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Peripheral contribution of NGF and ASIC1a to colonic hypersensitivity in a rat model of irritable bowel syndrome

Authors

  • J. Matricon,

    1. NEURO-DOL, Pharmacologie Fondamentale et Clinique de la Douleur, Faculté de Médecine, INSERM/UdA, UMR 1107, Université d'Auvergne, Clermont-Ferrand, France
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  • E. Muller,

    1. NEURO-DOL, Pharmacologie Fondamentale et Clinique de la Douleur, Faculté de Médecine, INSERM/UdA, UMR 1107, Université d'Auvergne, Clermont-Ferrand, France
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  • A. Accarie,

    1. NEURO-DOL, Pharmacologie Fondamentale et Clinique de la Douleur, Faculté de Médecine, INSERM/UdA, UMR 1107, Université d'Auvergne, Clermont-Ferrand, France
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  • M. Meleine,

    1. NEURO-DOL, Pharmacologie Fondamentale et Clinique de la Douleur, Faculté de Médecine, INSERM/UdA, UMR 1107, Université d'Auvergne, Clermont-Ferrand, France
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  • M. Etienne,

    1. NEURO-DOL, Pharmacologie Fondamentale et Clinique de la Douleur, Faculté de Médecine, INSERM/UdA, UMR 1107, Université d'Auvergne, Clermont-Ferrand, France
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  • N. Voilley,

    1. Institut de Pharmacologie Moléculaire et Cellulaire, Institut Paul Hamel, CNRS UMR6097, Université de Nice-Sophia Antipolis, Sophia Antipolis, Valbonne, France
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  • J. Busserolles,

    1. Institut Universitaire de Technologie, Campus des Cézeaux, INSERM/UdA UMR 1107, NEURO-DOL, Aubière, France
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  • A. Eschalier,

    1. NEURO-DOL, Pharmacologie Fondamentale et Clinique de la Douleur, Faculté de Médecine, INSERM/UdA, UMR 1107, Université d'Auvergne, Clermont-Ferrand, France
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  • M. Lazdunski,

    1. Institut de Pharmacologie Moléculaire et Cellulaire, Institut Paul Hamel, CNRS UMR6097, Université de Nice-Sophia Antipolis, Sophia Antipolis, Valbonne, France
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  • S. Bourdu,

    1. NEURO-DOL, Pharmacologie Fondamentale et Clinique de la Douleur, Faculté de Médecine, INSERM/UdA, UMR 1107, Université d'Auvergne, Clermont-Ferrand, France
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  • A. Gelot,

    1. Institut Universitaire de Technologie, Campus des Cézeaux, INSERM/UdA UMR 1107, NEURO-DOL, Aubière, France
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  • D. Ardid

    Corresponding author
    1. Institut Universitaire de Technologie, Campus des Cézeaux, INSERM/UdA UMR 1107, NEURO-DOL, Aubière, France
    • NEURO-DOL, Pharmacologie Fondamentale et Clinique de la Douleur, Faculté de Médecine, INSERM/UdA, UMR 1107, Université d'Auvergne, Clermont-Ferrand, France
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Address for Correspondence

D. Ardid, Institut Universitaire de Technologie, Campus des Cézeaux, INSERM/UdA, UMR 1107 NEURO-DOL, BP86, Aubière Cedex 63172, France.

Tel: 00 (33) 4 73 17 82 30; fax: 00 (33) 4 73 27 71 62; e-mail: Denis.ARDID@udamail.fr

Abstract

Background

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder associated with idiopathic colonic hypersensitivity (CHS). However, recent studies suggest that low-grade inflammation could underlie CHS in IBS. The pro-inflammatory mediator nerve growth factor (NGF) plays a key role in the sensitization of peripheral pain pathways and several studies have reported its contribution to visceral pain development. NGF modulates the expression of Acid-Sensing Ion Channels (ASICs), which are proton sensors involved in sensory neurons sensitization. This study examined the peripheral contribution of NGF and ASICs to IBS-like CHS induced by butyrate enemas in the rat colon.

Methods

Colorectal distension and immunohistochemical staining of sensory neurons were used to evaluate NGF and ASICs contribution to the development of butyrate-induced CHS.

Key Results

Systemic injection of anti-NGF antibodies or the ASICs inhibitor amiloride prevented the development of butyrate-induced CHS. A significant increase in NGF and ASIC1a protein expression levels was observed in sensory neurons of rats displaying butyrate-induced CHS. This increase was specific of small- and medium-diameter L1 + S1 sensory neurons, where ASIC1a was co-expressed with NGF or trkA in CGRP-immunoreactive somas. ASIC1a was also overexpressed in retrogradely labeled colon sensory neurons. Interestingly, anti-NGF antibody administration prevented ASIC1a overexpression in sensory neurons of butyrate-treated rats.

Conclusions & Inferences

Our data suggest that peripheral NGF and ASIC1a concomitantly contribute to the development of butyrate-induced CHS NGF-ASIC1a interplay may have a pivotal role in the sensitization of colonic sensory neurons and as such, could be considered as a potential new therapeutic target for IBS treatment.

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