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Spinal nitration of tyrosine residuesa key event in central nociception

, : Spinal nitration of tyrosine residuesa key event in central nociception. Society for Neuroscience Abstract Viewer & Itinerary Planner : Abstract No 437 9

Numerous studies have shown that glutamate-mediated activation of the N-methyl-D-aspartate (NMDA) receptor is fundamental in the development of hyperalgesia. Overt activation of this receptor release superoxide (SO) and nitric oxide that in turn form peroxynitrite (PN). An important mechanism of SO/PN in disease states is nitration of tyrosine residues in various receptors and enzymes. The present study tested the hypothesis that SO-driven nitration is key in the development and maintenance of central sensitization.Thermal hyperalgesia was induced by intrathecal (i.t.)administration of NMDA in rats and nitration was assessed by immunoprecipitation assay. M40403 a synthetic SO dismutase mimetic (SODm) known to remove SO and its inactive congener M40404 were used as pharmacological probes.NMDA-mediated thermal hyperalgesia was blocked by systemic injection of M40403 but not by M40404 indicating that SO is critical in NMDA-mediated hyperalgesia. At time near-to-maximal hyperalgesia, endogenous manganese superoxide dismutase(MnSOD) was nitrated and deactivated in the spinal cord and SODm prevented MnSOD nitration and inhibited the hyperalgesia. Furthermore,after i.t. injection of NMDA,spinal nitration of the NMDA receptor subunits NR1 and NR2B was observed,an event that leads to potentiation of synaptic currents,calcium influx and hyperalgesia. Synaptically released glutamate is normally converted into nontoxic glutamine by the glia specific enzyme glutamine synthase (GS). During NMDA-mediated hyperalgesia GS is nitrated an event that results in loss of activity of this enzyme. I.t. injection of SODm prevents nitration of NR1,NR2B and GS and overall inhibition of hyperalgesia.The results of our study support the hypothesis that SO mediated PN formation and subsequent nitration is key in the development and maintenance of central sensitization. MnSOD, GS and NMDA receptor subunits are key targets in this pathway.


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