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Techniques in Coloproctology

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01-07-2014 | Review

Serotonin receptors and their role in the pathophysiology and therapy of irritable bowel syndrome

Authors: C. Stasi, M. Bellini, G. Bassotti, C. Blandizzi, S. Milani

Published in: Techniques in Coloproctology | Issue 7/2014

Abstract

Background

Irritable bowel syndrome (IBS) is a functional disorder of the gastrointestinal tract characterized by abdominal discomfort, pain and changes in bowel habits, often associated with psychological/psychiatric disorders. It has been suggested that the development of IBS may be related to the body’s response to stress, which is one of the main factors that can modulate motility and visceral perception through the interaction between brain and gut (brain–gut axis). The present review will examine and discuss the role of serotonin (5-hydroxytryptamine, 5-HT) receptor subtypes in the pathophysiology and therapy of IBS.

Methods

Search of the literature published in English using the PubMed database.

Results

Several lines of evidence indicate that 5-HT and its receptor subtypes are likely to have a central role in the pathophysiology of IBS. 5-HT released from enterochromaffin cells regulates sensory, motor and secretory functions of the digestive system through the interaction with different receptor subtypes. It has been suggested that pain signals originate in intrinsic primary afferent neurons and are transmitted by extrinsic primary afferent neurons. Moreover, IBS is associated with abnormal activation of central stress circuits, which results in altered perception during visceral stimulation.

Conclusions

Altered 5-HT signaling in the central nervous system and in the gut contributes to hypersensitivity in IBS. The therapeutic effects of 5-HT agonists/antagonists in IBS are likely to be due also to the ability to modulate visceral nociception in the central stress circuits. Further studies are needed in order to develop an optimal treatment.

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

Stasi C, Rosselli M, Bellini M et al (2012) Altered neuro-endocrine-immune pathways in the irritable bowel syndrome: the top-down and the bottom-up model. J Gastroenterol 47:1177–1185PubMed

Ford AC, Talley NJ, Schoenfeld PS et al (2009) Efficacy of antidepressants and psychological therapies in irritable bowel syndrome: systematic review and meta-analysis. Gut 58:367–378PubMed

Bearcroft CP, Perret D, Farthing MJ (1998) Postprandial plasma 5-hydroxytryptamine in diarrhea-predominant irritable bowel syndrome: a pilot study. Gut 42:42–46PubMedCentralPubMed

Houghton LA, Foster JM, Whorwell PJ (2003) Alosetron, a 5-HT3 receptor antagonist, delays colonic transit in patients with irritable bowel syndrome and healthy volunteers. Aliment Pharmacol Ther 14:775–782

Spiller RC, Jenkins D, Thornley JP (2000) Increased rectal mucosal entero-endocrine cells, T lynphocytes, and increased gut permeability following acute Campilobacter enteris and in post-dysenteric irritable bowel syndrome. Gut 47:804–811PubMedCentralPubMed

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

Kim DY, Camilleri M (2000) Serotonin: a mediator of the brain-gut connection. Am J Gastroenterol 95:2698–2709PubMed

Grundy D, Al-Chaer ED, Aziz Q et al (2006) Fundamentals of neurogastroenterology: basic science. Gastroenterology 130:1391–1411PubMed

10.

Varnas K, Halldin C, Hall H (2004) Autoradiographic distribution of serotonin transporters and receptor subtypes in human brain. Hum Brain Mapp 22:246–260PubMed

11.

Kirchgessner AL, Liu MT, Raymond JR et al (1996) Identification of cells that express 5-hydroxytryptamine1A receptors in the nervous systems of the bowel and pancreas. J Comp Neurol 364:439–455PubMed

12.

Fiorica-Howells E, Hen R, Gingrich J et al (2002) 5-HT(2A) receptors: location and functional analysis in intestines of wild-type and 5-HT(2A) knockout mice. Am J Physiol Gastrointest Liver Physiol 282:G877–G893PubMed

13.

Hoffman JM, Tyler K, MacEachern SJ et al (2012) Activation of colonic mucosal 5-HT(4) receptors accelerates propulsive motility and inhibits visceral hypersensitivity. Gastroenterology 142:844–854PubMedCentralPubMed

14.

Mawe GM, Branchek TA, Gershon MD (1986) Peripheral neural serotonin receptors: identification and characterization with specific antagonists and agonists. Proc Natl Acad Sci USA 83:9799–9803PubMedCentralPubMed

15.

Gershon MD (1999) Roles played by 5-hydroxytryptamine in the physiology of the bowel. Aliment Pharmacol Ther 13:15–30PubMed

16.

Tonini M (2005) 5-Hydroxytryptamine effects in the gut: the 3, 4 and 7 receptors. Neurogastroenterol Motil 17:637–642PubMed

17.

Pazos A, Prost TA, Palacios JM (1987) Serotonin receptors in the human brain III. Autoradiographic mapping of serotonin-1 receptors. Neuroscience 21:97–122PubMed

18.

Pineyro G, Blier P (1999) Autoregulation of serotonin neurons: role in antidepressant drug action. Pharmacol Rev 51:533–591PubMed

19.

Wang GD, Wang XY, Zou F et al (2013) Mast cell expression of the serotonin1A receptor in guinea pig and human intestine. Am J Physiol Gastrointest Liver Physiol 304:G855–G863PubMedCentralPubMed

20.

Humprey PP, Hartig P, Hoyer D (1993) A proposed new nomenclature for 5-HT receptors. Trends Pharmacol Sci 14:233–236

21.

Tepper SJ, Rapoport AM, Sheftell FD (2002) Mechanisms of action of the 5-HT1B/1D receptor agonists. Arch Neurol 59:1084–1088PubMed

22.

Hamel E, Fan E, Linville D et al (1993) Expression of mRNA for the serotonin 5-hydroxytryptamine1D beta receptor subtype in human and bovine cerebral arteries. Mol Pharmacol 44:242–246PubMed

23.

Levy FO, Gudermann T, Peres-Reyes E et al (1992) Molecular cloning of a human serotonin receptor (S12) with a pharmacological profile resembling that of the 5-HT1D subtype. J Biol Chem 267:7553–7562PubMed

24.

Jin H, Oksenberg D, Ashkenazi A et al (1992) Characterization of the human 5-hydroxytryptamine1B receptor. J Biol Chem 267:5735–5738PubMed

25.

Weinshank RL, Zgombick JM, Macchi MJ et al (1992) Human serotonin 1D receptor is encoded by a subfamily of two distinct genes: 5-HT1Dα and 5-HT1Dβ. Proc Natl Acad Sci USA 89:3630–3634PubMedCentralPubMed

26.

Lowther S, De Paermentier F, Crompton MR et al (1992) The distribution of 5-HT(1D) and 5-HT(lE) binding sites in human brain. Eur J Pharmacol 222:137–142PubMed

27.

McAllister G, Charlesworth A, Snodin C et al (1992) Molecular cloning of a serotonin receptor from human brain (5HT1E): a fifth 5HT1-like subtype. Proc Natl Acad Sci USA 89:5517–5521PubMedCentralPubMed

28.

Adham N, Kao HT, Schecter LE et al (1993) Cloning of another human serotonin receptor (5-HT1F): a fifth 5-HT1 receptor subtype coupled to the inhibition of adenylate cyclase. Proc Natl Acad Sci USA 90:408–412PubMedCentralPubMed

29.

Molderings GJ, Werner K, Likungu J et al (1990) Inhibition of noradrenaline release from the sympathetic nerves of the human saphenous vein via presynaptic 5-HT receptor similar to the 5-HT(1D) subtype. Naunyn Schmiedebergs Arch Pharmacol 342:371–377PubMed

30.

Bax WA, Renzenbrink GJ, Van Heuven-Nolsen D et al (1993) 5-HT receptors mediating contractions of the isolated human coronary artery. Eur J Pharmacol 239:203–210PubMed

31.

Tack J, Coulier B, Wilmer A et al (1998) Actions of the 5-hydroxytryptamine 1 receptor agonist sumatriptan on interdigestive gastrointestinal motility in man. Gut 42:36–41PubMedCentralPubMed

32.

Foguet M, Hoyer D, Pardo LA et al (1992) Cloning and functional characterization of the rat stomach fundus serotonin receptor. EMBO J 11:3481–3487PubMedCentralPubMed

33.

Bubar MJ, Cunningham KA (2006) Serotonin 5-HT2A and 5-HT2C receptors as potential targets for modulation of psychostimulant use and dependence. Curr Top Med Chem 6:1971–1985PubMed

34.

Vane JR (1959) The relative activities of some tryptamine analogues on the isolated rat stomach strip preparation. Br J Pharmacol 14:87–98

35.

Cohen ML, Wittenauer LA (1987) Serotonin receptor activation of phos-phoinositide turnover in uterine, fundal, vascular and tracheal smooth muscle. J Cardiovasc Pharmacol 10:176–181PubMed

36.

Kursar JD, Nelson DL, Wainscott DB et al (1992) Molecular cloning, functional expression and pharmacological characterisation of a novel serotonin receptor (5-hydroxytryptamine2F) from rat stomach fundus. Mol Pharmacol 42:549–557PubMed

37.

Kennet GA, Aiswworth K, Trail B et al (1997) BW 723C86, a 5HT2B receptor antagonist, causes hyperphagia and reduced grooming in rats. Neuropharmacology 36:23–39

38.

Gershon MD (2003) Serotonin and its implication for the management of irritable bowel syndrome. Rev Gastroenterol Disord 3:S25–S34PubMed

39.

Pasqualetti M, Ori M, Castagna M et al (1999) Distribution and cellular localization of the serotonin type 2C receptor messenger RNA in human brain. Neuroscience 92:601–611PubMed

40.

Boess FG, Martin IL (1994) Molecular biology of 5HT receptors. Neuropharmacology 33:275–317PubMed

41.

Pratt GD, Bowery NG, Kilpatrick GJ et al (1990) Consensus meeting agrees distribution of 5-HT3 receptors in mammalian hindbrain. Trends Pharmacol Sci 11:135–137PubMed

42.

Thompson AJ, Lummis SC (2007) The 5-HT3 receptor as a therapeutic target. Expert Opin Ther Targets 11:527–540PubMedCentralPubMed

43.

Kidd EJ, Laporte AM, Langlois X et al (1993) 5-HT3 receptors in the rat central nervous system are mainly located on nerve fibres and terminals. Brain Res 612:289–298PubMed

44.

Hamon M, Gallissot MC, Menard F et al (1989) 5-HT3 receptor binding sites are on capsaicin-sensitive fibres in the rat spinal cord. Eur J Pharmacol 164:315–322PubMed

45.

Takaki M (2003) Gut pacemaker cells: the interstitial cells of Cajal. J Smooth Muscle Res 39:137–161PubMed

46.

Liu HN, Ohya S, Nishizawa Y et al (2011) Serotonin augments gut pacemaker activity via 5-HT3 receptors. PLoS ONE 6:e24928PubMedCentralPubMed

47.

Marchetti E, Dumuis A, Bockaert J et al (2000) Differential modulation of the 5-HT(4) receptor agonists and antagonist on rat learning and memory. Neuropharmacology 39:2017–2027PubMed

48.

King MV, Marsden CA, Fone KC (2008) A role for the 5-HT(1A), 5-HT4 and 5-HT6 receptors in learning and memory. Trends Pharmacol Sci 29:482–492PubMed

49.

Salmon E (2007) A review of the literature on neuroimaging of serotoninergic function in Alzheimer’s disease and related disorders. J Neural Transm 114:1179–1185PubMed

50.

Bockaert J, Claeysen S, Compan V et al (2011) 5-HT(4) receptors, a place in the sun: act two. Curr Opin Pharmacol 11:87–93PubMed

51.

Madsen K, Haahr MT, Marner L et al (2011) Age and sex effects on 5-HT(4) receptors in the human brain: a [(11)C]SB207145 PET study. J Cereb Blood Flow Metab 31:1475–1481PubMedCentralPubMed

52.

Tack J, Camilleri M, Chang L et al (2012) Systematic review: cardiovascular safety profile of 5-HT4 agonists developed for gastrointestinal disorders. Aliment Pharmacol Ther 35:745–767PubMedCentralPubMed

53.

Schoemaker RG, Du XY, Bax WA et al (1993) 5-Hydroxytryptamine stimulates human isolated atrium but not ventricle. Eur J Pharmacol 239:103–105

54.

Oliver KR, Kinsey AM, Wainwright A et al (2000) Localization of 5-HT5A receptor-like immunoreactivity in the rat brain. Brain Res 867:131–142PubMed

55.

Pasqualetti M, Ori M, Nardi I et al (1998) Distribution of the 5-HT5A serotonin receptor mRNA in the human brain. Mol Brain Res 56:1–8PubMed

56.

Plassat J-L, Boschert U, Amlaiky N et al (1992) The mouse 5-HT5A receptor reveals a remarkable heterogeneity within the 5-HT1D receptor family. EMBO J 11:4779–4786PubMedCentralPubMed

57.

Grailhe R, Grabtree GW, Hen R (2001) Human 5-HT(5) receptors: the 5-HT(5A) receptor is functional but the 5-HT(5B) receptor was lost during mammalian evolution. Eur J Pharmacol 418:157–167PubMed

58.

Wesolowski A (2002) In the search for selective ligands of 5-HT5, 5-HT6 and 5-HT7 serotonin receptors. Pol J Pharmacol 54:327–341

59.

Thomas DR, Hagan JJ (2004) 5-HT7 receptors. Curr Drug Targets CNS Neurol Disord 3:81–90PubMed

60.

Tonini M, Vicini R, Cervio E et al (2005) 5-HT(7) receptors modulate peristalsis and accommodation in the guinea pig ileum. Gastroenterology 129:1557–1566PubMed

61.

Bülbring E, Lin RC (1985) The effect of intraluminal application of 5-hydroxytryptamine and 5-hydroxytryptophan on peristalsis; the local production of 5-HT and its release in relation to intraluminal pressure and propulsive activity. J Physiol 140:381–407

62.

Grider JR (1994) CGRP as a transmitter in the sensory pathway mediating peristaltic reflex. Am J Physiol 266:G1139–G1145PubMed

63.

Danzebrink RM, Gebhart GF (1991) Evidence that spinal 5-HT1, 5-HT2 and 5-HT3 receptor subtypes modulate responses to noxious colorectal distension in the rat. Brain Res 538:64–75PubMed

64.

Miftahof R, Akhmadeev NR (2007) Neurochemical bases of visceral nociception: mathematical model. J Theor Biol 249:343–360PubMed

65.

Almeida TF, Roizenblatt S, Tufik S (2004) Afferent pain pathways: a neuroanatomical review. Brain Res 1000:40–56PubMed

66.

Camilleri M, Coulie B, Tack JF (2001) Visceral hypersensitivity: facts, speculations, and challenges. Gut 48:125–131PubMedCentralPubMed

67.

Bueno L, Fioramonti J, Delvaux M et al (1997) Mediators and pharmacology of visceral sensitivity: from basic to clinical investigations. Gastroenterology 112:1714–1743PubMed

68.

Keszthelyi D, Troost FJ, Jonkers DM et al (2013) Decreased levels of kynurenic acid in the intestinal mucosa of IBS patients: relation to serotonin and psychological state. J Psychosom Res 74:501–504PubMed

69.

Stasi C, Bellini M, Costa F et al (2013) Neuroendocrine markers and psychological features in patients with irritable bowel syndrome. Int J Colorectal Dis 28:1203–1208PubMed

70.

Muller-Lissner SA, Bollani S, Brummer RJ et al (2001) Epidemiological aspects of irritable bowel syndrome in Europe and North America. Digestion 64:200–204PubMed

71.

Nakai A, Kumakura Y, Boivin M et al (2003) Sex differences of brain serotonin synthesis in patients with irritable bowel syndrome using alpha-[11C]methyl-L-tryptophan, positron emission tomography and statistical parametric mapping. Can J Gastroenterol 17:191–196PubMed

72.

Creed F, Fernandes L, Guthrie E et al (2003) The cost-effectiveness of psychotherapy and paroxetine for severe irritable bowel syndrome. Gastroenterology 124:303–317PubMed

73.

Creed F, Tomenson B, Guthrie E et al (2008) The relationship between somatisation and outcome in patients with severe irritable bowel syndrome. J Psychosom Res 64:613–620PubMed

74.

Mayer EA, Naliboff BD, Chang L (2001) Basic pathophysiologic mechanisms in irritable bowel syndrome. Dig Dis 19:212–218PubMed

75.

Mertz H (2002) Role of the brain and sensory pathways in gastrointestinal sensory disorders in humans. Gastroenterology 51:i29–i33

76.

Whitehead WE, Engel BT, Schuster MM (1980) Irritable bowel syndrome: physiological and psychological differences between diarrhea-predominant and constipation-predominant patients. Dig Dis Sci 25:404–413PubMed

77.

Prior A, Maxton DG, Whorwell PJ (1990) Anorectal manometry in irritable bowel syndrome: differences between diarrhoea and constipation predominant subjects. Gut 31:458–462PubMedCentralPubMed

78.

Simrén M, Abrahamsson H, Bjornsson ES (2001) An exaggerated sensory component of the gastrocolonic response in patients with irritable bowel syndrome. Gut 48:20–27PubMedCentralPubMed

79.

Slater BJ, Plusa SM, Smith AN, Varma JS (1997) Rectal hypersensitivity in the irritable bowel syndrome. Int J Colorectal Dis 12:29–32PubMed

80.

Harraf F, Schmulson M, Saba L et al (1998) Subtypes of constipation predominant irritable bowel syndrome based on rectal perception. Gut 43:388–394PubMedCentralPubMed

81.

Steens J, Van Der Schaar PJ, Penning C et al (2002) Compliance, tone and sensitivity of the rectum in different subtypes of irritable bowel syndrome. Neurogastroenterol Motil 14:241–247PubMed

82.

Drossman DA, Ringel Y, Vogt BA et al (2003) Alterations of brain activity associated with resolution of emotional distress and pain in a case of severe irritable bowel syndrome. Gastroenterology 124:754–761PubMed

83.

Baciu MV, Bonaz BL, Papillon E et al (1999) Central processing of rectal pain: a functional MR imaging study. Am J Neuroradiol 20:1920–1924PubMed

84.

Bonaz B, Baciu M, Papillon E et al (2002) Central processing of rectal pain in patients with irritable bowel syndrome: an fMRI study. Am J Gastroenterol 97:654–661PubMed

85.

Suzuki R, Rygh LJ, Dickenson AH (2004) Bad news from the brain: descending 5-HT pathways that control spinal pain processing. Trends Pharmacol Sci 25:613–617PubMed

86.

Sharma HS, Cervos-Navarro J, Dey PK (1991) Increased blood–brain barrier permeability following acute short-term swimming exercise in conscious normotensive young rats. Neurosci Res 10:211–221PubMed

87.

Oatway MA, Chen Y, Weaver LC (2004) The 5-HT3 receptor facilitates at-level mechanical allodynia following spinal cord injury. Pain 110:259–268PubMed

88.

Borman RA, Tilford NS, Harmen DW et al (2002) 5-HT(2B) receptors play a key role in mediating the excitatory effects of 5-HT in human colon in vitro. Br J Pharmacol 135:1141–1151

89.

Beattie DT, Smith JA, Marquess D et al (2004) The 5-HT4 receptor agonist, tegaserod, is a potent 5-HT2B receptor antagonist in vitro and in vivo. Br J Pharmacol 143:549–560PubMedCentralPubMed

90.

Gore S, Gilmore IT, Haigh CG et al (1990) Colonic transit in man is slowed by ondansetron (GR38032F), a selective 5-hydroxytryptamine receptor (type 3) antagonist. Aliment Pharmacol Ther 4:139–144PubMed

91.

Steadman CJ, Talley NJ, Phillips SF et al (1992) Selective 5-hydroxytryptamine type 3 receptor antagonism with ondansetron as treatment for diarrhea-predominant irritable bowel syndrome: a pilot study. Mayo Clin Proc 67:732–738PubMed

92.

Goldberg PA, Kamm MA, Setti-Carraro P et al (1996) Modification of visceral sensitivity and pain in irritable bowel syndrome by 5-HT3 antagonism (ondansetron). Digestion 57:478–483PubMed

93.

Viramontes BE, Camilleri M, McKinzie S et al (2001) Gender-related differences in slowing colonic transit by a 5-HT3 antagonist in subjects with diarrhea-predominant irritable bowel syndrome. Am J Gastroenterol 96:2671–2676PubMed

94.

Bharucha AE, Camilleri M, Haydock S et al (2000) Effects of a serotonin 5-HT(4) receptor antagonist SB-207266 on gastrointestinal motor and sensory function in humans. Gut 47:667–674PubMedCentralPubMed

95.

De Ponti F, Tonini M (2001) Irritable bowel syndrome: new agents targeting serotonin receptor subtypes. Drugs 61:317–332PubMed

96.

Camilleri M (2001) Review article: tegaserod. Aliment Pharmacol Ther 15:277–289PubMed

97.

Frampton JE (2009) Prucalopride. Drugs 69:2463–2476PubMed

98.

Kozlowski CM, Green A, Grundy D et al (2000) The 5-HT(3) receptor antagonist alosetron inhibits the colorectal distention induced depressor response and spinal c-fos expression in the anaesthetised rat. Gut 46:474–480PubMedCentralPubMed

99.

Lee KJ, Kim NY, Kwon JK et al (2011) Efficacy of ramosetron in the treatment of male patients with irritable bowel syndrome with diarrhea: a multicenter, randomized clinical trial, compared with mebeverine. Neurogastroenterol Motil 23:1098–1104PubMed

100.

Schikowski A, Thewissen M, Mathis C et al (2002) Serotonin type-4 receptors modulate the sensitivity of intramural mechanoreceptive afferents of the cat rectum. Neurogastroenterol Motil 14:221–227PubMed

101.

Evans BW, Clark WK, Moore DJ et al (2007) Tegaserod for the treatment of irritable bowel syndrome and chronic constipation. Cochrane Database Syst Rev 4:003960

102.

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

103.

Johnson DE, Drummond E, Grimwood S et al (2012) The 5-hydroxytryptamine4 receptor agonists prucalopride and PRX-03140 increase acetylcholine and histamine levels in the rat prefrontal cortex and the power of stimulated hippocampal θ oscillations. J Pharmacol Exp Ther 341:681–691PubMed

104.

Manini ML, Camilleri M, Goldberg M et al (2010) Effects of Velusetrag (TD-5108) on gastrointestinal transit and bowel function in health and pharmacokinetics in health and constipation. Neurogastroenterol Motil 22(42–49):e7–e8

105.

Hoffman JM, Tyler K, MacEachern SJ et al (2012) Activation of colonic mucosal 5-HT4 receptors accelerates propulsive motility and inhibits visceral hypersensitivity. Gastroenterology 142(844–854):e4PubMed

Title: Serotonin receptors and their role in the pathophysiology and therapy of irritable bowel syndrome
Authors: C. Stasi
M. Bellini
G. Bassotti
C. Blandizzi
S. Milani
Publication date: 01-07-2014
Publisher: Springer Milan
Published in: Techniques in Coloproctology / Issue 7/2014
Print ISSN: 1123-6337
Electronic ISSN: 1128-045X
DOI: https://doi.org/10.1007/s10151-013-1106-8

At a glance: The STEP trials

Springer Medicine

Serotonin receptors and their role in the pathophysiology and therapy of irritable bowel syndrome

Abstract

Background

Methods

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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