ERK MAP kinase activation in superficial spinal cord neurons induces prodynorphin and NK-1 upregulation and contributes to persistent inflammatory pain hypersensitivity.
Activation of ERK (extracellular signal-regulated kinase) MAP (mitogen-activated protein) kinase in dorsal horn neurons of the spinal cord by peripheral noxious stimulation contributes to short-term pain hypersensitivity. We investigated ERK activation by peripheral inflammation and its involvement in regulating gene expression in the spinal cord and in contributing to inflammatory pain hypersensitivity. Injection of complete Freund's adjuvant (CFA) into a hindpaw produced a persistent inflammation and a sustained ERK activation in neurons in the superficial layers (laminae I-IIo) of the dorsal horn. CFA also induced an upregulation of prodynorphin and neurokinin-1 (NK-1) in dorsal horn neurons, which was suppressed by intrathecal delivery of the MEK (MAP kinase kinase) inhibitor U0126. CFA-induced phospho-ERK primarily colocalized with prodynorphin and NK-1 in superficial dorsal horn neurons. Although intrathecal injection of U0126 did not affect basal pain sensitivity, it did attenuate both the establishment and maintenance of persistent inflammatory heat and mechanical hypersensitivity. Activation of the ERK pathway in a subset of nociceptive spinal neurons contributes, therefore, to persistent pain hypersensitivity, possibly via transcriptional regulation of genes, such as prodynorphin and NK-1.
Ji
Ru-Rong
RR
Neural Plasticity Research Group, Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02129, USA. ji@helix.mgh.harvard.edu
Befort
Katia
K
Brenner
Gary J
GJ
Woolf
Clifford J
CJ
D000818:Animals; D002070:Butadienes / Q000008:administration & dosage; D004195:Disease Models, Animal; D004745:Enkephalins / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005620:Freund's Adjuvant; D006614:Hindlimb / Q000294:innervation / Q000503:physiopathology; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology*; D007249:Inflammation / Q000503:physiopathology; D007278:Injections, Spinal; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009570:Nitriles / Q000008:administration & dosage; D010146:Pain / Q000503:physiopathology; D020671:Posterior Horn Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D013373:Substance P / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D002070:Butadienes; D004745:Enkephalins; D004791:Enzyme Inhibitors; D009570:Nitriles; D011498:Protein Precursors; D012333:RNA, Messenger; C113580:U 0126; D013373:Substance P; D005620:Freund's Adjuvant; C033660:preproenkephalin; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases