Brain-Gut interactions increase peripheral nociceptive signaling in mice with postinfectious irritable bowel syndrome

Charles Ibeakanma, Fernando Ochoa-Cortes, Marcela Miranda-Morales, Todd G McDonald, Ian Spreadbury, Nicolas Cenac, Fiore Cattaruzza, David J Hurlbut, Stephanie J Vanner, Nigel William Bunnett, Nathalie Vergnolle, Stephen Vanner

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Abstract

Background Aims: To investigate the peripheral sensory effects of repeated stress in patients with postinfectious irritable bowel syndrome (IBS), we tested whether stress following self-limiting bacterial colitis increases colonic dorsal root ganglia (DRG) nociceptive signaling. Methods: C57BL/6 mice were infected with Citrobacter rodentium. Stress was induced using a 9-day water avoidance paradigm (days 2130 after infection). Colonic DRG neuronal excitability was measured using perforated patch clamp techniques, in vitro multi-unit afferent recordings, and measurements of visceromotor reflexes. Results: Combined stress and prior infection increased corticosterone and epinephrine levels, compared with infected animals, but did not alter the resolution of colonic inflammation. These changes were associated with increased neuronal excitability and parallel changes in multi-unit afferent recordings and visceromotor reflex thresholds. Protease activity was increased at day 30 following infection with C rodentium. Protease inhibitors markedly reduced the effects of colonic supernatants on neuronal excitability from C rodentium but not stressed animals. Colonic DRG neurons expressed messenger RNAs for the I? 2 adrenergic and glucocorticoid receptors; incubation with stress mediators recapitulated the effects on neuronal excitability observed with chronic stress alone. PAR2 activation with concentrations of the activating peptide SLIGRL that had no effect on neuronal excitability in controls caused marked increases in excitability when applied to neurons from chronically stressed animals. Conclusions: Stress, combined with prior acute colitis, results in exaggerated peripheral nociceptive signaling. Proteases and stress mediators can signal directly to colonic DRG neurons; further analysis of these pathways could provide new targets for treatment of patients with postinfectious IBS.
Original languageEnglish
Pages (from-to)2098 - 2108.e5
Number of pages11
JournalGastroenterology
Volume141
Issue number6
DOIs
Publication statusPublished - 2011
Externally publishedYes

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