Redox manipulation of NMDA receptors in vivo: alteration of acute pain transmission and dynorphin-induced allodynia.
The redox modulatory site of the N-methyl-D-aspartate (NMDA) receptor directly regulates NMDA receptor function. Sulfhydryl reducing agents, such as dithiothreitol (DTT), potentiate NMDA receptor-evoked currents in vitro, whereas oxidizing agents, such as 5,5'-dithio-bis-(2-nitrobenzoic acid) (DTNB), attenuate these currents. In this study, we examined the effect of this redox manipulations on nociceptive spinal cord signaling in mice. Intrathecal (i.t.) administration of DTT (0.1-30 nmol), presumably reducing the NMDA receptor, dose-dependently enhanced NMDA-induced nociceptive behaviors, and this enhancement was blocked by the oxidizing agent, DTNB. Pretreatment with DTT (10 nmol, i.t.) enhanced NMDA-induced tail-flick thermal hyperalgesia and intraplantar formalin-induced nociceptive behaviors. Finally, DTT pretreatment enhanced the long lasting allodynia induced by i.t. administration of dynorphin, whereas post-treatment with DTNB reduced the permanent allodynia induced by dynorphin for 5 days. Potentiation of all four of these NMDA-dependent nociceptive behaviors by DTT suggests that the reduction of the NMDA receptor by endogenous reducing agents may contribute to augmented pain transmission in response to activation by endogenous glutamate. Moreover, blockade of in vivo NMDA receptor reducing agents or oxidation of the NMDA receptor redox site may prove therapeutically useful in the treatment of chronic pain.
Laughlin
T M
TM
Department of Pharmacology, University of Minnesota, Minneapolis 55455, USA.
Kitto
K F
KF
Wilcox
G L
GL
D000208:Acute Disease; D000818:Animals; D004228:Dithionitrobenzoic Acid / Q000008:administration & dosage / Q000494:pharmacology; D004229:Dithiothreitol / Q000008:administration & dosage / Q000494:pharmacology; D004399:Dynorphins / Q000008:administration & dosage; D018690:Excitatory Amino Acid Agonists / Q000008:administration & dosage / Q000494:pharmacology; D006930:Hyperalgesia / Q000139:chemically induced / Q000503:physiopathology; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D016202:N-Methylaspartate / Q000008:administration & dosage / Q000494:pharmacology; D010084:Oxidation-Reduction; D010146:Pain / Q000139:chemically induced / Q000503:physiopathology*; D010147:Pain Measurement; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019163:Reducing Agents / Q000008:administration & dosage / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects / Q000503:physiopathology; D013439:Sulfhydryl Reagents / Q000008:administration & dosage / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects*
D018690:Excitatory Amino Acid Agonists; D016194:Receptors, N-Methyl-D-Aspartate; D019163:Reducing Agents; D013439:Sulfhydryl Reagents; D016202:N-Methylaspartate; D004399:Dynorphins; D004228:Dithionitrobenzoic Acid; D004229:Dithiothreitol