title: Posttranslational nitration of tyrosine residues modulates glutamate transmission and contributes to N-methyl-D-aspartate-mediated thermal hyperalgesia.
abstract: Activation of the N-methyl-D-aspartate receptor (NMDAR) is fundamental in the development of hyperalgesia. Overactivation of this receptor releases superoxide and nitric oxide that, in turn, forms peroxynitrite (PN). All of these events have been linked to neurotoxicity. The receptors and enzymes involved in the handling of glutamate pathway--specifically NMDARs, glutamate transporter, and glutamine synthase (GS)--have key tyrosine residues which are targets of the nitration process causing subsequent function modification. Our results demonstrate that the thermal hyperalgesia induced by intrathecal administration of NMDA is associated with spinal nitration of GluN1 and GluN2B receptor subunits, GS, that normally convert glutamate into nontoxic glutamine, and glutamate transporter GLT1. Intrathecal injection of PN decomposition catalyst FeTM-4-PyP(5+) prevents nitration and overall inhibits NMDA-mediated thermal hyperalgesia. Our study supports the hypothesis that nitration of key proteins involved in the regulation of glutamate transmission is a crucial pathway used by PN to mediate the development and maintenance of NMDA-mediated thermal hyperalgesia. The broader implication of our findings reinforces the notion that free radicals may contribute to various forms of pain events and the importance of the development of new pharmacological tool that can modulate the glutamate transmission without blocking its actions directly.
authors.affiliation: Department of Health Sciences, University, Magna Graecia, Edificio Bioscienze, Viale Europa, Campus Salvatore Venuta, Germaneto, 88100 Catanzaro, Italy. muscoli@unicz.it
authors.forename: Carolina
authors.initials: C
authors.lastname: Muscoli
authors.forename: Concetta
authors.initials: C
authors.lastname: Dagostino
authors.forename: Sara
authors.initials: S
authors.lastname: Ilari
authors.forename: Filomena
authors.initials: F
authors.lastname: Lauro
authors.forename: Micaela
authors.initials: M
authors.lastname: Gliozzi
authors.forename: Erlisa
authors.initials: E
authors.lastname: Bardhi
authors.forename: Ernesto
authors.initials: E
authors.lastname: Palma
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Mollace
authors.forename: Daniela
authors.initials: D
authors.lastname: Salvemini
mesh_terms: D000818:Animals; D003600:Cytosol / Q000378:metabolism; D018698:Glutamic Acid / Q000737:chemistry*; D005973:Glutamine / Q000378:metabolism; D006358:Hot Temperature; D006930:Hyperalgesia / Q000378:metabolism*; D047468:Immunoprecipitation; D008159:Lumbar Vertebrae / Q000378:metabolism; D008297:Male; D016202:N-Methylaspartate / Q000378:metabolism*; D009584:Nitrogen / Q000737:chemistry*; D011499:Protein Processing, Post-Translational; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D009435:Synaptic Transmission; D013574:Synaptosomes / Q000378:metabolism; D014443:Tyrosine / Q000737:chemistry*
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D005973:Glutamine; D018698:Glutamic Acid; D014443:Tyrosine; D016202:N-Methylaspartate; D009584:Nitrogen