Small intestine neuromuscular dysfunction in a mouse model of dextran sulfate sodium-induced ileitis: Involvement of dopaminergic neurotransmission

Aims: Anomalies in dopaminergic machinery have been shown in inflammatory bowel disease (IBD) patients and preclinical models of IBD. Thus, we aimed to evaluate the impact of dextran sodium sulfate (DSS)-induced ileitis on enteric dopaminergic pathways. Materials and methods: Male C57/Bl6 mice (10 +/- 2 weeks old) received 2% DSS in drinking water for 5 days and were then switched to regular drinking water for 3 days. To measure ileitis severity inflammatory cytokines (IL1 beta, TNF alpha, IL-6) levels were assessed. Changes in ileal muscle tension were isometrically recorded following: 1) cumulative addition of dopamine on basal tone (0.1-1000 mu M); ii) 4-Hz electric field stimulation (EFS) in the presence of 30 mu M dopamine with/without 10 mu M SCH-23390 (dopamine D1 receptor (D1R) antagonist) or 10 mu M sulpiride (D2R antagonist). Immunofluorescence distribution of the neuronal HuC/D protein, glial S100 beta marker, D1R, and dopamine transporter (DAT) were determined in longitudinal-muscle-myenteric plexus wholemounts (LMMPs) by confocal microscopy. D1R and D2R mRNA transcripts were evaluated by qRT-PCR. Key findings: DSS caused an inflammatory process in the small intestine associated to dysmotility and altered barrier permeability, as suggested by decreased fecal output and enhanced stool water content. DSS treatment caused a significant increase of DAT and D1R myenteric immunoreactivity as well as of D1R and D2R mRNA levels, accompanied by a significant reduction of dopamine-mediated relaxation, involving primarily D1-like receptors. Significance: Mouse ileitis affects enteric dopaminergic neurotransmission mainly involving D1R-mediated responses. These findings provide novel information on the participation of dopaminergic pathways in IBDmediated neuromuscular dysfunction.

Automated summary

This study aims to evaluate the impact of ileitis on enteric dopaminergic pathways, and finds that ileitis mainly affects D1 receptor-mediated dopaminergic neurotransmission.