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

University of Florence, Florens, Tuscany, Italy
AJP Gastrointestinal and Liver Physiology (Impact Factor: 3.8). 09/2006; 291(2):G219-28. DOI: 10.1152/ajpgi.00097.2006
Source: PubMed


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 microM) decreased NMDAR currents in neurons from colitis but not control rats. Conversely, pretreatment of DRG neurons from control animals with 100 microM 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.

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Available from: Marcello Trevisani
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    • "This potentiation of NMDA receptors in primary afferents probably occurs in chronic pain disorders other than neuropathic pain. Thus, in a rat model of colitis there was an increase in NMDA receptor currents in DRG neurons mediated by SFKs (Li et al., 2006). Perhaps this can explain why Liu et al. (1997) found that intrathecal NMDA induced NK1R internalization: an undetected inflammation in their rats could have potentiated these NMDA receptors. "
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    ABSTRACT: NMDA receptors in primary afferent terminals can contribute to hyperalgesia by increasing neurotransmitter release. In rats and mice, we found that the ability of intrathecal NMDA to induce neurokinin 1 receptor (NK1R) internalization (a measure of substance P release) required a previous injection of BDNF. Selective knock-down of NMDA receptors in primary afferents decreased NMDA-induced NK1R internalization, confirming the presynaptic location of these receptors. The effect of BDNF was mediated by tropomyosin-related kinase B (trkB) receptors and not p75 neurotrophin receptors (p75(NTR) ), because it was not produced by proBDNF and was inhibited by the trkB antagonist ANA-12 but not by the p75(NTR) inhibitor TAT-Pep5. These effects are probably mediated through the truncated form of the trkB receptor as there is little expression of full-length trkB in dorsal root ganglion (DRG) neurons. Src family kinase inhibitors blocked the effect of BDNF, suggesting that trkB receptors promote the activation of these NMDA receptors by Src family kinase phosphorylation. Western blots of cultured DRG neurons revealed that BDNF increased Tyr(1472) phosphorylation of the NR2B subunit of the NMDA receptor, known to have a potentiating effect. Patch-clamp recordings showed that BDNF, but not proBDNF, increased NMDA receptor currents in cultured DRG neurons. NMDA-induced NK1R internalization was also enabled in a neuropathic pain model or by activating dorsal horn microglia with lipopolysaccharide. These effects were decreased by a BDNF scavenger, a trkB receptor antagonist and a Src family kinase inhibitor, indicating that BDNF released by microglia potentiates NMDA receptors in primary afferents during neuropathic pain.
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    • "Despite extensive studies on the role of postsynaptic NMDARs in the development and maintenance of pathological pain including neuropathic pain, the role of presynaptic NMDARs of primary afferents in the spinal nociceptive sensory processing remains elusive. NMDARs are present in primary afferent terminals in the spinal dorsal horn and dorsal root ganglion neurons, as repeatedly confirmed both anatomically and physiologically (Liu et al. 1994; Bardoni et al. 2004; Li et al. 2006; Zeng et al. 2006). Activation of presynaptic NMDARs with intrathecal injection of the NMDAR agonist NMDA results in increased release of substance P from primary afferents in adult rats (Liu et al. 1997). "
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    Preview · Article · Jan 2013 · The Journal of Physiology
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    • "Peripheral NMDARs are targets for the treatment of neuropathic pain (Wu & Zhuo, 2009). NMDARs expressed on spinal afferent neurons are upregulated in the lumbosacral dorsal root ganglia (DRG) following experimental colitis (Li et al., 2006). Peripheral NMDARs play a role in behavioral pain responses to colonic distention, suggesting that these receptors are important in visceral pain transmission (McRoberts et al., 2001). "
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