Physiological, Pathophysiological and Therapeutic Impact of the Enteric Serotonergic System

Abstract

Serotonin (5-hydroxytryptamine, 5-HT) induces various effects in the central nervous system, cardiovascular system and gastrointestinal tract. The response depends primarily on the nature of the 5-HT receptors involved. In the light of the current knowledge about the anatomy and physiology of the serotonergic system and the distribution of the various 5-HT receptors in the gut, the established and potential therapeutic impact of 5-HT receptor ligands are discussed. In particular, selective 5-HT receptor ligands influencing intestinal motility and pain perception such as the 5-HT₄ receptor agonist prucalopride appear promising for the treatment of irritable bowel syndrome.

Key words

serotonin - 5-HT - enteric nervous system - irritable bowel disease - 5-HT receptors

• References

• 1 Ludwig C, Schmidt A. Das Verhalten der Gase, welche mit dem Blut durch den reizbaren Säugethiermuskel strömen. Arb a d Physiol Anst z Leipzig 1868; 3: 1-61
• 2 Rapport MM, Green AA, Page IH. Serum vasoconstrictor, serotonin; isolation and characterization. In: Journal of Biological Chemistry 1948; 176: 1243-1251
• 3 Erspamer V, Vialli M. Ricerche sul secreto delle cellule enterochromaffini. Boll Soc Med Chir Pavia 1937; 51: 357-363
• 4 Erspamer V, Asero B. Identification of enteramine, the specific hormone of the enterochromaffin cell system, as 5-hydroxytryptamine. Nature 1952; 169: 800-801
• 5 Hannon J, Hoyer D. Molecular biology of 5-HT receptors. Behav Brain Res 2008; 195: 198-213
• 6 Hoyer D, Hannon JP, Martin GR. Molecular, pharmacological and functional diversity of 5-HT receptors. Pharmacol Biochem Behav 2002; 71: 533-554
• 7 Ahlmann H, Dahlström A. Storage and release of 5-hydroxytryptamine in enterochromaffin cells of the small intestine. In: De Clerck F, Vanhoutte PM. (eds.). 5-Hydroxytryptamine in peripheral reactions. Raven Press; New York: 1982: 1-9
• 8 Verbeuren TJ. Synthesis, storage, release, and metabolism of 5-hydroxytryptamine in peripheral tissues. In: Fozard JR. (ed.). The peripheral actions of 5-hydroxytryptamine. Oxford University Press; Oxford: 1989: 1-25
• 9 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
• 10 Ringvall M, Rönnberg E, Wernersson S et al. Serotonin and histamine storage in mast cell secretory granules is dependent on serglycin proteoglycan. J Allergy Clin Immunol 2008; 121: 1020-1026
• 11 Kanerva K, Lappalainen J, Mäkitie LT et al. Expression of antizyme inhibitor 2 in mast cells and role of polyamines as selective regulators of serotonin secretion. PLoS One 2009; 4: e6858
• 12 Törk I. Anatomy of the serotonergic system. Ann N Y Acad Sci 1990; 600: 9-34
• 13 Mercado CP, Kilic F. Molecular mechanisms of SERT in platelets: regulation of plasma serotonin levels. Mol Interv 2010; 10: 231-241
• 14 Tyce GM. Origin and metabolism of serotonin. J Cardiovasc Pharmacol 1990; 16 (Suppl. 03) S1-S7
• 15 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
• 16 Murphy DL, Lerner A, Rudnick G et al. Serotonin transporter: gene, genetic disorders, and pharmacogenetics. Mol Interv 2004; 4: 109-123
• 17 Gershon MD, Tack J. The serotonin signaling system: from basic understanding to drug development for functional GI disorders. Gastroenterology 2007; 132: 397-414
• 18 Liddle RA. Gastrointestinal hormones and neurotransmitters. In: Sleisenger and Fordtran’s Gastrointestinal and Liver Disease. Brandt LJ, Friedmann LS, Feldman M. (eds.). Elsevier LTD; Oxford UK: 8^th edition 2006. 1. 3-25
• 19 Molderings GJ. Mast cell function in physiology and pathophysiology. BIOTREND Rev 2010; 5: 1-9
• 20 Furness JB, Costa M. Neurons with 5-hydroxytryptamine-like immunoreactivity in the enteric nervous system: their projections in the guinea pig small intestine. Neuroscience 1982; 7: 341-350
• 21 Costa M, Furness JB, Cuello AC et al. Neurons with 5-hydroxytryptamine-like immunoreactivity in the enteric nervous system: their visualization and reactions to drug treatment. Neuroscience 1982; 7: 351-363
• 22 Gershon MD. Nerves, reflexes, and the enteric nervous system: pathogenesis of the irritable bowel syndrome. J Clin Gastroenterol 2005; 39: S184-S193
• 23 Racké K, Schwörer H, Kilbinger H. Adrenergic modulation of the release of 5-hydroxytryptamine from the vascularly perfused ileum of the guinea-pig. Br J Pharmacol 1988; 95: 923-931
• 24 Kirchgessner AL, Liu MT, Howard MJ et al. Detection of the 5-HT_1A receptor and 5-HT_1A receptor mRNA in the rat bowel and pancreas: comparison with 5-HT_1P receptors. J Comp Neurol 1993; 327: 233-250
• 25 Kirchgessner AL, Liu MT, Raymond JR et al. Identification of cells that express 5-hydroxytryptamine_1A receptors in the nervous systems of the bowel and pancreas. J Comp Neurol 1996; 364: 439-455
• 26 Galligan JJ. Electrophysiological studies of 5-hydroxytryptamine receptors on enteric neurons. Behav Brain Res 1996; 73: 199-201
• 27 Pan H, Galligan JJ. 5-HT_1A and 5-HT₄ receptors mediate inhibition and facilitation of fast synaptic transmission in enteric neurons. Am J Physiol 1994; 266: G230-G238
• 28 Boeckxstaens GE, Tytgat GN, Wajs E et al. The influence of the novel 5-HT_1A agonist R137696 on the proximal stomach function in healthy volunteers. Neurogastroenterol Motil 2006; 18: 919-926
• 29 Alfieri AB, Cubeddu LX. Comparative efficacy of a single oral dose of ondansetron and of buspirone against cisplatin-induced emesis in cancer patients. Br J Cancer 1995; 72: 1013-1015
• 30 Chial HJ, Camilleri M, Burton D et al. Selective effects of serotonergic psychoactive agents on gastrointestinal functions in health. Am J Physiol 2003; 284: G130-G137
• 31 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
• 32 Pierce PA, Xie GX, Levine JD et al. 5-Hydroxytryptamine receptor subtype messenger RNAs in rat peripheral sensory and sympathetic ganglia: a polymerase chain reaction study. Neuroscience 1996; 70: 553-559
• 33 Pierce PA, Xie GX, Meuser T et al. 5-Hydroxytryptamine receptor subtype messenger RNAs in human dorsal root ganglia: a polymerase chain reaction study. Neuroscience 1997; 81: 813-819
• 34 Coulie B, Tack J, Maes B et al. 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
• 35 Coulie B, Tack J, Sifrim D et al. Role of nitric oxide in fasting gastric fundus tone and in 5-HT₁ receptor-mediated relaxation of gastric fundus. Am J Physiol 1999; 276: G373-G377
• 36 Sifrim D, Holloway RH, Tack J et al. Effect of sumatriptan, a 5-HT₁ agonist, on the frequency of transient lower esophageal sphincter relaxations and gastroesophageal reflux in healthy subjects. Am J Gastroenterol 1999; 94: 3158-3164
• 37 Tack J, Coulie B, Wilmer A et al. Influence of sumatriptan on gastric fundus tone and on the perception of gastric distension in man. Gut 2000; 46: 468-473
• 38 Calvert EL, Whorwell PJ, Houghton LA. Inter-digestive and post-prandial antro-pyloro-duodenal motor activity in humans: effect of 5-hydroxytryptamine agonism. Aliment Pharmacol Ther 2004; 19: 805-815
• 39 Borman RA, Burleigh DE. 5-HT_1D and 5-HT_2B receptors mediate contraction of smooth muscle in human small intestine. Ann NY Acad Sci 1997; 812: 222-223
• 40 Adham N, Kao HT, Schechter LE et al. Cloning of another human serotonin receptor (5-HT_1F): a fifth 5-HT₁ receptor subtype coupled to the inhibition of adenylate cyclase. Proc Natl Acad Sci USA 1993; 90: 408-412
• 41 Barnes NM, Sharp T. A review of central 5-HT receptors and their function. Neuropharmacology 1999; 38: 1083-1152
• 42 Janssen P, Tack J, Sifrim D et al. Influence of 5-HT₁ receptor agonists on feline stomach relaxation. Eur J Pharmacol 2004; 492: 259-267
• 43 Liu M, Gershon MD. Slow excitatory (‘5-HT_1P’-like) responses of mouse myenteric neurons to 5-HT: mediation by heterodimers of 5-HT_1B/1D and Drd2 receptors. Gastroenterology 2005; 128 (Suppl. 02) A87
• 44 Monro RL, Bornstein JC, Bertrand PP. Slow excitatory postsynaptic potentials in myenteric AH neurons of the guinea pig ileum are reduced by the 5-hydroxytryptamine(7) receptor antagonist SB 269970. Neuroscience 2005; 134: 975-986
• 45 Tonini M. 5-Hydroxytryptamine effects in the gut: the 3, 4, and 7 receptors. Neurogastroenterol Motil 2005; 17: 637-642
• 46 Branchek TA, Mawe GM, Gershon MD. Characterization and localization of a peripheral neural 5-hydroxytryptamine receptor subtype (5-HT_1P) with a selective agonist, ³H-5-hydroxyindalpine. J Neurosci 1988; 8: 2582-2595
• 47 Fiorica-Howells E, Hen R, Gingrich J et al. 5-HT_2A receptors: location and functional analysis in intestines of wild-type and 5-HT_2A knockout mice. Am J Physiol 2002; 282: G877-G893
• 48 Leysen JE. 5-HT₂ receptors. Curr Drug Target CNS Neurol Disord 2004; 3: 11-26
• 49 Bonaventure P, Nepomuceno D, Miller K et al. Molecular and pharmacological characterization of serotonin 5-HT_2A and 5-HT_2B receptor subtypes in dogs. Eur J Pharmacol 2005; 513: 181-192
• 50 Borman RA, Burleigh DE. Human colonic mucosa possesses a mixed population of 5-HT receptors. Eur J Pharmacol 1996; 309: 271-274
• 51 Hansen MB, Skadhauge E. Signal transduction pathways for serotonin as an intestinal secretagogue. Comp Biochem Physiol A Physiol 1997; 118: 283-290
• 52 Imada-Shirakata Y, Kotera T, Ueda S et al. Serotonin activates electrolyte transport via 5-HT_2A receptor in rat colonic crypt cells. Biochem Biophys Res Commun 1997; 230: 437-441
• 53 Kuemmerle JF, Murthy KS, Grider JR et al. Coexpression of 5-HT_2A and 5-HT₄ receptors coupled to distinct signaling pathways in human intestinal muscle cells. Gastroenterology 1995; 109: 1791-1800
• 54 Borman RA, Tilford NS, Harmer DW et al. 5-HT_2B receptors play a key role in mediating the excitatory effects of 5-HT in human colon in vitro. Br J Pharmacol 2002; 135: 1144-1151
• 55 Wouters MM, Farrugia G, Schemann M. 5-HT receptors on interstitial cells of Cajal, smooth muscle and enteric nerves. Neurogastroenterol Motil 2007; 19 (Suppl. 02) 5-12
• 56 Wouters MM, Gibbons SJ, Roeder JL et al. Exogenous serotonin regulates proliferation of interstitial cells of Cajal in mouse jejunum through 5-HT_2B receptors. Gastroenterology 2007; 133: 897-906
• 57 Gershon MD. 5-HT (serotonin) physiology and related drugs. Curr Opin Gastroenterol 2000; 16: 113-120
• 58 Borman RA, Burleigh DE. Functional evidence for a 5-HT_2B receptor mediating contraction of longitudinal muscle in human small intestine. Br J Pharmacol 1995; 114: 1525-1527
• 59 Hofmann C, Penner U, Dorow R et al. Lisuride a dopamine receptor agonist with 5-HT_2B receptor antagonist properties: absence of cardiac valvulopathy adverse drug reaction reports supports the concept of a crucial role for 5-HT_2B receptor agonism in cardiac valvular fibrosis. Clin Neuropharmacol 2002; 29: 80-86
• 60 Horowski R, Jahnichen S, Pertz HH. Fibrotic valvular heart disease is not related to chemical class but to biological function: 5-HT_2B receptor activation plays crucial role. Mov Disord 2004; 19: 1523-1524
• 61 Niesler B, Frank B, Kapeller J et al. Cloning, physical mapping and expression analysis of the human 5-HT3 serotonin receptor-like genes HTR3C, HTR3D and HTR3E. Gene 2003; 310: 101-111
• 62 Kapeller J, Möller D, Lasitschka F et al. Serotonin receptor diversity in the human colon: Expression of serotonin type 3 receptor subunits 5-HT_3C, 5-HT_3D, and 5-HT_3E . J Comp Neurol 2011; 519: 420-432
• 63 Glatzle J, Sternini C, Robin C et al. Expression of 5-HT₃ receptors in the rat gastrointestinal tract. Gastroenterology 2002; 123: 217-226
• 64 Raybould HE, Glatzle J, Robin C et al. Expression of 5-HT₃ receptors by extrinsic duodenal afferents contribute to intestinal inhibition of gastric emptying. Am J Physiol 2003; 284: G367-G372
• 65 Bertrand PP, Kunze WA, Furness JB et al. The terminals of myenteric intrinsic primary afferent neurons of the guinea-pig ileum are excited by 5-hydroxytryptamine acting at 5-hydroxytryptamine-3 receptors. Neuroscience 2000; 101: 459-469
• 66 Liu HN, Ohya S, Nishizawa Y et al. Serotonin augments gut pacemaker activity via 5-HT₃ receptors. PLoS One 2011; 6: e24928
• 67 Schworer H, Ramadori G. Autoreceptors can modulate 5-hydroxytryptamine release from porcine and human small intestine in vitro. Naunyn-Schmiedeberg’s Arch Pharmacol 1998; 357: 548-552
• 68 Roila F, Fatigoni S. New antiemetic drugs. Ann Oncol 2006; 17 (Suppl. 02) 96-100
• 69 Gore S, Gilmore IT, Haigh CG et al. Colonic transit in man is slowed by ondansetron (GR38032F), a selective 5-hydroxytryptamine receptor (type 3) antagonist. Aliment Pharmacol Ther 1990; 4: 139-144
• 70 Houghton LA, Foster JM, Whorwell PJ. Alosetron, a 5-HT₃ receptor antagonist, delays colonic transit in patients with irritable bowel syndrome and healthy volunteers. Aliment Pharmacol Ther 2000; 14: 775-782
• 71 Stacher G, Weber U, Stacher-Janotta G et al. Effects of the 5-HT₃ antagonist cilansetron vs placebo on phasic sigmoid colonic motility in healthy man: a double-blind crossover trial. Br J Clin Pharmacol 2000; 49: 429-436
• 72 Clemens CHM, Samson M, Van Berge Henegouwen GP et al. Effect of alosetron on left colonic motility in non-constipated patients with irritable bowel syndrome and healthy volunteers. Aliment Pharmacol Ther 2002; 16: 993-1002
• 73 Kuo B, Camilleri M, Burton D et al. Effects of 5-HT₃ antagonism on postprandial gastric volume and symptoms in humans. Aliment Pharmacol Ther 2002; 16: 225-233
• 74 Medhurst AD, Lezoualch F, Fischmeister R et al. Quantitative mRNA analysis of five C-terminal splice variants of the human 5-HT₄ receptor in the central nervous system by TaqMan real time RT-PCR. Brain Res Mol Brain Res 2001; 90: 125-134
• 75 Vilaro MT, Domenech T, Palacios JM et al. Cloning and characterization of a novel human 5-HT₄ receptor variant that lacks the alternatively spliced carboxy terminal exon. RT-PCR distribution in human brain and periphery of multiple 5-HT₄ receptor variants. Neuropharmacology 2002; 42: 60-73
• 76 Brattelid T, Kvingedal AM, Krobert KA et al. Cloning, pharmacological characterisation and tissue distribution of a novel 5-HT₄ receptor splice variant, 5-HT_4(i) . Naunyn Schmiedeberg’s Arch Pharmacol 2004; 369: 616-628
• 77 Claeysen S, Sebben M, Becamel C et al. Novel brain-specific 5-HT₄ receptor splice variants show marked constitutive activity: role of the C-terminal intracellular domain. Mol Pharmacol 1999; 55: 910-920
• 78 Bender E, Pindon A, Van Oers I et al. Structure of the human serotonin 5-HT₄ receptor gene and cloning of a novel 5-HT₄ splice variant. J Neurochem 2000; 74: 478-489
• 79 Pindon A, Van Hecke G, Van Gompel P et al. Differences in signal transduction of two 5-HT₄ receptor splice variants: compound specificity and dual coupling with Galphas- and Galphai/o-proteins. Mol Pharmacol 2002; 61: 85-96
• 80 Ponimaskin EG, Heine M, Joubert L et al. The 5-hydroxytryptamine_4a receptor is palmitoylated at two different sites, and acylation is critically involved in regulation of receptor constitutive activity. J Biol Chem 2002; 277: 2534-2546
• 81 Mialet J, Fischmeister R, Lezoualch F. Characterization of human 5-HT_4d receptor desensitization in CHO cells. Br J Pharmacol 2003; 138: 445-452
• 82 Castro L, Mialet-Perez J, Guillemeau A et al. Differential functional effects of two 5-HT₄ receptor isoforms in adult cardiomyocytes. J Mol Cell Cardiol 2005; 39: 335-344
• 83 Grider JR. Neurotransmitters mediating the intestinal peristaltic reflex in the mouse. J Pharmacol Exp Ther 2003; 307: 460-467
• 84 Pan H, Gershon MD. Activation of intrinsic afferent pathways in submucosal ganglia of the guinea pig small intestine. J Neurosci 2000; 20: 3295-3309
• 85 Galligan JJ, Pan H, Messori E. Signalling mechanism coupled to 5-hydroxytryptamine₄ receptor-mediated facilitation of fast synaptic transmission in the guinea pig ileum myenteric plexus. Neurogastroenterol Motil 2003; 15: 523-529
• 86 Tam FS, Hillier K, Bunce KT. Characterization of the 5-hydroxytryptamine receptor type involved in inhibition of spontaneous activity of human isolated colonic circular muscle. Br J Pharmacol 1994; 113: 143-150
• 87 Borman RA, Burleigh DE. Heterogeneity of 5-HT receptors mediating secretion in the human intestine. Ann NY Acad Sci 1997; 812: 224-225
• 88 Emmanuel AV, Kamm MA, Roy AJ et al. Effect of a novel prokinetic drug, R093877, on gastrointestinal transit in healthy volunteers. Gut 1998; 42: 511-516
• 89 Bouras EP, Camilleri M, Burton DD et al. Selective stimulation of colonic transit by the benzofuran 5HT₄ agonist, prucalopride, in healthy humans. Gut 1999; 44: 682-686
• 90 Poen AC, Felt-Bersma RJF, Van Dongen PAM et al. Effect of prucalopride, a new enterokinetic agent, on gastrointestinal transit and anorectal function in healthy volunteers. Aliment Pharmacol Ther 1999; 13: 1493-1497
• 91 Degen L, Matzinger D, Merz M et al. Tegaserod, a 5-HT₄ receptor partial agonist, accelerates gastric emptying and gastrointestinal transit in healthy male subjects. Aliment Pharmacol Ther 2001; 15: 1745-1751
• 92 Coffin B, Farmachidi JP, Rueegg P et al. Tegaserod, a 5-HT₄ receptor partial agonist, decreases sensitivity to rectal distension in healthy subjects. Aliment Pharmacol Ther 2003; 17: 577-585
• 93 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
• 94 Manini ML, Camilleri M, Goldberg M et al. Effects of Velusetrag (TD-5108) on gastrointestinal transit and bowel function in health and pharmacokinetics in health and constipation. Neurogastroenterol Motil 2010; 22: 42-49
• 95 Muller-Lissner SA. Treatment of chronic constipation with cisapride and placebo. Gut 1987; 28: 1033-1038
• 96 Abell TL, Camilleri M, DiMagno EP et al. Long-term efficacy of oral cisapride in symptomatic upper gut dysmotility. Dig Dis Sci 1991; 36: 616-620
• 97 Prather CM, Camilleri M, Zinsmeister AR et al. Tegaserod accelerates orocecal transit in patients with constipation-predominant irritable bowel syndrome. Gastroenterology 2000; 118: 462-468
• 98 Camilleri M. Review article: tegaserod. Aliment Pharmacol Ther 2001; 15: 277-289
• 99 Deruyttere M, Lepoutre L, Heylen H et al. Cisapride in the management of chronic functional dyspepsia: a multicenter, double-blind, placebo-controlled study. Clin Ther 1987; 10: 44-51
• 100 Emmanuel AV, Roy AJ, Nicholls TJ et al. Prucalopride, a systemic enterokinetic, for the treatment of constipation. Aliment Pharmacol Ther 2002; 16: 1347-1356
• 101 Sloots CE, Poen AC, Kerstens R et al. Effects of prucalopride on colonic transit, anorectal function and bowel habits in patients with chronic constipation. Aliment Pharmacol Ther 2002; 16: 759-767
• 102 Camilleri M, McKinzie S, Fox J et al. Effect of renzapride on transit in constipation-predominant irritable bowel syndrome. Clin Gastroenterol Hepatol 2004; 2: 895-904
• 103 Johanson JF. Review article: tegaserod for chronic constipation. Aliment Pharmacol Ther 2004; 20 (Suppl. 07) 20-24
• 104 Rodriguez-Stanley S, Zubaidi S, Proskin HM et al. Effect of tegaserod on esophageal pain threshold, regurgitation, and symptom relief in patients with functional heartburn and mechanical sensitivity. Clin Gastroenterol Hepatol 2006; 4: 442-450
• 105 Ruth M, Hamelin B, Rohss K et al. The effect of mosapride, a novel prokinetic, on acid reflux variables in patients with gastro-oesophageal reflux disease. Aliment Pharmacol Ther 1998; 12: 35-40
• 106 Kahrilas PJ, Quigley EM, Castell DO et al. The effects of tegaserod (HTF 919) on oesophageal acid exposure in gastrooesophageal reflux disease. Aliment Pharmacol Ther 2000; 14: 1503-1509
• 107 Finizia C, Lundell L, Cange L et al. The effect of cisapride on oesophageal motility and lower sphincter function in patients with gastro-oesophageal reflux disease. Eur J Gastroenterol Hepatol 2002; 14: 9-14
• 108 Fox M, Menne D, Stutz B et al. The effects of tegaserod on oesophageal function and bolus transport in healthy volunteers: studies using concurrent high-resolution manometry and videofluoroscopy. Aliment Pharmacol Ther 2006; 24: 1017-1027
• 109 Tutuian R, Mainie I, Allan R et al. Effects of a 5-HT₄ receptor agonist on oesophageal function and gastro-oesophageal reflux: studies using combined impedance-manometry and combined impedance-pH. Aliment Pharmacol Ther 2006; 24: 155-162
• 110 Mackie AD, Ferrington C, Cowan S et al. The effects of renzapride, a novel prokinetic agent, in diabetic gastroparesis. Aliment Pharmacol Ther 1991; 5: 135-142
• 111 Banh HL, MacLean C, Topp T et al. The use of tegaserod in critically ill patients with impaired gastric motility. Clin Pharmacol Ther 2005; 77: 583-586
• 112 Zuberi BF, Quraishy MS, Faisal N et al. Idiopathic gastroparesis. J Coll Physicians Surgeons Pakistan 2005; 15: 566-577
• 113 Friedenberg FK, Parkman HP. Delayed gastric emptying: whom to test, how to test, and what to do. Curr Treat Options Gastroenterol 2006; 9: 295-304
• 114 Thumshirn M, Fruehauf H, Stutz B et al. Clinical trial: effects of tegaserod on gastric motor and sensory function in patients with functional dyspepsia. Aliment Pharmacol Ther 2007; 26: 1399-1407
• 115 Tack J, Janssen P, Bisschops R et al. Influence of tegaserod on proximal gastric tone and on the perception of gastric distention in functional dyspepsia. Neurogastroenterol Motil 2011; 23: e32-e39
• 116 Bharucha AE, Camilleri M, Haydock S et al. Effects of a serotonin 5-HT₄ receptor antagonist SB-207266 on gastrointestinal motor and sensory function in humans. Gut 2000; 47: 667-674
• 117 De Ponti F, Tonini M. Irritable bowel syndrome: new agents targeting serotonin receptor subtypes. Drugs 2001; 61: 317-332
• 118 Mitchell ES, Neumaier JF. 5-HT₆ receptors: a novel target for cognitive enhancement. Pharmacol Ther 2005; 108: 320-333
• 119 Ruat M, Traiffort E, Arrang JM et al. A novel rat serotonin (5-HT₆) receptor: molecular cloning, localization and stimulation of cAMP accumulation. Biochem Biophys Res Commun 1993; 193: 268-276
• 120 Irving HR, Tan YY, Tochon-Danguy N et al. Comparison of 5-HT₄ and 5- HT₇ receptor expression and function in the circular muscle of the human colon. Life Sci 2007; 80: 1198-1205
• 121 Jasper JR, Kosaka A, To ZP et al. Cloning, expression and pharmacology of a truncated splice variant of the human 5-HT₇ receptor (h5-HT7b). Br J Pharmacol 1997; 122: 126-132
• 122 Krobert KA, Bach T, Syversveen T et al. The cloned human 5-HT₇ receptor splice variants: a comparative characterization of their pharmacology, function and distribution. Naunyn-Schmiedeberg’s Arch Pharmacol 2001; 363: 620-632
• 123 Carter D, Champney M, Hwang B et al. Characterization of a postjunctional 5-HT receptor mediating relaxation of guinea pig isolated ileum. Eur J Pharmacol 1995; 280: 243-250
• 124 Prins NH, Briejer MR, Van Bergen PJ et al. Evidence for 5-HT₇ receptors mediating relaxation of human colonic circular smooth muscle. Br J Pharmacol 1999; 128: 849-852
• 125 Meier Y, Eloranta JJ, Darimont J et al. Regional distribution of solute carrier mRNA expression along the human intestinal tract. Drug Metab Dispos 2007; 35: 590-594
• 126 Van Lelyveld N, Ter Linde J, Schipper ME et al. Regional differences in expression of TPH-1, SERT, 5-HT₃ and 5-HT₄ receptors in the human stomach and duodenum. Neurogastroenterol Motil 2007; 19: 342-348
• 127 Gill RK, Pant N, Saksena S et al. Function, expression, and characterization of the serotonin transporter in the native human intestine. Am J Physiol Gastrointest Liver Physiol 2008; 294: G254-G262
• 128 Li ZS, Pham TD, Tamir H et al. Enteric dopaminergic neurons: definition, developmental lineage, and effects of extrinsic denervation. J Neurosci 2004; 24: 1330-1339
• 129 Fuller RW, Wong DT. Serotonin uptake and serotonin uptake inhibition. Ann N Y Acad Sci 1990; 600: 68-80
• 130 Gorard DA, Libby GW, Farthing MJ. Effect of a tricyclic antidepressant on small intestinal motility in health and diarrhea-predominant irritable bowel syndrome. Dig Dis Sci 1995; 40: 86-95
• 131 Chen JX, Pan H, Rowbotham TP et al. Guinea pig 5-HT transporter: cloning, expression, distribution and function in intestinal sensory reception. Am J Physiol 1998; 275: G433-G448
• 132 Spigset O. Adverse reactions of selective reuptake inhibitors: reports from a spontaneous reporting system. Drug Saf 1999; 20: 277-287
• 133 Vanner SJ, Depew WT, Paterson WG et al. Predictive value of the Rome criteria for diagnosing the irritable bowel syndrome. Am J Gastroenterol 1999; 94: 2912-2917
• 134 Ohman L, Simrén M. Pathogenesis of IBS: role of inflammation, immunity and neuroimmune interactions. Nat Rev Gastroenterol Hepatol 2010; 7: 163-173
• 135 El-Salhy M, Gundersen D, Ostgaard H et al. Low Densities of serotonin and peptide YY cells in the colon of patients with irritable bowel syndrome. Dig Dis Sci 2011; in press
• 136 Coates MD, Mahoney CR, Linden DR et al. Molecular defects in mucosal serotonin content and decreased serotonin reuptake transporter in ulcerative colitis and irritable bowel syndrome. Gastroenterology 2004; 126: 1657-1664
• 137 Dunlop SP, Coleman NS, Blackshaw E et al. Abnormalities of 5-hydroxytryptamine metabolism in irritable bowel syndrome. Clin Gastroenterol Hepatol 2005; 3: 349-357
• 138 Atkinson W, Lockhart S, Whorwell PJ et al. Altered 5-hydroxytryptamine signaling in patients with constipation- and diarrhea-predominant irritable bowel syndrome. Gastroenterology 2006; 130: 34-43
• 139 Bearcroft CP, Perrett D, Farthing MJ. Postprandial plasma 5-hydroxytryptamine in diarrhoea predominant irritable bowel syndrome: a pilot study. Gut 1998; 42: 42-46
• 140 Houghton LA, Atkinson W, Whitaker RP et al. 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
• 141 Cremon C, Carini G, Wang B et al. Intestinal serotonin release, sensory neuron activation, and abdominal pain in irritable bowel syndrome. Am J Gastroenterol 2011; 106: 1290-1298
• 142 Buhner S, Li Q, Vignali S et al. Activation of human enteric neurons by supernatants of colonic biopsy specimens from patients with irritable bowel syndrome. Gastroenterology 2009; 137: 1425-1434
• 143 Frieling T, Meis K, Kolck UW et al. Evidence for mast cell activation in patients with therapy-resistant irritable bowel syndrome. Z Gastroenterol 2011; 49: 191-194
• 144 Santos J, Alonso C, Guilarte M et al. Targeting mast cells in the treatment of functional gastrointestinal disorders. Curr Opin Pharmacol 2006; 6: 541-546
• 145 Klooker TK, Braak B, Koopman KE et al. The mast cell stabiliser ketotifen decreases visceral hypersensitivity and improves intestinal symptoms in patients with irritable bowel syndrome. Gut 2010; 59: 1213-1221
• 146 Markoutsaki T, Karantanos T, Gazouli M et al. 5-HT2A receptor gene polymorphisms and irritable bowel syndrome. J Clin Gastroenterol 2011; 45: 514-517
• 147 Kapeller J, Houghton LA, Monnikes H et al. First evidence for an association of a functional variant in the microRNA-510 target site of the serotonin receptor-type 3E gene with diarrhea predominant irritable bowel syndrome. Hum Mol Genet 2008; 17: 2967-2977
• 148 Niesler B. 5-HT(3) receptors: potential of individual isoforms for personalised therapy. Curr Opin Pharmacol 2011; 11: 81-86
• 149 Moss HE, Sanger GJ. The effects of granisetron, ICS 205-930 and ondansetron on the visceral pain reflex induced by duodenal distension. Br J Pharmacol 1990; 100: 497-501
• 150 Prior A, Read NW. Reduction of rectal sensitivity and post-prandial motility by granisetron, a 5-HT₃-receptor antagonist, in patients with irritable bowel syndrome. Aliment Pharmacol Ther 1993; 7: 175-180
• 151 Hammer J, Phillips SF, Talley NJ et al. Effect of a 5HT₃-antagonist (ondansetron) on rectal sensitivity and compliance in health and the irritable bowel syndrome. Aliment Pharmacol Ther 1993; 7: 543-551
• 152 Zerbib F, Bruley des Varannes S, Oriola RC et al. Alosetron does not affect the visceral perception of gastric distension in healthy subjects. Aliment Pharmacol Ther 1994; 8: 403-407
• 153 Zighelboim J, Talley NJ, Phillips SF et al. Visceral perception in irritable bowel syndrome. Rectal and gastric responses to distension and serotonin type 3 antagonism. Dig Dis Sci 1995; 40: 819-827
• 154 Delvaux M, Louvel D, Mamet JP et al. Effect of alosetron on responses to colonic distension in patients with irritable bowel syndrome. Aliment Pharmacol Ther 1998; 12: 849-855
• 155 Klatt S, Bock W, Rentschler J et al. Effects of tropisetron, a 5-HT₃ receptor antagonist, on proximal gastric motor and sensory function in nonulcer dyspepsia. Digestion 1999; 60: 147-152
• 156 Ladabaum U, Brown MB, Pan W et al. Effects of nutrients and serotonin 5-HT₃ antagonism on symptoms evoked by distal gastric distension in humans. Am J Physiol Gastrointest Liver Physiol 2001; 280: G201-G208
• 157 von der Ohe MR, Hanson RB, Camilleri M. Serotonergic mediation of postprandial colonic tonic and phasic responses in humans. Gut 1994; 35: 536-541
• 158 Maxton DG, Morris J, Whorwell PJ. Selective 5-hydroxytryptamine antagonism: a role in irritable bowel syndrome and functional dyspepsia?. Aliment Pharmacol Ther 1996; 10: 595-599
• 159 Andresen V, Montori VM, Keller J et al. Effects of 5-hydroxytryptamine (serotonin) type 3 antagonists on symptom relief and constipation in nonconstipated irritable bowel syndrome: a systematic review and meta-analysis of randomized controlled trials. Clin Gastroenterol Hepatol 2008; 6: 545-555
• 160 Lewis JH. The risk of ischaemic colitis in irritable bowel syndrome patients treated with serotonergic therapies. Drug Saf 2011; 34: 545-565
• 161 Kellow J, Lee OY, Chang FY et al. An Asia-Pacific, double blind, placebo controlled, randomised study to evaluate the efficacy, safety, and tolerability of tegaserod in patients with irritable bowel syndrome. Gut 2003; 52: 671-676
• 162 Barbey JT, Lazzara R, Zipes DP. Spontaneous adverse event reports of serious ventricular arrhythmias, QT prolongation, syncope, and sudden death in patients treated with cisapride. J Cardiovasc Pharmacol Ther 7: 65-76
• 163 Pasricha PJ. Desperately seeking serotonin…A commentary on the withdrawal of tegaserod and the state of drug development for functional and motility disorders. Gastroenterology 2007; 132: 2287-2290
• 164 Bouras EP, Camilleri M, Burton DD et al. Prucalopride accelerates gastrointestinal and colonic transit in patients with constipation without a rectal evacuation disorder. Gastroenterology 2001; 120: 354-360
• 165 Coremans G, Kerstens R, De Pauw M et al. Prucalopride is effective in patients with severe chronic constipation in whom laxatives fail to provide adequate relief. Results of a doubleblind, placebo-controlled clinical trial. Digestion 2003; 67: 82-89
• 166 Frampton JE. Prucalopride. Drugs 2009; 69: 2463-2476
• 167 Camilleri M, Kerstens R, Rykx A et al. A placebo-controlled trial of prucalopride for severe chronic constipation. N Engl J Med 2008; 358: 2344-2354
• 168 Quigley EM, Vandeplassche L, Kerstens R et al. Clinical trial: the efficacy, impact on quality of life, and safety and tolerability of prucalopride in severe chronic constipation – a 12-week, randomized, double-blind, placebo-controlled study. Aliment Pharmacol Ther 2009; 29: 315-328
• 169 Tack J, van Outryve M, Beyens G et al. Prucalopride (Resolor) in the treatment of severe chronic constipation in patients dissatisfied with laxatives. Gut 2009; 58: 357-365
• 170 Petersen KU. Prucaloprid: Optimierung eines Wirkprinzips. Verdauungskrankheiten 2010; 28: 266-272
• 171 Pau D, Workman AJ, Kane KA et al. Electrophysiological effects of prucalopride, a novel enterokinetic agent, on isolated atrial myocytes from patients treated with beta-adrenoceptor antagonists. J Pharmacol Exp Ther 2005; 313: 146-153
• 172 Kaumann AJ, Lynham JA, Brown AM. Comparison of the densities of 5-HT₄ receptors, ß₁- and ß₂-adrenoceptors in human atrium: functional implications. Naunyn- Schmiedebergs Arch Pharmacol 1996; 353: 592-595
• 173 Mialet J, Berque-Bestel I, Eftekhari P et al. Isolation of the serotoninergic 5-HT_4e receptor from human heart and comparative analysis of its pharmacological profile in C6-glial and CHO cell lines. Br J Pharmacol 2000; 129: 771-781
• 174 Markoutsaki T, Karantanos T, Gazouli M et al. Serotonin transporter and g protein Beta 3 subunit gene polymorphisms in greeks with irritable bowel syndrome. Dig Dis Sci 2011; 56: 3276-3280
• 175 Colucci R, Blandizzi C, Bellini M et al. The genetics of the serotonin transporter and irritable bowel syndrome. Trends Mol Med 2008; 14: 295-304
• 176 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
• 177 Camilleri M, Andrews CN, Bharucha AE et al. Alterations in expression of p11 and SERT in mucosal biopsy specimens of patients with irritable bowel syndrome. Gastroenterology 2007; 132: 17-25
• 178 Kerckhoffs AP, Ter Linde JJ, Akkermans LM et al. Trypsinogen IV, serotonin transporter transcript levels and serotonin content are increased in small intestine of irritable bowel syndrome patients. Neurogastroenterol Motil 2008; 20: 900-907
• 179 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
• 180 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
• 181 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
• 182 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
• 183 Masand PS, Gupta S, Schwartz TL et al. Open-label treatment with citalopram in patients with irritable bowel syndrome: a pilot study. Prim Care Companion J Clin Psychiatry 2005; 7: 162-166
• 184 Vahedi H, Merat S, Rashidioon A et al. The effect of fluoxetine in patients with pain and constipation-predominant irritable bowel syndrome: a double-blind randomized-controlled study. Aliment Pharmacol Ther 2005; 22: 381-385
• 185 Tack J, Broekaert D, Corsetti M et al. Influence of acute serotonin reuptake inhibition on colonic sensorimotor function in man. Aliment Pharmacol Ther 2006; 23: 265-274