<i>N</i>-Methyl-d-aspartate receptor antagonism decreases motility and inflammatory activation in the early phase of acute experimental colitis in the rat

Abstract

BACKGROUND: Inflammatory bowel diseases are accompanied by severe motility disorders. The aim of our study was to investigate whether the blockade of peripheral N-methyl-D-aspartate (NMDA)-sensitive glutamate receptors (NMDA-Rs) alters motility changes in chemically induced acute colitis and how this modulation is accomplished. METHODS: The inflammatory and motility changes in 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis were studied in anaesthetized Wistar rats following treatment with the natural NMDA-R antagonist kynurenic acid (KynA) or SZR-72, a blood-brain barrier-permeable synthetic KynA analogue. The macrohaemodynamics, serosal microcirculation (visualized by intravital videomicroscopy), plasma levels of tumour necrosis factor alpha (TNF-alpha), inflammatory enzyme activities (xanthine oxidoreductase (XOR), myeloperoxidase (MPO) and nitric oxide synthase (NOS)), and colonic motility (with a strain-gauge technique) were evaluated 17 h after colitis induction and compared with the control conditions. KEY RESULTS: The TNBS enema induced a systemic hyperdynamic circulatory reaction, increased the serosal capillary blood flow, significantly elevated the mucosal XOR, MPO and NOS activities and augmented the colonic motility relative to the controls. The NMDA-R antagonist treatment with KynA or SZR-72 significantly reduced the XOR, NOS and MPO activities, decreased the motility and increased the tone of the colon. CONCLUSIONS & INFERENCES: These data demonstrate a potential modulatory mechanism of NMDA-R in altered colonic motility in TNBS colitis. Inhibition of the enteric NMDA-Rs may provide a therapeutic option via which to influence intestinal hypermotility, microcirculatory changes and inflammatory activation simultaneously.