Review
The neuronal 5-HT3 receptor network after 20 years of research — Evolving concepts in management of pain and inflammation

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Abstract

The 5-HT3 receptor is a pentameric ligand-gated cation channel which is found in the central and peripheral nervous system and on extraneuronal locations like lymphocytes, monocytes and fetal tissue. Five monomer subtypes, the 5-HT3A–E subunits, have been identified which show differences in the amino-terminal and the transmembrane region. The functional relevance of different receptor compositions is not yet clarified. 5-HT3 receptors are located predominantly in CNS regions that are involved in the integration of the vomiting reflex, pain processing, the reward system and anxiety control. The preferential localization on nerve endings is consistent with a physiological role of 5-HT3 receptors in the control of neurotransmitter release such as dopamine, cholecystokinin, glutamate, acetylcholine, GABA, substance P, or serotonin itself. 5-HT3-receptor agonists cause unpleasant effects like nausea and anxiety, and no clinical use has been considered. In contrast, the introduction of 5-HT3-receptor antagonists for chemotherapy-induced vomiting was extremely successful. After development of other gastrointestinal indications like postoperative vomiting and diarrhea-predominant irritable bowel syndrome recent research focuses on rheumatological indications such as fibromyalgia, rheumatoid arthritis and tendinopathies. Positive effects have also been observed for pain syndromes such as chronic neuropathic pain and migraine. These effects seem to be related to substance P-mediated inflammation and hyperalgesia. Furthermore, antiinflammatory and immunomodulatory properties have been observed for 5-HT3-receptor antagonists which might explain promising findings in systemic sclerosis and other immunological conditions. For all of these innovative indications the optimal dosing schedule is a crucial issue, since a bell-shaped dose–response curve has been observed repeatedly for 5-HT3-receptor antagonists, particularly in CNS effects.

Introduction

20 years after the first characterization of a so-called selective 5-HT3-antagonist the time has come to re-examine the acknowledged concepts and rate critically new perspectives for this compound class.

In the early 1990s the introduction of 5-HT3-receptor antagonists into the market was perceived as a tremendous step forward to combat chemotherapy-induced emesis. This great success transiently dampened the attention to other treatment areas like psychiatric diseases and pain management where clinical development of these compounds originally had started. During the last years researchers increasingly turned back to the beginnings, encouraged by promising results in challenging indications like fibromyalgia and irritable bowel syndrome.

This review focuses on recent investigations on the pharmacology of the 5-HT3 receptor with its embedding in a complex neurotransmitter network and the recently emerging promising indications for 5-HT3-receptor antagonists.

Section snippets

Structure

Among the seven known classes of serotonin receptors the 5-HT3 receptor occupies a special place: it is phylogenetically much older than the other serotonin receptors, all of which have developed from a single primordial 5-HT receptor and belong to the G-protein coupled receptors. In contrast, the 5-HT3 receptor is a ligand-gated cation channel belonging to the nicotine/gamma-amino-butyrate (GABA) receptor super-family, and it shares structural and functional features with other members of this

5-HT3-receptor ligands — is receptor selectivity of ‘setrons’ an outdated concept?

Application of 5-HT3-receptor agonists like 2-methyl-5-hydroxytryptamine and meta-chlorophenylbiguanide (mCPBG) causes unfavourable effects like nausea and anxiety. No clinical use is targeted at present.

Six 5-HT3-receptor antagonists are currently available on the market (further compounds are in the pipeline): tropisetron, ondansetron, granisetron, dolasetron, palonosetron and alosetron. All of these are highly potent compounds which can induce complete competitive blockade of peripheral and

New perspectives in clinical use of 5-HT3-receptor antagonists

Blockade of the 5-HT3 receptors in animal models does not modify normal behavioural patterns, and the only changes observed in physiological functions in healthy volunteers are a certain prolongation of intestinal transit time and discrete, clinically insignificant changes in cardiac conduction, but no evidence of particular CNS effects.

In certain pathological conditions, however, central and/or peripheral 5-HT3-receptor blockade has very pronounced effects. Significance of 5-HT3-receptor

Conclusion

The synthesis of 5-HT3-receptor antagonists 20 years ago resulted in a milestone in supportive cancer therapy since chemotherapy-induced emesis was suppressed far more effectively than with any other drug. The dominating idea at that time was that of a highly selective compound class with mainly gastrointestinal effects. During the last two decades it has been replaced by a concept of drugs which interfere with complex central nervous processes, which show immunomodulatory functions and which

References (75)

  • W.P. Hu et al.

    Potentiation of 5-HT3 receptor function by the activation of coexistent 5-HT2 receptors in trigeminal ganglion neurons of rats

    Neuropharmacology

    (2004)
  • H. Ito et al.

    Comparative study of the affinities of the 5-HT3 receptor antagonists, YM060, YM114 (KAE-393), granisetron and ondansetron in rat vagus nerve and cerebral cortex

    Neuropharmacology

    (1995)
  • D.M. Lovinger et al.

    Ethanol and trichloroethanol alter gating of 5-HT3 receptor-channels in NCB-20 neuroblastoma cells

    Neuropharmacology

    (2000)
  • J.E. Macor et al.

    The 5-HT3 antagonist tropisetron (ICS 205–930) is a potent and selective alpha7 nicotinic receptor partial agonist

    Bioorg. Med. Chem. Lett.

    (2001)
  • B. Niesler et al.

    Cloning, physical mapping and expression analysis of the human 5-HT3 serotonin receptor-like genes HTR3C, HTR3D and HTR3E

    Gene

    (2003)
  • R.L. Papke et al.

    Molecular dissection of tropisetron, an alpha7 nicotinic acetylcholine receptor-selective partial agonist

    Neurosci. Lett.

    (2005)
  • L.M. Pinkus et al.

    Antagonism of [3H]zacopride binding to 5-HT3 recognition sites by its ® and (S) enantiomers

    Eur. J. Pharmacol.

    (1990)
  • L.A. Ricci et al.

    Serotonin type 3 receptors stimulate offensive aggression in Syrian hamsters

    Behav. Brain Res.

    (2005)
  • T.J. Turner et al.

    Calcium influx through presynaptic 5-HT3 receptors facilitates GABA release in the hippocampus: in vitro slice and synaptosome studies

    Neuroscience

    (2004)
  • N. Ait-Daoud et al.

    Ondansetron with and without naltrexone as a treatment of biologic alcoholism: concepts and updated findings

    Addict. Disord. Treat.

    (2002)
  • A.A. Alhaider et al.

    Spinal 5-HT3-mediated anti-nociception — possible release of GABA

    J. Neurosci.

    (1991)
  • E. Alon et al.

    Prevention and treatment of postoperative nausea and vomiting with 5-HT3-receptor blockade

    Anasthesiol. Intensivmed. Notfallmed. Schmerzther.

    (1996)
  • CR. Ashby et al.

    Effect produced by acute and chronic administration of the selective 5-HT-3 receptor antagonist BRL 46470 on the number of spontaneously active midbrain dopamine cells in the rat

    Drug Dev. Res.

    (1994)
  • N.P. Barrera et al.

    Atomic force microscopy reveals the stoichiometry and subunit arrangement of 5-HT3 receptors

    PNAS

    (2005)
  • R. Bell et al.

    Effects of the 5-HT3 receptor agonist SR 57227A and antagonist Y-25130 on the behaviour of rats in the elevated zero-maze model of anxiety

    J. Psychopharmacol. (Oxford)

    (2003)
  • F. Carvalho et al.

    Hyperglycemia induced by pharmacological activation of central serotonergic pathways depends on the functional integrity of brain CRH system and 5-HT3 receptors

    Horm. Metab. Res.

    (2005)
  • E.G.M. Couturier et al.

    First clinical study of the selective 5-HT3 antagonist, granisetron (BRL 43694), in the acute treatment of migraine headache

    Headache

    (1991)
  • L. De la Vega et al.

    The 5-HT3 receptor antagonist tropisetron inhibits T cell activation by targeting the calcineurin pathway

    Biochem. Pharmacol.

    (2005)
  • B. Eisensamer et al.

    Antidepressants are functional antagonists at the serotonin type 3 (5-HT3) receptor

    Mol. Psychiatry

    (2003)
  • B. Eisensamer et al.

    Antidepressants and antipsychotic drugs colocalize with 5-HT3 receptors in raft-like domains

    J. Neurosci.

    (2005)
  • L. Faerber

    Short-term treatment of primary fibromyalgia with the 5-HT3 receptor antagonist tropisetron. Results of a randomized, double-blind, placebo-controlled multicenter trial in 418 patients

    Int. J. Clin. Pharmacol. Res.

    (2001)
  • P. Feyer et al.

    Radiotherapy-induced emesis. An overview

    Strahlenther. Onkol.

    (1998)
  • B.L. Fiebich et al.

    Antiinflammatory effects of 5-HT3 receptor antagonists in lipopolysaccharide-stimulated primary human monocytes

    Scand. J. Rheumatol.

    (2004)
  • M. Funahashi et al.

    Activation of presynaptic 5-HT3 receptors facilitates glutamatergic synaptic input to area postrema neurons in rat brain slices

    Methods Find. Exp. Clin. Pharmacol.

    (2004)
  • A. Gebauer et al.

    Modulation by 5-HT3 and 5-HT4 receptors of the release of 5-hydroxytryptamine from the guinea-pig small intestine

    Naunyn-Schmiedeberg's Arch. Pharmacol.

    (1993)
  • O.T. Ginawi et al.

    Involvement of some 5-ht receptors in methamphetamine-induced locomotor activity in mice

    J. Physiol. Pharmacol.

    (2004)
  • A.J. Greenshaw et al.

    The non-antiemetic uses of serotonin 5-HT3 receptor antagonists

    Drugs

    (1997)
  • Cited by (0)

    Preparation of the manuscript was supported by Novartis Pharma GmbH, Nuremberg.

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