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NEUROREGULATION AND MOTILITY

Experimental colitis modulates the functional properties of NMDA receptors in dorsal root ganglia neurons

Departments of ¹Medicine, ²Physiology, and ³Psychology, ⁴Center for Neurovisceral Sciences and Women's Health, and ⁵Brain Research Institute, Geffen School of Medicine, University of California, Los Angeles, California; and ⁶Department of Critical Care Medicine and Surgery, University of Florence, Florence, Italy

Submitted 28 February 2006 ; accepted in final form 23 March 2006

N-methyl-D-aspartate (NMDA) receptors (NMDARs) on spinal afferent neurons regulate the peripheral and central release of neuropeptides involved in the development of hyperalgesia. We examined the effect of experimental colitis on the molecular and functional properties of NMDARs on these neurons. Lumbosacral dorsal root ganglia (DRG) were collected from adult rats 5 days after the induction of colitis for whole cell patch-clamp recording, Western blot analysis, and quantitative RT-PCR. Compared with neurons from control rats, those taken from animals with colitis had a threefold higher density of NMDA currents in both retrograde-labeled, colon-specific, and unlabeled DRG neurons. Increased current densities were not observed in DRG neurons taken from thoracic spinal levels. There was no significant change in NMDA or glycine affinity or in voltage-dependent Mg²⁺ inhibition; however, there was a 10-fold decrease in sensitivity to the NR2B subunit-selective antagonist ifenprodil. Quantitative RT-PCR and Western blot analysis indicated a 28% increase in the expression of NR2B with little or no change in the other three NR2 subunits. The addition of the Src family tyrosine kinase inhibitor PP2 (10 µM) decreased NMDAR currents in neurons from colitis but not control rats. Conversely, pretreatment of DRG neurons from control animals with 100 µM sodium orthovanadate increased NMDAR currents and decreased ifenprodil sensitivity to levels similar to those observed in neurons from animals with colitis. In conclusion, colonic inflammation upregulates the activity of NMDARs in all DRG neurons within ganglia innervating this tissue through mechanisms involving increased expression and persistent tyrosine phosphorylation.

inflammation; tyrosine kinase; ifenprodil; trinitrobenzenesulfonic acid; N-methyl-D-aspartate