Afferent hypersensitivity in a mouse model of post-inflammatory gut dysfunction: role of altered serotonin metabolism.
Visceral hypersensitivity is an important clinical feature associated with irritable bowel syndrome which in some patients has been linked to prior infection. Here we employ an animal model in which transient infection leads to persistent gut dysfunction to investigate the role of altered 5-HT metabolism upon afferent mechanosensensitivity in the post-infected gut. Jejunal segments isolated from Trichinella spiralis-infected mice were used to assess 5-HT metabolism whilst afferent activity in T. spiralis-infected mice was studied by extracellular recordings from jejunal mesenteric afferent bundles and patch clamp recordings of isolated nodose ganglion neurons (NGNs). During acute infection, intestinal 5-HT content and release increased, 5-HT turnover decreased and afferent discharge in response to mechanical stimulation was attenuated. By day 28 post infection (PI), 5-HT turnover had normalized, but 5-HT content and release were still elevated. This was associated with afferent mechano-hypersensitivity, which persisted for 8 weeks PI and was susceptible to 5-HT(3) receptor blockade. NGNs from post-infected animals were more excitable than controls but their current densities in response to 2-methyl-5-HT were lower. T. spiralis infection increased mucosal 5-HT bioavailability and affected the spontaneous activity and mechanosensitivity of gastrointestinal sensory nerves. This involved an initial hyposensitivity occurring during acute infection followed by long-term hypersensitivity in the post-infectious period that was in part mediated by 5-HT acting via 5-HT(3) receptors. Functional down-regulation of 5-HT(3) receptors also occurs in the post-infected animals, which may represent an adaptive response to increased mucosal 5-HT bioavailability.
Keating
Christopher
C
Department of Biomedical Sciences, Florey Building, University of Sheffield, Sheffield, S10 2TN, UK.
Beyak
Michael
M
Foley
Stephen
S
Singh
Gulzar
G
Marsden
Charles
C
Spiller
Robin
R
Grundy
David
D
D000818:Animals; D054884:Host-Pathogen Interactions; D066298:In Vitro Techniques; D043183:Irritable Bowel Syndrome / Q000188:drug therapy / Q000378:metabolism* / Q000382:microbiology / Q000503:physiopathology; D007583:Jejunum / Q000294:innervation / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D051379:Mice; D023421:Models, Animal; D009475:Neurons, Afferent / Q000378:metabolism*; D009620:Nodose Ganglion / Q000503:physiopathology; D012701:Serotonin / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000627:therapeutic use; D017160:Trichinella spiralis / Q000502:physiology; D014235:Trichinellosis / Q000150:complications*
D017366:Serotonin Receptor Agonists; D012701:Serotonin