context of the relative efficacy of anti-emetic drugs against nausea as compared to retching and vomiting.


Motion Sickness Nucleus Tractus Solitarius Area Postrema Enteroendocrine Cell Vagal Afferents 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Alfieri AB, Cubeddu LX (1995) Treatment with para-chlorophenylalanine antagonises the emetic response and the serotonin-releasing actions of cisplatin in cancer patients. Br J Cancer 71(3):629–632PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Allen ME, McKay C, Eaves DM, Hamilton D (1986) Naloxone enhances motion sickness: endorphins implicated. Aviat Space Environ Med 57(7):647–653PubMedGoogle Scholar
  3. 3.
    Andersen R, Krohg K (1976) Pain as a major cause of postoperative nausea. Can Anaesth Soc J 23(4):366–369PubMedCrossRefGoogle Scholar
  4. 4.
    Andrews PLR, Davis CJ, Bingham S, Davidson HI, Hawthorn J, Maskell L (1990) The abdominal visceral innervation and the emetic reflex: pathways, pharmacology, and plasticity. Can J Physiol Pharmacol 68(2):325–345PubMedCrossRefGoogle Scholar
  5. 5.
    Andrews PLR, Sanger GJ (2014) Nausea and the quest for the perfect anti-emetic. Eur J Pharmacol 722:108–121. doi: 10.1016/j.ejphar.2013.09.072 PubMedCrossRefGoogle Scholar
  6. 6.
    Andrews PLR (1994) 5-HT3 receptors and anti-emesis. In: King FD, Jones BJ, Sanger GJ (eds) 5-hydroxytryptamine-3 receptor antagonists. CRC Press, Boca Raton, pp 255–317Google Scholar
  7. 7.
    Andrews PLR, Davis CJ (1993) The mechanisms of emesis induced by anti-cancer therapies. In: Andres PLR, Sanger GJ (eds) Emesis and anti-cancer therapy. Chapman and Hall Medical, London, p 256Google Scholar
  8. 8.
    Andrews PLR, Rudd JA (2004) The role of tachykinins and the tachykinin receptor in nausea and emesis. In: Holzer P (ed) Handbook of experimental pharmacology, vol 164. Springer, Berlin, pp 359–440Google Scholar
  9. 9.
    Babaoglu MO, Bayar B, Aynacioglu AS, Kerb R, Abali H, Celik I, Bozkurt A (2005) Association of the ABCB1 3435C>T polymorphism with antiemetic efficacy of 5-hydroxytryptamine type 3 antagonists. Clin Pharmacol Ther 78(6):619–626. doi: 10.1016/j.clpt.2005.08.015 PubMedCrossRefGoogle Scholar
  10. 10.
    Barcroft H, Swan HJC (1953) Sympathetic control of human blood vessels. Edward Arnold & Co., LondonGoogle Scholar
  11. 11.
    Barnes JM, Barnes NM, Costall B, Naylor RJ, Tattersall FD (1988) Reserpine, para-chlorophenylalanine and fenfluramine antagonise cisplatin-induced emesis in the ferret. Neuropharmacology 27(8):783–790PubMedCrossRefGoogle Scholar
  12. 12.
    Barnes NM, Ge J, Jones WG, Naylor RJ, Rudd JA (1990) Cisplatin induced emesis: preliminary results indicative of changes in plasma levels of 5-hydroxytryptamine. Br J Cancer 62(5):862–864PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Barreca T, Corsini G, Cataldi A, Garibaldi A, Cianciosi P, Rolandi E, Franceschini R (1996) Effect of the 5-HT3 receptor antagonist ondansetron on plasma AVP secretion: a study in cancer patients. Biomed Pharmacother 50(10):512–514PubMedCrossRefGoogle Scholar
  14. 14.
    Bearcroft CP, Andre EA, Farthing MJ (1997) In vivo effects of the 5-HT3 antagonist alosetron on basal and cholera toxin-induced secretion in the human jejunum: a segmental perfusion study. Aliment Pharmacol Ther 11(6):1109–1114PubMedCrossRefGoogle Scholar
  15. 15.
    Bermudez J, Boyle EA, Miner WD, Sanger GJ (1988) The anti-emetic potential of the 5-hydroxytryptamine3 receptor antagonist BRL 43694. Br J Cancer 58(5):644–650PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Bertrand PP, Bertrand RL (2010) Serotonin release and uptake in the gastrointestinal tract. Auton Neurosci 153(1–2):47–57. doi: 10.1016/j.autneu.2009.08.002 PubMedCrossRefGoogle Scholar
  17. 17.
    Beswick FW (1983) Chemical agents used in riot control and warfare. Hum Toxicol 2(2):247–256PubMedCrossRefGoogle Scholar
  18. 18.
    Bhandari P, Gupta YK, Seth SD (1988) Effect of diethyldithiocarbamate on cisplatin induced emesis in dogs. Asia Pac J Pharmacol 3:247–250Google Scholar
  19. 19.
    Borison HL (1989) Area postrema: chemoreceptor circumventricular organ of the medulla oblongata. Prog Neurobiol 32(5):351–390PubMedCrossRefGoogle Scholar
  20. 20.
    Borst P, Schinkel AH (2013) P-glycoprotein ABCB1: a major player in drug handling by mammals. J Clin Invest 123(10):4131–4133. doi: 10.1172/JCI70430 PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Bouganim N, Dranitsaris G, Hopkins S, Vandermeer L, Godbout L, Dent S, Wheatley-Price P, Milano C, Clemons M (2012) Prospective validation of risk prediction indexes for acute and delayed chemotherapy-induced nausea and vomiting. Curr Oncol 19(6):e414–e421. doi: 10.3747/co.19.1074 PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Brookes SJ, Spencer NJ, Costa M, Zagorodnyuk VP (2013) Extrinsic primary afferent signalling in the gut. Nat Rev Gastroenterol Hepatol 10(5):286–296. doi: 10.1038/nrgastro.2013.29 PubMedCrossRefGoogle Scholar
  23. 23.
    Cannon DS, Best MR, Batson JD, Feldman M (1983) Taste familiarity and apomorphine-induced taste aversions in humans. Behav Res Ther 21(6):669–673PubMedCrossRefGoogle Scholar
  24. 24.
    Caras SD, Soykan I, Beverly V, Lin Z, McCallum RW (1997) The effect of intravenous vasopressin on gastric myoelectrical activity in human subjects. Neurogastroenterol Motil 9(3):151–156PubMedCrossRefGoogle Scholar
  25. 25.
    Castejon AM, Paez X, Hernandez L, Cubeddu LX (1999) Use of intravenous microdialysis to monitor changes in serotonin release and metabolism induced by cisplatin in cancer patients: comparative effects of granisetron and ondansetron. J Pharmacol Exp Ther 291(3):960–966PubMedGoogle Scholar
  26. 26.
    Christie DA, Tansey EM (2007) The discovery, use and impact of platinum salts as chemotherapy agents for cancer. Welcome Witn Twentieth Century Med 30:117Google Scholar
  27. 27.
    Ciarimboli G (2012) Membrane transporters as mediators of Cisplatin effects and side effects. Scientifica 2012:473829. doi: 10.6064/2012/473829 PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Cubeddu LX (1992) Mechanisms by which cancer chemotherapeutic drugs induce emesis. Semin Oncol 19(6 Suppl 15):2–13PubMedGoogle Scholar
  29. 29.
    Cubeddu LX, Hoffmann IS (1993) Participation of serotonin on early and delayed emesis induced by initial and subsequent cycles of cisplatinum-based chemotherapy: effects of antiemetics. J Clin Pharmacol 33(8):691–697PubMedCrossRefGoogle Scholar
  30. 30.
    Cubeddu LX, O’Connor DT, Hoffmann I, Parmer RJ (1995) Plasma chromogranin A marks emesis and serotonin release associated with dacarbazine and nitrogen mustard but not with cyclophosphamide-based chemotherapies. Br J Cancer 72(4):1033–1038PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Cubeddu LX, O’Connor DT, Parmer RJ (1995) Plasma chromogranin A: a marker of serotonin release and of emesis associated with cisplatin chemotherapy. J Clin Oncol 13(3):681–687PubMedGoogle Scholar
  32. 32.
    Darmani NA, Crim JL, Janoyan JJ, Abad J, Ramirez J (2009) A re-evaluation of the neurotransmitter basis of chemotherapy-induced immediate and delayed vomiting: evidence from the least shrew. Brain Res 1248:40–58. doi: 10.1016/j.brainres.2008.10.063 PubMedCrossRefGoogle Scholar
  33. 33.
    Darmani NA, McClanahan BA, Trinh C, Petrosino S, Valenti M, Di Marzo V (2005) Cisplatin increases brain 2-arachidonoylglycerol (2-AG) and concomitantly reduces intestinal 2-AG and anandamide levels in the least shrew. Neuropharmacology 49(4):502–513PubMedCrossRefGoogle Scholar
  34. 34.
    Darmani NA, Ray AP (2009) Evidence for a re-evaluation of the neurochemical and anatomical bases of chemotherapy-induced vomiting. Chem Rev 109(7):3158–3199. doi: 10.1021/cr900117p PubMedCrossRefGoogle Scholar
  35. 35.
    Davis CJ, Harding RK, Leslie RA, Andrews PLR (1986) The organisation of vomiting as a protective reflex: a commentary on the first day’s discussions. In: Davis CJ, Lake-Bakarr GV, Grahame-Smith DG (eds) Nausea and vomiting: mechanisms and treatment. Springer, Berlin, pp 65–75CrossRefGoogle Scholar
  36. 36.
    De Jonghe BC, Horn CC (2008) Chemotherapy-induced pica and anorexia are reduced by common hepatic branch vagotomy in the rat. Am J Physiol Regul Integr Comp Physiol 294(3):R756–R765PubMedCrossRefGoogle Scholar
  37. 37.
    De Jonghe BC, Horn CC (2009) Chemotherapy agent cisplatin induces 48-h Fos expression in the brain of a vomiting species, the house musk shrew (Suncus murinus). Am J Physiol Regul Integr Comp Physiol 296(4):R902–R911. doi: 10.1152/ajpregu.90952.2008, 90952.2008 [pii]
  38. 38.
    Devinsky O, Frasca J, Pacia SV, Luciano DJ, Paraiso J, Doyle W (1995) Ictus emeticus: further evidence of nondominant temporal involvement. Neurology 45(6):1158–1160PubMedCrossRefGoogle Scholar
  39. 39.
    Dey D, Abad J, Ray AP, Darmani NA (2010) Differential temporal changes in brain and gut substance P mRNA expression throughout the time-course of cisplatin-induced vomiting in the least shrew (Cryptotis parva). Brain Res 1310:103–112. doi: 10.1016/j.brainres.2009.11.005
  40. 40.
    Di Maio M, Gallo C, Leighl NB, Piccirillo MC, Daniele G, Nuzzo F, Gridelli C, Gebbia V, Ciardiello F, De Placido S, Ceribelli A, Favaretto AG, de Matteis A, Feld R, Butts C, Bryce J, Signoriello S, Morabito A, Rocco G, Perrone F (2015) Symptomatic toxicities experienced during anticancer treatment: agreement between patient and physician reporting in three randomized trials. J Clin Oncol 33(8):910–915. doi: 10.1200/JCO.2014.57.9334 PubMedCrossRefGoogle Scholar
  41. 41.
    du Bois A, Vach W, Wechsel U, Holy R, Schaefer W (1996) 5-Hydroxyindoleacetic acid (5-HIAA) and cortisol excretion as predictors of chemotherapy-induced emesis. Br J Cancer 74(7):1137–1140PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Edwards CM, Carmichael J, Baylis PH, Harris AL (1989) Arginine vasopressin – a mediator of chemotherapy induced emesis? Br J Cancer 59(3):467–470PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Eiseman JL, Beumer JH, Rigatti LH, Strychor S, Meyers K, Dienel S, Horn CC (2015) Plasma pharmacokinetics and tissue and brain distribution of cisplatin in musk shrews. Cancer Chemother Pharmacol 75(1):143–152. doi: 10.1007/s00280-014-2623-5 PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Endo T, Sugawara J, Nemoto M, Minami M, Blower PR (1998) Effects of granisetron, a selective 5-HT3 receptor antagonist, on ouabain-induced emesis in ferrets. Res Commun Mol Pathol Pharmacol 102(3):227–239PubMedGoogle Scholar
  45. 45.
    Erwald R, Wiechel KL, Strandell T (1976) Effect of vasopressin on regional splanchnic blood flows in conscious man. Acta Chir Scand 142(1):36–42PubMedGoogle Scholar
  46. 46.
    Eversmann T, Gottsmann M, Uhlich E, Ulbrecht G, von Werder K, Scriba PC (1978) Increased secretion of growth hormone, prolactin, antidiuretic hormone, and cortisol induced by the stress of motion sickness. Aviat Space Environ Med 49(1 Pt 1):53–57PubMedGoogle Scholar
  47. 47.
    Faas H, Feinle C, Enck P, Grundy D, Boesiger P (2001) Modulation of gastric motor activity by a centrally acting stimulus, circular vection, in humans. Am J Physiol Gastrointest Liver Physiol 280(5):G850–G857PubMedGoogle Scholar
  48. 48.
    Farmer AD, Al Omran Y, Aziz Q, Andrews PLR (2014) The role of the parasympathetic nervous system in visually induced motion sickness: systematic review and meta-analysis. Exp Brain Res 232(8):2665–2673. doi: 10.1007/s00221-014-3964-3 PubMedCrossRefGoogle Scholar
  49. 49.
    Farmer AD, Ban VF, Coen SJ, Sanger GJ, Barker GJ, Gresty MA, Giampietro VP, Williams SC, Webb DL, Hellstrom 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. doi: 10.1113/jphysiol.2014.284240 PubMedCrossRefGoogle Scholar
  50. 50.
    Feldman M, Samson WK, O’Dorisio TM (1988) Apomorphine-induced nausea in humans: release of vasopressin and pancreatic polypeptide. Gastroenterology 95(3):721–726PubMedGoogle Scholar
  51. 51.
    Fetting JH, Wilcox PM, Sheidler VR, Enterline JP, Donehower RC, Grochow LB (1985) Tastes associated with parenteral chemotherapy for breast cancer. Cancer Treat Rep 69(11):1249–1251PubMedGoogle Scholar
  52. 52.
    Finger TE, Kinnamon SC (2011) Taste isn’t just for taste buds anymore. F1000 Biol Rep 3:20. doi: 10.3410/B3-20 PubMedCentralPubMedCrossRefGoogle Scholar
  53. 53.
    Fisher RD, Rentschler RE, Nelson JC, Godfrey TE, Wilbur DW (1982) Elevation of plasma antidiuretic hormones (ADH) associated with chemotherapy-induced emesis in man. Cancer Treat Rep 66(1):25–29PubMedGoogle Scholar
  54. 54.
    Forster ER, Palmer JL (1994) Comment: Ondansetron for treating nausea and vomiting in the poisoned patient. Ann Pharmacother 28(10):1203–1204PubMedGoogle Scholar
  55. 55.
    Foss JF, Yuan CS, Roizen MF, Goldberg LI (1998) Prevention of apomorphine- or cisplatin-induced emesis in the dog by a combination of methylnaltrexone and morphine. Cancer Chemother Pharmacol 42(4):287–291PubMedCrossRefGoogle Scholar
  56. 56.
    Fredrikson M, Hursti T, Wik G (1995) Neural networks in chemotherapy-induced delayed nausea – a pilot-study using positron emission tomography. Oncol Rep 2(6):1001–1003PubMedGoogle Scholar
  57. 57.
    Fredrikson M, Hursti TJ, Steineck G, Furst CJ, Borjesson S, Peterson C (1994) Delayed chemotherapy-induced nausea is augmented by high levels of endogenous noradrenaline. Br J Cancer 70(4):642–645PubMedCentralPubMedCrossRefGoogle Scholar
  58. 58.
    Fukuda H, Koga T, Furukawa N, Nakamura E, Hatano M, Yanagihara M (2003) The site of the antiemetic action of NK1 receptor antagonists. In: Donnerer J (ed) Antiemetic therapy. Karger, Basel, pp 33–77CrossRefGoogle Scholar
  59. 59.
    Fukui H, Yamamoto M, Ando T, Sasaki S, Sato S (1993) Increase in serotonin levels in the dog ileum and blood by cisplatin as measured by microdialysis. Neuropharmacology 32(10):959–968PubMedCrossRefGoogle Scholar
  60. 60.
    Fukui H, Yamamoto M, Sasaki S, Sato S (1993) Involvement of 5-HT3 receptors and vagal afferents in copper sulfate- and cisplatin-induced emesis in monkeys. Eur J Pharmacol 249(1):13–18PubMedCrossRefGoogle Scholar
  61. 61.
    Fukui H, Yamamoto M, Sato S (1992) Vagal afferent fibers and peripheral 5-HT3 receptors mediate cisplatin-induced emesis in dogs. Jpn J Pharmacol 59(2):221–226PubMedCrossRefGoogle Scholar
  62. 62.
    Furness JB (2012) The enteric nervous system and neurogastroenterology. Nat Rev Gastroenterol Hepatol 9(5):286–294. doi: 10.1038/nrgastro.2012.32 PubMedCrossRefGoogle Scholar
  63. 63.
    Gal R (1975) Assessment of seasickness and its consequences by a method of peer evaluation. Aviat Space Environ Med 46(6):836–839PubMedGoogle Scholar
  64. 64.
    Gale DA, Blakemore SJ, Cook S, Kidwai S, Moore I, Moore GBT, Moore SE, Sanger GJ, Holbrook JD, Lui Y-L, Mailik N, Andrews PLR (2005) Modulation of gene expression in the glandular and non-glandular regions of the rat stomach after treatment with the anti-cancer drug cisplatin. Gastroenterology 128:A-545, Abstr T1762Google Scholar
  65. 65.
    Gilman A (1946) Therapeutic applications of chemical warfare agents. Fed Proc 5:285–292PubMedGoogle Scholar
  66. 66.
    Golding JF (2006) Motion sickness susceptibility. Auton Neurosci 129(1–2):67–76. doi: 10.1016/j.autneu.2006.07.019 PubMedCrossRefGoogle Scholar
  67. 67.
    Gupta YK, Sharma SS (1996) Antiemetic activity of antioxidants against cisplatin-induced emesis in dogs. Environ Toxicol Pharmacol 1(3):179–184PubMedCrossRefGoogle Scholar
  68. 68.
    Hagbom M, Istrate C, Engblom D, Karlsson T, Rodriguez-Diaz J, Buesa J, Taylor JA, Loitto VM, Magnusson KE, Ahlman H, Lundgren O, Svensson L (2011) Rotavirus stimulates release of serotonin (5-HT) from human enterochromaffin cells and activates brain structures involved in nausea and vomiting. PLoS Pathog 7(7), e1002115. doi: 10.1371/journal.ppat.1002115 PubMedCentralPubMedCrossRefGoogle Scholar
  69. 69.
    Harris AL (1982) Cytotoxic-therapy-induced vomiting is mediated via enkephalin pathways. Lancet 1(8274):714–716PubMedCrossRefGoogle Scholar
  70. 70.
    Harris AL, Cantwell BMJ (1986) Mechanisms and treatments of cytotoxic-induced nausea and vomiting. In: Davis CJ, Lake-Bakaar GV, Grahame-Smith DG (eds) Nausea and vomiting: mechanisms and treatment. Springer, Berlin, pp 65–75Google Scholar
  71. 71.
    Hawthorn J, Ostler KJ, Andrews PLR (1988) The role of the abdominal visceral innervation and 5-hydroxytryptamine M-receptors in vomiting induced by the cytotoxic drugs cyclophosphamide and cis-platin in the ferret. Q J Exp Physiol 73(1):7–21PubMedCrossRefGoogle Scholar
  72. 72.
    Hesketh PJ, Rossi G, Rizzi G, Palmas M, Alyasova A, Bondarenko I, Lisyanskaya A, Gralla RJ (2014) Efficacy and safety of NEPA, an oral combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy: a randomized dose-ranging pivotal study. Ann Oncol 25(7):1340–1346. doi: 10.1093/annonc/mdu110 PubMedCentralPubMedCrossRefGoogle Scholar
  73. 73.
    Hesketh PJ, Van Belle S, Aapro M, Tattersall FD, Naylor RJ, Hargreaves R, Carides AD, Evans JK, Horgan KJ (2003) Differential involvement of neurotransmitters through the time course of cisplatin-induced emesis as revealed by therapy with specific receptor antagonists. Eur J Cancer 39(8):1074–1080PubMedCrossRefGoogle Scholar
  74. 74.
    Higa GM, Auber ML, Altaha R, Piktel D, Kurian S, Hobbs G, Landreth K (2006) 5-Hydroxyindoleacetic acid and substance P profiles in patients receiving emetogenic chemotherapy. J Oncol Pharm Pract 12(4):201–209PubMedCrossRefGoogle Scholar
  75. 75.
    Higa GM, Auber ML, Hobbs G (2012) Identification of a novel marker associated with risk for delayed chemotherapy-induced vomiting. Support Care Cancer 20(11):2803–2809. doi: 10.1007/s00520-012-1402-2 PubMedCrossRefGoogle Scholar
  76. 76.
    Hirsch AT, Dzau VJ, Majzoub JA, Creager MA (1989) Vasopressin-mediated forearm vasodilation in normal humans. Evidence for a vascular vasopressin V2 receptor. J Clin Invest 84(2):418–426. doi: 10.1172/JCI114182
  77. 77.
    Horn CC, Ciucci M, Chaudhury A (2007) Brain Fos expression during 48 h after cisplatin treatment: neural pathways for acute and delayed visceral sickness. Auton Neurosci 132(1–2):44–51PubMedCentralPubMedCrossRefGoogle Scholar
  78. 78.
    Horn CC, De Jonghe BC, Matyas K, Norgren R (2009) Chemotherapy-induced kaolin intake is increased by lesion of the lateral parabrachial nucleus of the rat. Am J Physiol Regul Integr Comp Physiol 297(5):R1375–R1382. doi: 10.1152/ajpregu.00284.2009 PubMedCentralPubMedCrossRefGoogle Scholar
  79. 79.
    Horn CC, Kimball BA, Wang H, Kaus J, Dienel S, Nagy A, Gathright GR, Yates BJ, Andrews PLR (2013) Why can’t rodents vomit? A comparative behavioral, anatomical, and physiological study. PLoS ONE 8(4), e60537. doi: 10.1371/journal.pone.0060537 PubMedCentralPubMedCrossRefGoogle Scholar
  80. 80.
    Horn CC, Richardson EJ, Andrews PLR, Friedman MI (2004) Differential effects on gastrointestinal and hepatic vagal afferent fibers in the rat by the anti-cancer agent cisplatin. Auton Neurosci 115(1–2):74–81PubMedCrossRefGoogle Scholar
  81. 81.
    Hu DL, Zhu G, Mori F, Omoe K, Okada M, Wakabayashi K, Kaneko S, Shinagawa K, Nakane A (2007) Staphylococcal enterotoxin induces emesis through increasing serotonin release in intestine and it is downregulated by cannabinoid receptor 1. Cell Microbiol 9(9):2267–2277. doi: 10.1111/j.1462-5822.2007.00957.x PubMedCrossRefGoogle Scholar
  82. 82.
    Hursti TJ, Borjeson S, Hellstrom PM, Avall-Lundqvist E, Stock S, Steineck G, Peterson C (2005) Effect of chemotherapy on circulating gastrointestinal hormone levels in ovarian cancer patients: relationship to nausea and vomiting. Scand J Gastroenterol 40(6):654–661PubMedCrossRefGoogle Scholar
  83. 83.
    Hursti TJ, Fredrikson M, Steineck G, Borjeson S, Furst CJ, Peterson C (1993) Endogenous cortisol exerts antiemetic effect similar to that of exogenous corticosteroids. Br J Cancer 68(1):112–114PubMedCentralPubMedCrossRefGoogle Scholar
  84. 84.
    Janelsins MC, Tejani MA, Kamen C, Peoples AR, Mustian KM, Morrow GR (2013) Current pharmacotherapy for chemotherapy-induced nausea and vomiting in cancer patients. Expert Opin Pharmacother 14(6):757–766. doi: 10.1517/14656566.2013.776541 PubMedCentralPubMedCrossRefGoogle Scholar
  85. 85.
    Jarve RK, Aggarwal SK (1997) Cisplatin-induced inhibition of the calcium-calmodulin complex, neuronal nitric oxide synthase activation and their role in stomach distention. Cancer Chemother Pharmacol 39(4):341–348. doi: 10.1007/s002800050581 PubMedCrossRefGoogle Scholar
  86. 86.
    Jordan NS, Schauer PK, Schauer A, Nightingale C, Golub G, Martin RS, Williams HM (1985) The effect of administration rate on cisplatin-induced emesis. J Clin Oncol 3(4):559–561PubMedGoogle Scholar
  87. 87.
    Kiernan BD, Soykan I, Lin Z, Dale A, McCallum RW (1997) A new nausea model in humans produces mild nausea without electrogastrogram and vasopressin changes. Neurogastroenterol Motil 9(4):257–263PubMedCrossRefGoogle Scholar
  88. 88.
    Kim J, Napadow V, Kuo B, Barbieri R (2011) A combined HRV-fMRI approach to assess cortical control of cardiovagal modulation by motion sickness. Conf Proc IEEE Eng Med Biol Soc 2011:2825–2828. doi: 10.1109/IEMBS.2011.6090781 PubMedCentralPubMedGoogle Scholar
  89. 89.
    Kim MS, Chey WD, Owyang C, Hasler WL (1997) Role of plasma vasopressin as a mediator of nausea and gastric slow wave dysrhythmias in motion sickness. Am J Physiol 272(4 Pt 1):G853–G862PubMedGoogle Scholar
  90. 90.
    Kobrinsky NL, Pruden PB, Cheang MS, Levitt M, Bishop AJ, Tenenbein M (1988) Increased nausea and vomiting induced by naloxone in patients receiving cancer chemotherapy. Am J Pediatr Hematol Oncol 10(3):206–208PubMedCrossRefGoogle Scholar
  91. 91.
    Koch KL (1997) A noxious trio: nausea, gastric dysrhythmias and vasopressin. Neurogastroenterol Motil 9(3):141–142PubMedCrossRefGoogle Scholar
  92. 92.
    Kris MG, Gralla RJ, Clark RA, Tyson LB, O’Connell JP, Wertheim MS, Kelsen DP (1985) Incidence, course, and severity of delayed nausea and vomiting following the administration of high-dose cisplatin. J Clin Oncol 3(10):1379–1384PubMedGoogle Scholar
  93. 93.
    LaCount LT, Barbieri R, Park K, Kim J, Brown EN, Kuo B, Napadow V (2011) Static and dynamic autonomic response with increasing nausea perception. Aviat Space Environ Med 82(4):424–433PubMedCentralPubMedCrossRefGoogle Scholar
  94. 94.
    Ladabaum U, Koshy SS, Woods ML, Hooper FG, Owyang C, Hasler WL (1998) Differential symptomatic and electrogastrographic effects of distal and proximal human gastric distension. Am J Physiol 275(3 Pt 1):G418–G424PubMedGoogle Scholar
  95. 95.
    Landas S, Fischer J, Wilkin LD, Mitchell LD, Johnson AK, Turner JW, Theriac M, Moore KC (1985) Demonstration of regional blood-brain barrier permeability in human brain. Neurosci Lett 57(3):251–256PubMedCrossRefGoogle Scholar
  96. 96.
    Leslie RA (1986) Comparative aspects of the area postrema: fine-structural considerations help to determine its function. Cell Mol Neurobiol 6(2):95–120PubMedCrossRefGoogle Scholar
  97. 97.
    Lindstrom PA, Brizzee KR (1962) Relief of intractable vomiting from surgical lesions in the area postrema. J Neurosurg 19:228–236PubMedCrossRefGoogle Scholar
  98. 98.
    Lumsden K, Holden WS (1969) The act of vomiting in man. Gut 10(3):173–179PubMedCentralPubMedCrossRefGoogle Scholar
  99. 99.
    Malik NM, Moore GB, Kaur R, Liu YL, Wood SL, Morrow RW, Sanger GJ, Andrews PLR (2008) Adaptive upregulation of gastric and hypothalamic ghrelin receptors and increased plasma ghrelin in a model of cancer chemotherapy-induced dyspepsia. Regul Pept 148(1–3):33–38. doi: 10.1016/j.regpep.2008.03.005 PubMedCrossRefGoogle Scholar
  100. 100.
    Maolood N, Meister B (2009) Protein components of the blood-brain barrier (BBB) in the brainstem area postrema-nucleus tractus solitarius region. J Chem Neuroanat 37(3):182–195. doi: 10.1016/j.jchemneu.2008.12.007 PubMedCrossRefGoogle Scholar
  101. 101.
    McWhinney SR, Goldberg RM, McLeod HL (2009) Platinum neurotoxicity pharmacogenetics. Mol Cancer Ther 8(1):10–16. doi: 10.1158/1535-7163.MCT-08-0840 PubMedCentralPubMedCrossRefGoogle Scholar
  102. 102.
    Miaskiewicz SL, Stricker EM, Verbalis JG (1989) Neurohypophyseal secretion in response to cholecystokinin but not meal-induced gastric distention in humans. J Clin Endocrinol Metab 68(4):837–843. doi: 10.1210/jcem-68-4-837 PubMedCrossRefGoogle Scholar
  103. 103.
    Mihara Y, Egashira N, Sada H, Kawashiri T, Ushio S, Yano T, Ikesue H, Oishi R (2011) Involvement of spinal NR2B-containing NMDA receptors in oxaliplatin-induced mechanical allodynia in rats. Mol Pain 7:8. doi: 10.1186/1744-8069-7-8 PubMedCentralPubMedCrossRefGoogle Scholar
  104. 104.
    Miller AD, Rowley HA, Roberts TP, Kucharczyk J (1996) Human cortical activity during vestibular- and drug-induced nausea detected using MSI. Ann N Y Acad Sci 781:670–672PubMedCrossRefGoogle Scholar
  105. 105.
    Miller AD, Rowley HA, Roberts TP, Kucharczyke J (1995) Activity of human cewrebral cortex during nausea recovery after ondansetron, as detected by magnetic source imaging. In: Serotonin and the scientific basis of anti-emetic therapy. Oxford Clinical Communications, Oxford, p 252Google Scholar
  106. 106.
    Miller CM, Wang BH, Moon SJ, Chen E, Wang H (2014) Neurenteric cyst of the area postrema. Case Rep Neurol Med 2014:718415. doi: 10.1155/2014/718415 PubMedCentralPubMedGoogle Scholar
  107. 107.
    Minami M, Endo T, Hirafuji M, Hamaue N, Liu Y, Hiroshige T, Nemoto M, Saito H, Yoshioka M (2003) Pharmacological aspects of anticancer drug-induced emesis with emphasis on serotonin release and vagal nerve activity. Pharmacol Ther 99(2):149–165PubMedCrossRefGoogle Scholar
  108. 108.
    Minami M, Endo T, Yokota H, Ogawa T, Nemoto M, Hamaue N, Hirafuji M, Yoshioka M, Nagahisa A, Andrews PLR (2001) Effects of CP-99, 994, a tachykinin NK(1) receptor antagonist, on abdominal afferent vagal activity in ferrets: evidence for involvement of NK(1) and 5-HT(3) receptors. Eur J Pharmacol 428(2):215–220PubMedCrossRefGoogle Scholar
  109. 109.
    Minami M, Ogawa T, Endo T, Hamaue N, Hirafuji M, Yoshioka M, Blower PR, Andrews PLR (1997) Cyclophosphamide increases 5-hydroxytryptamine release from the isolated ileum of the rat. Res Commun Mol Pathol Pharmacol 97(1):13–24PubMedGoogle Scholar
  110. 110.
    Miner WD, Sanger GJ (1986) Inhibition of cisplatin-induced vomiting by selective 5-hydroxytryptamine M-receptor antagonism. Br J Pharmacol 88(3):497–499PubMedCentralPubMedCrossRefGoogle Scholar
  111. 111.
    Modlin IM, Kidd M, Pfragner R, Eick GN, Champaneria MC (2006) The functional characterization of normal and neoplastic human enterochromaffin cells. J Clin Endocrinol Metab 91(6):2340–2348. doi: 10.1210/jc.2006-0110 PubMedCrossRefGoogle Scholar
  112. 112.
    Morrow GR (1984) Susceptibility to motion sickness and chemotherapy-induced side-effects. Lancet 1(8373):390–391PubMedCrossRefGoogle Scholar
  113. 113.
    Morrow GR, Andrews PLR, Hickok JT, Stern R (2000) Vagal changes following cancer chemotherapy: implications for the development of nausea. Psychophysiology 37(3):378–384PubMedCrossRefGoogle Scholar
  114. 114.
    Morrow GR, Angel C, Dubeshter B (1992) Autonomic changes during cancer chemotherapy induced nausea and emesis. Br J Cancer Suppl 19:S42–S45PubMedCentralPubMedGoogle Scholar
  115. 115.
    Morrow GR, Hickok JT, Andrews PLR, Stern RM (2002) Reduction in serum cortisol after platinum based chemotherapy for cancer: a role for the HPA axis in treatment-related nausea? Psychophysiology 39(4):491–495PubMedCrossRefGoogle Scholar
  116. 116.
    Morrow GR, Hickok JT, DuBeshter B, Lipshultz SE (1999) Changes in clinical measures of autonomic nervous system function related to cancer chemotherapy-induced nausea. J Auton Nerv Syst 78(1):57–63PubMedCrossRefGoogle Scholar
  117. 117.
    Mowrey DB, Clayson DE (1982) Motion sickness, ginger, and psychophysics. Lancet 1(8273):655–657PubMedCrossRefGoogle Scholar
  118. 118.
    Mutoh M, Imanishi H, Torii Y, Tamura M, Saito H, Matsuki N (1992) Cisplatin-induced emesis in Suncus murinus. Jpn J Pharmacol 58(3):321–324Google Scholar
  119. 119.
    Nalivaiko E, Rudd JA, So RHY (2015) Motion sickness, nausea and thermoregulation: the toxic hypothesis. Temperature 1:164–171CrossRefGoogle Scholar
  120. 120.
    Napadow V, Sheehan J, Kim J, Dassatti A, Thurler AH, Surjanhata B, Vangel M, Makris N, Schaechter JD, Kuo B (2013) Brain white matter microstructure is associated with susceptibility to motion-induced nausea. Neurogastroenterol Motil 25(5):448–450. doi: 10.1111/nmo.12084, e303PubMedCentralPubMedCrossRefGoogle Scholar
  121. 121.
    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(4):806–813. doi: 10.1093/cercor/bhs073 PubMedCentralPubMedCrossRefGoogle Scholar
  122. 122.
    Nussey SS, Hawthorn J, Page SR, Ang VT, Jenkins JS (1988) Responses of plasma oxytocin and arginine vasopressin to nausea induced by apomorphine and ipecacuanha. Clin Endocrinol (Oxf) 28(3):297–304CrossRefGoogle Scholar
  123. 123.
    Oman CM (2012) Are evolutionary hypotheses for motion sickness “just-so” stories? J Vestib Res 22(2):117–127. doi: 10.3233/VES-2011-0432 PubMedGoogle Scholar
  124. 124.
    Page SR, Peterson DB, Crosby SR, Ang VT, White A, Jenkins JS, Nussey SS (1990) The responses of arginine vasopressin and adrenocorticotrophin to nausea induced by ipecacuanha. Clin Endocrinol (Oxf) 33(6):761–770CrossRefGoogle Scholar
  125. 125.
    Percie du Sert N, Andrews PLR (2014) The ferret in nausea and vomiting research: lessons in translation of basic science to clinic. In: Biology and diseases of the ferret. Wiley, New Jersey, pp 735–778Google Scholar
  126. 126.
    Percie du Sert N, Rudd JA, Apfel CC, Andrews PLR (2011) Cisplatin-induced emesis: systematic review and meta-analysis of the ferret model and the effects of 5-HT(3) receptor antagonists. Cancer Chemother Pharmacol 67(3):667–686. doi: 10.1007/s00280-010-1339-4 PubMedCentralPubMedCrossRefGoogle Scholar
  127. 127.
    Percie du Sert N, Rudd JA, Moss R, Andrews PLR (2009) The delayed phase of cisplatin-induced emesis is mediated by the area postrema and not the abdominal visceral innervation in the ferret. Neurosci Lett 465(1):16–20. doi: 10.1016/j.neulet.2009.08.075, S0304-3940(09)01181-1 [pii]PubMedCrossRefGoogle Scholar
  128. 128.
    Perry MR, Rhee J, Smith WL (1994) Plasma levels of peptide YY correlate with cisplatin-induced emesis in dogs. J Pharm Pharmacol 46(7):553–557PubMedCrossRefGoogle Scholar
  129. 129.
    Peyrot des Gachons C, Beauchamp GK, Stern RM, Koch KL, Breslin PA (2011) Bitter taste induces nausea. Curr Biol CB 21(7):R247–R248. doi: 10.1016/j.cub.2011.02.028 PubMedCrossRefGoogle Scholar
  130. 130.
    Pi-Sunyer FX, Aronne LJ, Heshmati HM, Devin J, Rosenstock J (2006) Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-North America: a randomized controlled trial. JAMA 295(7):761–775PubMedCrossRefGoogle Scholar
  131. 131.
    Pivot X, Marghali N, Etienne MC, Bensadoun RJ, Thyss A, Otto J, Francois E, Renee N, Lagrange JL, Schneider M, Milano G (2000) A multivariate analysis for predicting cisplatin-induced delayed emesis. Oncol Rep 7(3):515–519PubMedGoogle Scholar
  132. 132.
    Popescu BF, Lennon VA, Parisi JE, Howe CL, Weigand SD, Cabrera-Gomez JA, Newell K, Mandler RN, Pittock SJ, Weinshenker BG, Lucchinetti CF (2011) Neuromyelitis optica unique area postrema lesions: nausea, vomiting, and pathogenic implications. Neurology 76(14):1229–1237. doi: 10.1212/WNL.0b013e318214332c PubMedCentralPubMedCrossRefGoogle Scholar
  133. 133.
    Racke K, Reimann A, Schworer H, Kilbinger H (1996) Regulation of 5-HT release from enterochromaffin cells. Behav Brain Res 73(1–2):83–87PubMedGoogle Scholar
  134. 134.
    Raghupathi R, Duffield MD, Zelkas L, Meedeniya A, Brookes SJ, Sia TC, Wattchow DA, Spencer NJ, Keating DJ (2013) Identification of unique release kinetics of serotonin from guinea-pig and human enterochromaffin cells. J Physiol 591(Pt 23):5959–5975. doi: 10.1113/jphysiol.2013.259796 PubMedCentralPubMedCrossRefGoogle Scholar
  135. 135.
    Ratelade J, Bennett JL, Verkman AS (2011) Intravenous neuromyelitis optica autoantibody in mice targets aquaporin-4 in peripheral organs and area postrema. PLoS ONE 6(11), e27412. doi: 10.1371/journal.pone.0027412 PubMedCentralPubMedCrossRefGoogle Scholar
  136. 136.
    Rojas C, Raje M, Tsukamoto T, Slusher BS (2014) Molecular mechanisms of 5-HT(3) and NK(1) receptor antagonists in prevention of emesis. Eur J Pharmacol 722:26–37. doi: 10.1016/j.ejphar.2013.08.049 PubMedCrossRefGoogle Scholar
  137. 137.
    Rowe JW, Shelton RL, Helderman JH, Vestal RE, Robertson GL (1979) Influence of the emetic reflex on vasopressin release in man. Kidney Int 16(6):729–735PubMedCrossRefGoogle Scholar
  138. 138.
    Rudd JA, Andrews PLR (2004) Mechanisms of acute, delayed and anticipatory vomiting in cancer and cancer treatment. In: Hesketh P (ed) Management of nausea and vomiting in cancer and cancer treatment. Jones and Barlett Publishers, New York, pp 15–66Google Scholar
  139. 139.
    Rudd JA, Cheng CH, Naylor RJ (1998) Serotonin-independent model of cisplatin-induced emesis in the ferret. Jpn J Pharmacol 78(3):253–260PubMedCrossRefGoogle Scholar
  140. 140.
    Rudd JA, Cheng CH, Naylor RJ, Ngan MP, Wai MK (1999) Modulation of emesis by fentanyl and opioid receptor antagonists in Suncus murinus (house musk shrew). Eur J Pharmacol 374(1):77–84Google Scholar
  141. 141.
    Rudd JA, Ngan MP, Wai MK (1998) 5-HT3 receptors are not involved in conditioned taste aversions induced by 5-hydroxytryptamine, ipecacuanha or cisplatin. Eur J Pharmacol 352(2–3):143–149PubMedCrossRefGoogle Scholar
  142. 142.
    Rudd JA, Tse JY, Wai MK (2000) Cisplatin-induced emesis in the cat: effect of granisetron and dexamethasone. Eur J Pharmacol 391(1-2):145–150PubMedCrossRefGoogle Scholar
  143. 143.
    Sanger GJ, Broad J, Andrews PLR (2013) The relationship between gastric motility and nausea: gastric prokinetic agents as treatments. Eur J Pharmacol 715(1–3):10–14. doi: 10.1016/j.ejphar.2013.06.031 PubMedCrossRefGoogle Scholar
  144. 144.
    Schaub N, Ng K, Kuo P, Aziz Q, Sifrim D (2014) Gastric and lower esophageal sphincter pressures during nausea: a study using visual motion-induced nausea and high-resolution manometry. Am J Physiol Gastrointest Liver Physiol 306(9):G741–G747. doi: 10.1152/ajpgi.00412.2013 PubMedCrossRefGoogle Scholar
  145. 145.
    Schworer H, Racke K, Kilbinger H (1991) Cisplatin increases the release of 5-hydroxytryptamine (5-HT) from the isolated vascularly perfused small intestine of the guinea-pig: involvement of 5-HT3 receptors. Naunyn Schmiedeberg’s Arch Pharmacol 344(2):143–149CrossRefGoogle Scholar
  146. 146.
    Sclocco R, Kinm J, Garcia RG, Sheenan JD, Beissner F, Bianchi AM, Cerutti S, Kuo B, Barbieri R, Napadow V (2014) Brain circuitry supporting multi-organ autonomic outflow in response to nausea. Cerebral Cortex. doi: 10.1093/cercor/bhu172
  147. 147.
    Scott RH, Woods AJ, Lacey MJ, Fernando D, Crawford JH, Andrews PLR (1995) An electrophysiological investigation of the effects of cisplatin and the protective actions of dexamethasone on cultured dorsal root ganglion neurones from neonatal rats. Naunyn Schmiedeberg’s Arch Pharmacol 352(3):247–255CrossRefGoogle Scholar
  148. 148.
    Sem-Jacobsen CW (1968) Vegetative changes in response to electrical brain stimulation. Electroencephalogr Clin Neurophysiol 24(1):88PubMedGoogle Scholar
  149. 149.
    Shih V, Wan HS, Chan A (2009) Clinical predictors of chemotherapy-induced nausea and vomiting in breast cancer patients receiving adjuvant doxorubicin and cyclophosphamide. Ann Pharmacother 43(3):444–452. doi: 10.1345/aph.1L437 PubMedCrossRefGoogle Scholar
  150. 150.
    Shinpo K, Hirai Y, Maezawa H, Totsuka Y, Funahashi M (2012) The role of area postrema neurons expressing H-channels in the induction mechanism of nausea and vomiting. Physiol Behav 107(1):98–103. doi: 10.1016/j.physbeh.2012.06.002 PubMedCrossRefGoogle Scholar
  151. 151.
    Shoji A, Toda M, Suzuki K, Takahashi H, Takahashi K, Yoshiike Y, Ogura T, Watanuki Y, Nishiyama H, Odagiri S (1999) Insufficient effectiveness of 5-hydroxytryptamine-3 receptor antagonists due to oral morphine administration in patients with cisplatin-induced emesis. J Clin Oncol 17(6):1926–1930PubMedGoogle Scholar
  152. 152.
    Sipiora ML, Murtaugh MA, Gregoire MB, Duffy VB (2000) Bitter taste perception and severe vomiting in pregnancy. Physiol Behav 69(3):259–267PubMedCrossRefGoogle Scholar
  153. 153.
    Soderpalm AH, Schuster A, de Wit H (2001) Antiemetic efficacy of smoked marijuana: subjective and behavioral effects on nausea induced by syrup of ipecac. Pharmacol Biochem Behav 69(3–4):343–350PubMedCrossRefGoogle Scholar
  154. 154.
    Stern RM, Koch KL, Andrews PLR (2011) Nausea: mechanisms and management. Oxford University Press, New YorkGoogle Scholar
  155. 155.
    Stott JJR (1986) Mechanisms and treatment of motion illness. In: Davis CB, Lake-Bakaar GV, Grahame-Smith DG (eds) Nausea and vomiting: mechanisms and treatment. Springer, Berlin, pp 110–129CrossRefGoogle Scholar
  156. 156.
    Stricker EM, McCann MJ, Flanagan LM, Verbalis JG (1988) Neurohypophyseal secretion and gastric function: biological correlates of nausea. In: Takagi H, Oomura Y, Ito M, Otsuka M (eds) Biowarning system in the brain, a Naito Foundation symposium. University of Tokyo Press, TokyoGoogle Scholar
  157. 157.
    Sugino S, Hayase T, Higuchi M, Saito K, Moriya H, Kumeta Y, Kurosawa N, Namiki A, Janicki PK (2014) Association of mu-opioid receptor gene (OPRM1) haplotypes with postoperative nausea and vomiting. Exp Brain Res 232(8):2627–2635. doi: 10.1007/s00221-014-3987-9 PubMedCrossRefGoogle Scholar
  158. 158.
    Sugino S, Janicki PK (2015) Pharmacogenetics of chemotherapy-induced nausea and vomiting. Pharmacogenomics 16(2):149–160. doi: 10.2217/pgs.14.168 PubMedCrossRefGoogle Scholar
  159. 159.
    Takeda N, Hasegawa S, Morita M, Matsunaga T (1993) Pica in rats is analogous to emesis: an animal model in emesis research. Pharmacol Biochem Behav 45(4):817–821PubMedCrossRefGoogle Scholar
  160. 160.
    Thomford NR, Sirinek KR (1975) Intravenous vasopressin in patients with portal hypertension: advantages of continuous infusion. J Surg Res 18(2):113–117PubMedCrossRefGoogle Scholar
  161. 161.
    Thomson AJ, Williams RJP, Resolva S (1972) The chemistry of complexes related to cis-Pt(II)NH3)Cl2. An anti-tumour drug. Struct Bond (Springer, Berlin) 11:1–46CrossRefGoogle Scholar
  162. 162.
    Torii Y, Mutoh M, Saito H, Matsuki N (1993) Involvement of free radicals in cisplatin-induced emesis in Suncus murinus. Eur J Pharmacol 248(2):131–135Google Scholar
  163. 163.
    Torii Y, Saito H, Matsuki N (1994) Induction of emesis in Suncus murinus by pyrogallol, a generator of free radicals. Br J Pharmacol 111(2):431–434Google Scholar
  164. 164.
    Treisman M (1977) Motion sickness: an evolutionary hypothesis. Science 197(4302):493–495PubMedCrossRefGoogle Scholar
  165. 165.
    Tremblay PB, Kaiser R, Sezer O, Rosler N, Schelenz C, Possinger K, Roots I, Brockmoller J (2003) Variations in the 5-hydroxytryptamine type 3B receptor gene as predictors of the efficacy of antiemetic treatment in cancer patients. J Clin Oncol 21(11):2147–2155PubMedCrossRefGoogle Scholar
  166. 166.
    Tsuji D, Kim YI, Nakamichi H, Daimon T, Suwa K, Iwabe Y, Hayashi H, Inoue K, Yoshida M, Itoh K (2013) Association of ABCB1 polymorphisms with the antiemetic efficacy of granisetron plus dexamethasone in breast cancer patients. Drug Metab Pharmacokinet 28:299–304PubMedCrossRefGoogle Scholar
  167. 167.
    Ueno S, Matsuki N, Saito H (1987) Suncus murinus: a new experimental model in emesis research. Life Sci 41(4):513–518Google Scholar
  168. 168.
    Ullah I, Subhan F, Rudd JA, Rauf K, Alam J, Shahid M, Sewell RD (2014) Attenuation of cisplatin-induced emetogenesis by standardized Bacopa monnieri extracts in the pigeon: behavioral and neurochemical correlations. Planta Med 80(17):1569–1579. doi: 10.1055/s-0034-1383121 PubMedCrossRefGoogle Scholar
  169. 169.
    Vera G, Castillo M, Cabezos PA, Chiarlone A, Martin MI, Gori A, Pasquinelli G, Barbara G, Stanghellini V, Corinaldesi R, De Giorgio R, Abalo R (2011) Enteric neuropathy evoked by repeated cisplatin in the rat. Neurogastroenterol Motil 23(4):370–378. doi: 10.1111/j.1365-2982.2011.01674.x, e162–373PubMedCrossRefGoogle Scholar
  170. 170.
    Vera G, Lopez-Perez AE, Martinez-Villaluenga M, Cabezos PA, Abalo R (2014) X-ray analysis of the effect of the 5-HT3 receptor antagonist granisetron on gastrointestinal motility in rats repeatedly treated with the antitumoral drug cisplatin. Exp Brain Res 232(8):2601–2612. doi: 10.1007/s00221-014-3954-5 PubMedCrossRefGoogle Scholar
  171. 171.
    Vera Pasamontes G, Uranga JA, Martin Fontelles MI, Abalo R (2012) Histopathology of the severe effects induced by repeated cisplatin in rat tissues. Neurogastroenterol Motil 24(Suppl 2):49Google Scholar
  172. 172.
    Wafai L, Taher M, Jovanovska V, Bornstein JC, Dass CR, Nurgali K (2013) Effects of oxaliplatin on mouse myenteric neurons and colonic motility. Front Neurosci 7:30. doi: 10.3389/fnins.2013.00030 PubMedCentralPubMedCrossRefGoogle Scholar
  173. 173.
    Wang Y, Aggarwal SK, Painter CL (1999) Immunocytochemical and in situ hybridization studies of gastrin after cisplatin treatment. J Histochem Cytochem 47(8):1057–1062PubMedCrossRefGoogle Scholar
  174. 174.
    Warr D (2014) Prognostic factors for chemotherapy induced nausea and vomiting. Eur J Pharmacol 722:192–196. doi: 10.1016/j.ejphar.2013.10.015 PubMedCrossRefGoogle Scholar
  175. 175.
    Wicks D, Wright J, Rayment P, Spiller R (2005) Impact of bitter taste on gastric motility. Eur J Gastroenterol Hepatol 17(9):961–965PubMedCrossRefGoogle Scholar
  176. 176.
    Wilder-Smith OH, Borgeat A, Chappuis P, Fathi M, Forni M (1993) Urinary serotonin metabolite excretion during cisplatin chemotherapy. Cancer 72(7):2239–2241PubMedCrossRefGoogle Scholar
  177. 177.
    Willis CL, Garwood CJ, Ray DE (2007) A size selective vascular barrier in the rat area postrema formed by perivascular macrophages and the extracellular matrix. Neuroscience 150(2):498–509PubMedCrossRefGoogle Scholar
  178. 178.
    Xu LH, Koch KL, Summy-Long J, Stern RM, Seaton JF, Harrison TS, Demers LM, Bingaman S (1993) Hypothalamic and gastric myoelectrical responses during vection-induced nausea in healthy Chinese subjects. Am J Physiol 265(4 Pt 1):E578–E584PubMedGoogle Scholar
  179. 179.
    Yu X, Yang J, Hou X, Zhang K, Qian W, Chen JD (2009) Cisplatin-induced gastric dysrhythmia and emesis in dogs and possible role of gastric electrical stimulation. Dig Dis Sci 54(5):922–927. doi: 10.1007/s10620-008-0470-0 PubMedCrossRefGoogle Scholar
  180. 180.
    Zabara J, Chaffee RB Jr, Tansy MF (1972) Neuroinhibition in the regulation of emesis. Space Life Sci 3(3):282–292PubMedGoogle Scholar
  181. 181.
    Zoto T, Kilickap S, Yasar U, Celik I, Bozkurt A, Babaoglu MO (2015) Improved anti-emetic efficacy of 5-HT3 receptor antagonists in cancer patients with genetic polymorphisms of ABCB1 (MDR1) drug transporter. Basic Clin Pharmacol Toxicol 116(4):354–360. doi: 10.1111/bcpt.12334 PubMedCrossRefGoogle Scholar
  182. 182.
    Zueva L, Rivera Y, Kucheryavykh L, Skatchkov SN, Eaton MJ, Sanabria P, Inyushin M (2014) Electron microscopy in rat brain slices reveals rapid accumulation of Cisplatin on ribosomes and other cellular components only in glia. Chemother Res Pract 2014:174039. doi: 10.1155/2014/174039 PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Division of Biomedical SciencesSt George’s University of LondonLondonUK
  2. 2.School of Biomedical Sciences, and Brain and Mind InstituteThe Chinese University of Hong KongHong KongChina

Personalised recommendations