NMDA-receptor activation and nitroxidative regulation of the glutamatergic pathway during nociceptive processing.
The role of peroxynitrite (PN) as a mediator of nociceptive signaling is emerging. We recently reported that the development of central sensitization that follows the intraplantar injection of carrageenan in rats is associated with spinal PN synthesis. We now demonstrate that a significant pathway through which spinal PN modulates central sensitization is post-translational tyrosine nitration of key proteins involved in the glutamatergic pathway, namely glutamate transporter GLT-1 and glutamine synthetase (GS). We also reveal that spinal activation of the N-methyl-d-aspartate (NMDA) receptor provides a source of PN in this setting. Intraplantar injection of carrageenan led to the development of thermal hyperalgesia as well as nitration of GLT-1 and GS in dorsal horn tissues. Pretreatment with the PN decomposition catalyst FeTM-4-PyP(5+) [Fe(III)5,10,15,20-tetrakis(N-methylpyridinium-4-yl)porphyrin] or the NMDA receptor antagonist MK-801 blocked the development of hyperalgesia. Carrageenan-induced hyperalgesia was also associated with nitration and inactivation of spinal mitochondrial superoxide dismutase (MnSOD) known to provide a critical source of PN during central sensitization. Nitration of GLT-1 and GS contributes to central sensitization by enhancing glutamatergic neurotransmission. Our results support the critical role of nitroxidative stress in the development of hyperalgesia and suggest that post-translational nitration of enzymes and transporters linked to glutamatergic neurotransmission represent a novel mechanism of central sensitization.
Chen
Zhoumou
Z
Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, 1402 South Grand Blvd., St. Louis, MO 63104, USA IRCCS San Raffaele Pisana, Rome, Italy Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Italy Department of Preclinical and Clinical Pharmacology, University of Florence, Italy.
Muscoli
Carolina
C
Doyle
Tim
T
Bryant
L
L
Cuzzocrea
Salvatore
S
Mollace
Vincenzo
V
Mastroianni
Rosanna
R
Masini
Emanuela
E
Salvemini
Daniela
D
D000818:Animals; D018698:Glutamic Acid / Q000378:metabolism*; D006930:Hyperalgesia / Q000378:metabolism*; D008297:Male; D010084:Oxidation-Reduction; D030421:Peroxynitrous Acid / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013116:Spinal Cord / Q000378:metabolism*
D030421:Peroxynitrous Acid; D018698:Glutamic Acid