Submitted on February 28, 2006
Accepted on March 23, 2006
Experimental colitis modulates the functional properties of NMDA receptors in dorsal root ganglia neurons
Jichang Li1, James A McRoberts1*, Helena S Ennes1, Marcello Trevisani2, Paola Nicoletti2, Yash Mittal3, and Emeran A Mayer4
1 Medicine, Geffen School of Medicine at UCLA, Los Angeles, California, United States; Center for Neurovisceral Sciences & Women's Health, Geffen School of Medicine at UCLA, Los Angeles, California, United States
2 Department of Critical Care Medicine and Surgery, University of Florence, Florence, Italy
3 Center for Neurovisceral Sciences & Women's Health, Geffen School of Medicine at UCLA, Los Angeles, California, United States
4 Medicine, Geffen School of Medicine at UCLA, Los Angeles, California, United States; Physiology, Psychology and the Brain Reseach Institute, Geffen School of Medicine at UCLA, Los Angeles, California, United States; Center for Neurovisceral Sciences & Women's Health, Geffen School of Medicine at UCLA, Los Angeles, California, United States
* To whom correspondence should be addressed. E-mail: mcrobert{at}ucla.edu.
Background and Aims: N-methyl-D-aspartate receptors (NMDAR) 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. Methods: Lumbosacral dorsal root ganglia (DRG) were collected from adult rats 5 days after induction of colitis for whole cell patch clamp recording, western blotting and quantitative RT-PCR. Results: Compared to neurons from control rats, those taken from animals with colitis had a 3-fold 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 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 blotting indicated a 28% increase in the expression of NR2B with little or no change in the other three NR2 subunits. Addition of the Src family tyrosine kinase inhibitor, PP2 (10µM), decreased NMDAR currents in neurons from colitis but not control rats. Conversely, pre-treatment of DRG neurons from control animals with 100µM sodium orthovanadate increased NMDAR currents and decreased ifenprodil sensitivity to levels similar to that observed in neurons from animals with colitis. Conclusions: Colonic inflammation up-regulates the activity of NMDARs in all DRG neurons within ganglia innervating this tissue through mechanisms involving increased expression and persistent tyrosine phosphorylation.
