Persistent alterations to enteric neural signaling in the guinea pig colon following the resolution of colitis

Abstract

Functional changes induced by inflammation persist following recovery from the inflammatory response, but the mechanisms underlying these changes are not well understood. Our aim was to investigate whether the excitability and synaptic properties of submucosal neurons remained altered 8 wk post-trinitrobenzene sulfonic acid (TNBS) treatment and to determine whether these changes were accompanied by alterations in secretory function in submucosal preparations voltage clamped in Ussing chambers. Mucosal serotonin (5-HT) release measurements and 5-HT reuptake transporter (SERT) immunohistochemistry were also performed. Eight weeks after TNBS treatment, colonic inflammation resolved, as assessed macroscopically and by myeloperoxidase assay. However, fast excitatory postsynaptic potential (fEPSP) amplitude was significantly increased in submucosal S neurons from previously inflamed colons relative to those in control tissue. In addition, fEPSPs from previously inflamed colons had a hexamethonium-insensitive component that was not evident in age-matched controls. AH neurons were hyperexcitable, had shorter action potential durations, and decreased afterhyperpolarization 8 wk following TNBS adminstration. Neuronally mediated colonic secretory function was significantly reduced after TNBS treatment, although epithelial cell signaling, as measured by responsiveness to both forskolin and bethanecol in the presence of tetrodotoxin, was comparable with control tissue. 5-HT levels and SERT immunoreactivity were comparable to controls 8 wk after the induction of inflammation, but there was an increase in glucagon-like peptide 2-immunoreactive L cells. In conclusion, sustained alterations in enteric neural signaling occur following the resolution of colitis, which are accompanied by functional changes in the absence of active inflammation.

Purinergic receptors and synaptic transmission in enteric neurons

“…Upregulation of presynaptic ATP release and/or alteration of postsynaptic P2X receptors appear to contribute in the submucous and myenteric plexes, respectively [65,106]. Recently this work has been extended to show that, following resolution of colitis, the increase in purinergic fast EPSP amplitude remains [108] and that there is an increase in fast EPSP amplitude in noninvolved tissue remote from the inflammation [109].…”

Gastrointestinal Motility Monitor (GIMM)

“…A number of studies have demonstrated that inflammation leads to changes in the electrical and synaptic properties of colonic neurons (Linden et al, 2003a;Lomax et al, 2005), and that these changes can persist for weeks following recovery from inflammation (Krauter et al, 2007;Lomax et al, 2007). The impact of colitis-induced neuroplastic changes on propulsive motility can be investigated in the guinea pig distal colon using the GIMM system.…”

Fundamentals of Neurogastroenterology: Basic Science

“…Therefore, inflammation-induced changes in neuronal function could be a contributing factor in IBS and refractory inflammatory bowel disease, but these changes in neuronal excitability and synaptic strength would not be detectable with current diagnostic techniques. Several inflammation-induced changes in the ENS, including AH neuron hyperexcitability, do persist beyond recovery of inflammation, 25,26 supporting the possibility that long-term changes in enteric circuitry could contribute to FGIDs.…”