Skip to main content

Advertisement

Log in

Metabolic Kinetics of 5-Hydroxytryptamine and the Research Targets of Functional Gastrointestinal Disorders

  • Review
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

5-Hydroxytryptamine (5-HT) is an important neurotransmitter in both the central and enteric nervous systems. It has diverse functions in regulating gastrointestinal motility and visceral sensitivity, emotion, appetite, pain and sensory perception, cognition, sexual activity and sleep. These functions are mainly associated with the metabolic kinetics of 5-HT in different tissues. Tryptophan hydroxylase is the rate-limiting enzyme and modulates serotonin synthesis. Vesicular monoamine transporter 1 plays a role in 5-HT storage and release. Degradation of 5-HT is mediated by monoamine oxidase-A. All these factors influence the action of 5-HT in vivo. Functional gastrointestinal disorders (FGIDs) are characterized by a series of symptoms including abdominal pain, diarrhea, constipation, anxiety and depression, in the absence of identifiable structural or biochemical abnormalities. They are frequently accompanied by changed gut motility or visceral sensitivity. An increasing body of research has found FGIDs to be closely associated with 5-HT, and drugs such as citalopram, paroxetine, venlafaxine, alosetron, tegaserod, prucalopride and mosapride have all been developed or discovered from the perspective of the metabolic kinetics of 5-HT. This review discusses the relationship between the metabolic kinetics of 5-HT and research targets in the field of FGIDs and suggests areas of future study that may be useful for understanding these disorders and identification of potential therapeutic targets.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Drossman DA. The functional gastrointestinal disorders and the Rome III process. Gastroenterology. 2006;130:1377–1390.

    Article  PubMed  Google Scholar 

  2. Mayer EA, Gebhart GF. Basic and clinical aspects of visceral hyperalgesia. Gastroenterology. 1994;107:271–293.

    PubMed  CAS  Google Scholar 

  3. Cervero F, Laird JM. Visceral pain. Lancet. 1999;353:2145–2148.

    Article  PubMed  CAS  Google Scholar 

  4. Gershon MD, Tack J. The serotonin signaling system: from basic understanding to drug development for functional GI disorders. Gastroenterology. 2007;132:397–414.

    Article  PubMed  CAS  Google Scholar 

  5. Tosic-Golubovic S, Miljkovic S, Nagorni A, et al. Irritable bowel syndrome, anxiety, depression and personality characteristics. Psychiatria Danubina. 2010;22:418–424.

    PubMed  Google Scholar 

  6. Locke GR, Weaver AL, Melton LJ, Talley NJ. Psychosocial factors are linked to functional gastrointestinal disorders: a population based nested case–control study. Am J Gastroenterol. 2004;99:350–357.

    Article  PubMed  Google Scholar 

  7. Miwa H, Nakajima K, Yamaguchi K, et al. Generation of dyspeptic symptoms by direct acid infusion into the stomach of healthy Japanese subjects. Aliment Pharmacol Ther. 2007;26:257–264.

    Article  PubMed  CAS  Google Scholar 

  8. Moayyedi P, Deeks J, Talley NJ, Delaney B, Forman D. An update of the Cochrane systematic review of Helicobacter pylori eradication therapy in nonulcer dyspepsia: resolving the discrepancy between systematic reviews. Am J Gastroenterol. 2003;98:2621–2626.

    Article  PubMed  Google Scholar 

  9. Gathaiya N, Locke GR, Camilleri M, Schleck CD, Zinsmeister AR, Talley NJ. Novel associations with dyspepsia: a community-based study of familial aggregation, sleep dysfunction and somatization. Neurogastroenterol Motil. 2009;21:922-e69.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Feinle-Bisset C, Azpiroz F. Dietary and lifestyle factors in functional dyspepsia. Nat Rev Gastroenterol Hepatol. 2013;10:150–157.

    Article  PubMed  CAS  Google Scholar 

  11. Mahadeva S, Yadav H, Rampal S, Goh KL. Risk factors associated with dyspepsia in a rural Asian population and its impact on quality of life. Am J Gastroenterol. 2010;105:904–912.

    Article  PubMed  Google Scholar 

  12. Erspamer V. Historical introduction: the Italian contribution to the discovery of 5-hydroxytryptamine (enteramine, serotonin). J Hypertens Suppl. 1986;4:S3–S5.

    PubMed  CAS  Google Scholar 

  13. Rapport MM, Green AA, Page IH. Serum vasoconstrictor, serotonin; isolation and characterization. J Biol Chem. 1948;176:1243–1251.

    PubMed  CAS  Google Scholar 

  14. Nichols DE, Nichols CD. Serotonin receptors. Chem Rev. 2008;108:1614–1641.

    Article  PubMed  CAS  Google Scholar 

  15. Berger M, Gray JA, Roth BL. The expanded biology of serotonin. Annu Rev Med. 2009;60:355–366.

    Article  PubMed  CAS  Google Scholar 

  16. Feijó FM, Bertoluci MC, Reis C. Serotonin and hypothalamic control of hunger: a review. Rev Assoc Med Bras. 2011;57:74–77.

    Google Scholar 

  17. Camilleri M. Serotonin in the gastrointestinal tract. Curr Opin Endocrinol Diabetes Obes. 2009;16:53–59.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  18. Manocha M, Khan W. Serotonin and GI disorders: an update on clinical and experimental studies. Clin Transl Gastroenterol. 2012;3:1–6.

    Google Scholar 

  19. Walther DJ, Peter JU, Bashammakh S, et al. Synthesis of serotonin by a second tryptophan hydroxylase isoform. Science. 2003;299:76.

    Article  PubMed  CAS  Google Scholar 

  20. Cote F, Thevenot E, Fligny C, et al. Disruption of the nonneuronal tph1 gene demonstrates the importance of peripheral serotonin in cardiac function. Proc Natl Acad Sci USA. 2003;100:13525–13530.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  21. Walther DJ, Bader M. A unique central tryptophan hydroxylase isoform. Biochem Pharmacol. 2003;66:1673–1680.

    Article  PubMed  CAS  Google Scholar 

  22. Schafermeyer A, Gratzl M, Rad R, et al. Isolation and receptor profiling of ileal enterochromaffin cells. Acta Physiol Scand. 2004;182:53–62.

    Article  PubMed  CAS  Google Scholar 

  23. Fujimiya M, Okumiya K, Kuwahara A. Immunoelectron microscopic study of the luminal release of serotonin from rat enterochromaffin cells induced by high intraluminal pressure. Histochem Cell Biol. 1997;108:105–113.

    Article  PubMed  CAS  Google Scholar 

  24. Wade PR, Chen J, Jaffe B, et al. Localization and function of a 5-HT transporter in crypt epithelia of the gastrointestinal tract. J Neurosci. 1996;16:2352–2364.

    PubMed  CAS  PubMed Central  Google Scholar 

  25. Houghton LA, Atkinson W, Whitaker RP, Whorwell PJ, Rimmer MJ. Increased platelet depleted plasma 5-hydroxytryptamine concentration following meal ingestion in symptomatic female subjects with diarrhoea predominant irritable bowel syndrome. Gut. 2003;52:663–670.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  26. Dunlop SP, Coleman NS, Blackshaw E, et al. Abnormalities of 5-hydroxytryptamine metabolism in irritable bowel syndrome. Clin Gastroenterol Hepatol. 2005;3:349–357.

    Article  PubMed  CAS  Google Scholar 

  27. Atkinson W, Lockhart S, Whorwell PJ, Keevil B, Houghton LA. Altered 5-hydroxytryptamine signaling in patients with constipation- and diarrhea-predominant irritable bowel syndrome. Gastroenterology. 2006;130:34–43.

    Article  PubMed  CAS  Google Scholar 

  28. Brown PM, Drossman DA, Wood AJ, et al. The tryptophan hydroxylase inhibitor LX1031 is effective for patients with nonconstipating irritable bowel syndrome. Gastroenterology. 2011;141:507–516.

    Article  PubMed  CAS  Google Scholar 

  29. Wang H, Steeds J, Motomura Y, et al. CD4+ T cell-mediated immunological control of enterochromaffin cell hyperplasia and 5-hydroxytryptamine production in enteric infection. Gut. 2007;56:949–957.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  30. Nakamura K, Sato T, Ohashi A, et al. Role of a serotonin precursor in development of gut microvilli. Am J Pathol. 2008;172:333–344.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  31. Muller T, Durk T, Blumenthal B, et al. 5-hydroxytryptamine modulates migration, cytokine and chemokine release and T-cell priming capacity of dendritic cells in vitro and in vivo. PLoS One. 2009;4:e6453.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Haub S, Ritze Y, Bergheim I, et al. Enhancement of intestinal inflammation in mice lacking interleukin 10 by deletion of the serotonin reuptake transporter. Neurogastroenterol Motil. 2010;22:826–834.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  33. Cloez-Tayarani I, Changeux JP. Nicotine and serotonin in immune regulation and inflammatory processes: a perspective. J Leukoc Biol. 2007;81:599–606.

    Article  PubMed  CAS  Google Scholar 

  34. Kushnir-Sukhov NM, Brown JM, Wu Y, et al. Human mast cells are capable of serotonin synthesis and release. J Allergy Clin Immunol. 2007;119:498–499.

    Article  PubMed  CAS  Google Scholar 

  35. O’Connell PJ, Wang X, Leon-Ponte M, et al. A novel form of immune signaling revealed by transmission of the inflammatory mediator serotonin between dendritic cells and T cells. Blood. 2006;107:1010–1017.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Foley S, Garsed K, Singh G, et al. Impaired uptake of serotonin by platelets from patients with irritable bowel syndrome correlates with duodenal immune activation. Gastroenterology. 2011;140:1434–1443.

    Article  PubMed  CAS  Google Scholar 

  37. Bearcroft CP, Perrett D, Farthing MJ. 5-hydroxytryptamine release into human jejunum by cholera toxin. Gut. 1996;39:528–531.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  38. Fukumoto S, Tatewaki M, Yamada T, et al. Short-chain fatty acids stimulate colonic transit via intraluminal 5-HT release in rats. Am J Physiol Regul Integr Comp Physiol. 2003;284:R1269–R1276.

    PubMed  CAS  Google Scholar 

  39. Kim M, Cooke HJ, Javed NH, et al. d-Glucose releases 5-hydroxytryptamine from human BON cells as a model of enterochromaffin cells. Gastroenterology. 2001;121:1400–1406.

    Article  PubMed  CAS  Google Scholar 

  40. O’Mahony L, McCarthy J, Kelly P, et al. Lactobacillus and bifidobacterium in irritable bowel syndrome: symptom responses and relationship to cytokine profiles. Gastroenterology. 2005;128:541–551.

    Article  PubMed  Google Scholar 

  41. Whorwell PJ, Altringer L, Morel J, et al. Efficacy of an encapsulated probiotic Bifidobacterium infantis 35624 in women with irritable bowel syndrome. Am J Gastroenterol. 2006;101:1581–1590.

    Article  PubMed  Google Scholar 

  42. Brenner DM, Moeller MJ, Chey WD, Schoenfeld PS. The utility of probiotics in the treatment of irritable bowel syndrome: a systematic review. Am J Gastroenterol. 2009;104:1033–1049.

    Article  PubMed  CAS  Google Scholar 

  43. Moayyedi P, Ford AC, Talley NJ, et al. The efficacy of probiotics in the treatment of irritable bowel syndrome: a systematic review. Gut. 2010;59:325–332.

    Article  PubMed  CAS  Google Scholar 

  44. Masand PS, Gupta S, Schwartz TL, et al. Paroxetine in patients with irritable bowel syndrome: a pilot open-label study. Prim Care Companion J Clin Psychiatry. 2002;4:12–16.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Masand PS, Gupta S, Schwartz TL, Virk S, Hameed A, Kaplan DS. Open-label treatment with citalopram in patients with irritable bowel syndrome: a pilot study. Prim Care Companion J Clin Psychiatry. 2005;7:162–166.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Creed F, Fernandes L, Guthrie E, et al. North of England IBS Research Group. The cost-effectiveness of psychotherapy and paroxetine for severe irritable bowel syndrome. Gastroenterology. 2003;124:303–317.

    Article  PubMed  Google Scholar 

  47. Kuiken SD, Tytgat GN, Boeckxstaens GE. The selective serotonin reuptake inhibitor fluoxetine does not change rectal sensitivity and symptoms in patients with irritable bowel syndrome: a double blind, randomized, placebo-controlled study. Clin Gastroenterol Hepatol. 2003;1:219–228.

    Article  PubMed  CAS  Google Scholar 

  48. Tack J, Broekaert D, Corsetti M, Fischler B, Janssens J. Influence of acute serotonin reuptake inhibition on colonic sensorimotor function in man. Aliment Pharmacol Ther. 2006;23:265–274.

    Article  PubMed  CAS  Google Scholar 

  49. Broekaert D, Fischler B, Sifrim D, Janssens J, Tack J. Influence of citalopram, a selective serotonin reuptake inhibitor, on oesophageal hypersensitivity: a double-blind, placebo-controlled study. Aliment Pharmacol Ther. 2006;23:365–370.

    Article  PubMed  CAS  Google Scholar 

  50. Tabas G, Beaves M, Wang J, et al. Paroxetine to treat irritable bowel syndrome not responding to high-fiber diet: a double-blind, placebo-controlled trial. Am J Gastroenterol. 2004;99:914–920.

    Article  PubMed  CAS  Google Scholar 

  51. Vahedi H, Merat S, Rashidioon A, Ghoddoosi A, Malekzadeh R. The effects of fluoxetine in patients with pain and constipation-predominant irritable bowel syndrome: a doubleblind randomized-controlled study. Aliment Pharmacol Ther. 2005;22:381–385.

    Article  PubMed  CAS  Google Scholar 

  52. Barkin RL, Barkin SJ. Antidepressants for the management of pain in geriatric patients. Anesth Today. 2004;15:23–26.

    Google Scholar 

  53. Bradley RH, Barkin RL, Jerome J, DeYoung K, Dodge CW. Efficacy of venlafaxine for the long term treatment of chronic pain with associated major depressive disorder. Am J Ther. 2003;10:318–323.

    Article  PubMed  Google Scholar 

  54. Mayer EA, Tillisch K, Bradesi S. Review article: modulation of the brain-gut axis as a therapeutic approach in gastrointestinal disease. Aliment Pharmacol Ther. 2006;24:919–933.

    Article  PubMed  CAS  Google Scholar 

  55. Kim DY, Camilleri M. Serotonin: a mediator of the brain–gut connection. Am J Gastroenterol. 2000;95:2698–2709.

    PubMed  CAS  Google Scholar 

  56. Hoyer D, Hannon JP, Martin GR. Molecular, pharmacological and functional diversity of 5-HT receptors. Pharmacol Biochem Behav. 2002;71:533–554.

    Article  PubMed  CAS  Google Scholar 

  57. Briejer MR, Mathis C, Schuurkes JA. 5-HT receptor types in the rat ileum longitudinal muscle: focus on 5-HT2 receptors mediating contraction. Neurogastroenterol Motil. 1997;9:231–237.

    Article  PubMed  CAS  Google Scholar 

  58. Gershon MD. 5-HT (serotonin) physiology and related drugs. Curr Opin Gastroenterol. 2000;16:113–120.

    Article  PubMed  CAS  Google Scholar 

  59. Coulie B, Tack J, Maes B, Geypens B, De Roo M, Janssens J. Sumatriptan, a selective 5-HT1 receptor agonist, induces a lag phase for gastric emptying of liquids in humans. Am J Physiol. 1997;272:G902–G908.

    PubMed  CAS  Google Scholar 

  60. Tuladhar BR, Ge L, Naylor RJ. 5-HT(7) receptors mediate the inhibitory effect of 5-HT on peristalsis in the isolated guinea-pig ileum. Br J Pharmacol. 2003;138:1210–1214.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  61. Prause A, Stoffel M, Portier C, Mevissen M. Expression and function of 5-HT7 receptors in smooth muscle preparations from equine duodenum, ileum, and pelvic flexure. Res Vet Sci. 2009;87:292–299.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  62. Tack J, Piessevaux H, Coulie B, et al. A placebo-controlled trial of buspirone, a fundus-relaxing drug, in functional dyspepsia: effect on symptoms and gastric sensory and motor function. Gastroenterology. 1999;116:A325.

    Google Scholar 

  63. Chial HJ, Camilleri M, Ferber I, et al. Effects of venlafaxine, buspirone, and placebo on colonic sensorimotor functions in healthy humans. Clin Gastroenterol Hepatol. 2003;1:211–218.

    Article  PubMed  CAS  Google Scholar 

  64. O’Mahony SM, Bulmer DC, Coelho AM, et al. 5-HT(2B) receptors modulate visceral hypersensitivity in a stress-sensitive animal model of brain–gut axis dysfunction. Neurogastroenterol Motil. 2010;22:573–578.

    Article  PubMed  Google Scholar 

  65. Kim S-K, Li Y, Abrol R, et al. Predicted structures and dynamics for agonists and antagonists bound to serotonin 5-HT2B and 5-HT2C receptors. J Chem Inf Model. 2011;51:420–433.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  66. Aapro MS. 5-HT3 receptor antagonists. An overview of their present status and future potential in cancer therapy-induced emesis. Drugs. 1991;42:551–568.

    Article  PubMed  CAS  Google Scholar 

  67. Delvaux M, Louvel D, Mamet JP, Campos-Oriola R, Frexinos J. Effect of alosetron on responses to colonic distension in patients with irritable bowel syndrome. Aliment Pharmacol Ther. 1998;12:849–855.

    Article  PubMed  CAS  Google Scholar 

  68. Bearcroft CP, Andre EA, Farthing MJ. 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. 1997;11:1109–1114.

    Article  PubMed  CAS  Google Scholar 

  69. Talley NJ, Phillips SF, Haddad A, et al. GR38032F (ondansetron), a selective 5-HT3 receptor antagonist, slows colonic transit in healthy human. Dig Dis Sci. 1990;35:477–480.

    Article  PubMed  CAS  Google Scholar 

  70. Horton R. Lotronex and the FDA: a fatal erosion of integrity. Lancet. 2001;357:1544–1545.

    Article  PubMed  CAS  Google Scholar 

  71. Friedel D, Thomas R, Fisher RS. Ischemic colitis during treatment with alosetron. Gastroenterology. 2001;120:557–560.

    Article  PubMed  CAS  Google Scholar 

  72. Asagarasu A, Matsui T, Hayashi H, et al. Discovery of a novel 5-HT(3) antagonist/5-HT(1A) agonist 3-amino-5,6,7,8-tetrahydro-2-{4-[4-(quinolin-2-yl) piperazin-1-yl]butyl} quinazolin-4 (3H)-one (TZB-30878) as an orally bioavailable agent for irritable bowel syndrome. J Med Chem. 2010;53:7549–7563.

    Article  PubMed  CAS  Google Scholar 

  73. Hee Sun KIM. 5-Hydroxytryptamine4 receptor agonists and colonic motility. J Smooth Muscle Res. 2009;45:25–29.

    Article  Google Scholar 

  74. Lewin MB, Bryant RM, Fenrich AL, Grifka RG. Cisapride-induced long QT interval. J Pediatr. 1996;128:279–281.

    Article  PubMed  CAS  Google Scholar 

  75. Emmanuel AV, Kamm MA, Roy AJ, Kerstens R, Vandeplassche L. Randomised clinical trial: the efficacy of prucalopride in patients with chronic intestinal pseudo-obstruction—a double-blind, placebo-controlled, cross-over, multiple n = 1 study. Aliment Pharmacol Ther. 2012;35:48–55.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  76. Goldberg M, Li YP, Johanson JF, et al. Clinical trial: the efficacy and tolerability of velusetrag, a selective 5-HT4 agonist with high intrinsic activity, in chronic idiopathic constipation—a 4-week, randomized, double-blind, placebo-controlled, dose-response study. Aliment Pharmacol Ther. 2010;32:1102–1112.

    Article  PubMed  CAS  Google Scholar 

  77. Camilleri M, Vazquez-Roque MI, Burton D, et al. Pharmacodynamic effects of a novel prokinetic 5-HT receptor agonist, ATI-7505, in humans. Neurogastroenterol Motil. 2007;19:30–38.

    Article  PubMed  CAS  Google Scholar 

  78. Hoyer D, Clarke DE, Fozard JR, et al. International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (serotonin). Pharmacol Rev. 1994;46:157–203.

    PubMed  CAS  Google Scholar 

  79. Prins NH, Briejer MR, Van Bergen PJ, Akkermans LM, Schuurkes JA. Evidence for 5-HT7 receptors mediating relaxation of human colonic circular smooth muscle. Br J Pharmacol. 1999;128:849–852.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  80. Dahlstrom A, Fuxe K. Localization of monoamines in the lower brain stem. Experientia. 1964;20:398–399.

    Article  PubMed  CAS  Google Scholar 

  81. Charnay Y, Leger L. Brain serotonergic circuitries. Dialogues Clin Neurosci. 2010;12:471–487.

    PubMed  PubMed Central  Google Scholar 

  82. Lydiard RB. Irritable bowel syndrome, anxiety, and depression: what are the links? J Clin Psychiatry. 2001;62:38–45.

    PubMed  Google Scholar 

  83. Dekel R, Drossman DA, Sperber AD. The use of psychotropic drugs in irritable bowel syndrome. Expert Opin Investig Drugs. 2013;22:329–339.

    Article  PubMed  CAS  Google Scholar 

  84. Grover M, Camilleri M. Effects on gastrointestinal functions and symptoms of serotonergic psychoactive agents used in functional gastrointestinal diseases. J Gastroenterol. 2013;48:177–181.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

Download references

Conflict of interest

None.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jun Zhang.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jing, F., Zhang, J. Metabolic Kinetics of 5-Hydroxytryptamine and the Research Targets of Functional Gastrointestinal Disorders. Dig Dis Sci 59, 2642–2648 (2014). https://doi.org/10.1007/s10620-014-3244-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-014-3244-x

Keywords

Navigation