Activation of the ERK1/2 signaling cascade by excitotoxic spinal cord injury.
The role of the ERK1/2 signal transduction pathway and related transcription factors in the regulation of gene expression and pain behavior following excitotoxic spinal cord injury (SCI) was examined. Specifically, phosphorylation of ERK1/2, activation of transcription factors NF-kB, ELK-1, and CREB, and gene expression of the neurokinin-1 receptor and NMDA receptor subunits NR1 and NR-2A were investigated. Excitotoxic injury was produced by intraspinal injection of quisqualic acid (QUIS) in male Sprague-Dawley rats. Western blots were used to evaluate phosphorylation and activation of ERK1/2 and transcription factors using phospho-specific or total antibodies. Real-time PCR was used to evaluate gene expression of NK-1R, NR-1, and NR-2A. Assessment of excessive grooming behavior was used to evaluate the presence of spontaneous pain behavior. Excitotoxic spinal injury resulted in: (1) increased phosphorylation of ERK1/2; (2) increased activation of NF-kB and phosphorylation of ELK-1; and (3) increased gene expression for the NK-1 receptor and NR1 and NR-2A subunits of the NMDA receptor. Blockade of the ERK cascade with the MEK inhibitor PD98059 inhibited phosphorylation of ELK-1, activation of NF-kB and gene expression of NR1, NR-2A and NK-1R, and prevented the development of excessive grooming behavior. The results have shown that excitotoxic spinal injury leads to the injury-induced activation of the ERK-->ELK-1 and NF-kB signaling cascades and transcriptional regulation of receptors important in the development of chronic pain. Blockade of this intracellular kinase cascade prevented the onset of injury-induced pain behavior.
Yu
Chen-Guang
CG
Department of Orthodontics and Neuroscience, College of Dentistry and McKnight Brain Institute, Comprehensive Center for Pain Research, University of Florida, Gainesville, FL 32610, USA.
Yezierski
Robert P
RP
D000818:Animals; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005809:Genes, Regulator / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009410:Nerve Degeneration / Q000139:chemically induced / Q000201:enzymology* / Q000503:physiopathology; D010146:Pain / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D016318:Quisqualic Acid; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000201:enzymology*; D013119:Spinal Cord Injuries / Q000139:chemically induced / Q000201:enzymology* / Q000503:physiopathology; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D004791:Enzyme Inhibitors; C409466:NR1 NMDA receptor; C120997:NR2A NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D018040:Receptors, Neurokinin-1; D014157:Transcription Factors; D016318:Quisqualic Acid; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3