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.