Spinal p38beta isoform mediates tissue injury-induced hyperalgesia and spinal sensitization.
Antagonist studies show that spinal p38 mitogen-activated protein kinase plays a crucial role in spinal sensitization. However, there are two p38 isoforms found in spinal cord and the relative contribution of these two to hyperalgesia is not known. Here we demonstrate that the isoforms are distinctly expressed in spinal dorsal horn: p38alpha in neurons and p38beta in microglia. In lieu of isoform selective inhibitors, we examined the functional role of these two individual isoforms in nociception by using intrathecal isoform-specific antisense oligonucleotides to selectively block the expression of the respective isoform. In these rats, down-regulation of spinal p38beta, but not p38alpha, prevented nocifensive flinching evoked by intraplantar injection of formalin and hyperalgesia induced by activation of spinal neurokinin-1 receptors through intrathecal injection of substance P. Both intraplantar formalin and intrathecal substance P produced an increase in spinal p38 phosphorylation and this phosphorylation (activation) was prevented when spinal p38beta, but not p38alpha, was down-regulated. Thus, spinal p38beta, probably in microglia, plays a significant role in spinal nociceptive processing and represents a potential target for pain therapy.
Svensson
Camilla I
CI
Department of Anesthesiology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Fitzsimmons
Bethany
B
Azizi
Sara
S
Powell
Henry C
HC
Hua
Xiao-Ying
XY
Yaksh
Tony L
TL
D000818:Animals; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D006930:Hyperalgesia / Q000378:metabolism* / Q000503:physiopathology; D007278:Injections, Spinal; D008297:Male; D017628:Microglia / Q000378:metabolism; D048290:Mitogen-Activated Protein Kinase 11 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020320:Oligoribonucleotides, Antisense; D010146:Pain / Q000378:metabolism* / Q000503:physiopathology; D010147:Pain Measurement / Q000187:drug effects; D020671:Posterior Horn Cells / Q000378:metabolism; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000187:drug effects / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism* / Q000503:physiopathology; D013373:Substance P / Q000378:metabolism / Q000494:pharmacology
D020320:Oligoribonucleotides, Antisense; D020033:Protein Isoforms; D018040:Receptors, Neurokinin-1; D013373:Substance P; D048290:Mitogen-Activated Protein Kinase 11; D048308:Mitogen-Activated Protein Kinase 14