title: Peripheral inflammation induces tumor necrosis factor dependent AMPA receptor trafficking and Akt phosphorylation in spinal cord in addition to pain behavior.
abstract: In the present study, intraplantar carrageenan induced increased mechanical allodynia, phosphorylation of PKB/Akt and GluR1 ser 845 (PKA site) as well as GluR1, but not GluR2 movement into neuronal membranes. This change in membrane GluR1/GluR2 ratio is indicative of Ca(2+) permeable AMPA receptor insertion. Pain behavior was reduced and biochemical changes blocked by spinal pretreatment, but not post-treatment, with a tumor necrosis factor (TNF) antagonist, Etanercept (100microg). Pain behavior was also reduced by spinal inhibition of phosphatidylinositol 3-kinase (PI-3K) (wortmannin; 1 and 5microg) and LY294002; 50 and 100microg) and Akt (Akt inhibitor IV; 3microg). Phosphorylated Akt was found exclusively in neurons in grey matter and in oligodendrocytes in white matter. Interestingly, this increase was seen first in superficial dorsal horn and alpha-motor neurons (peak 45min) and later (peak 2h post-injection) in deep dorsal horn neurons. Akt and GluR1 phosphorylation, AMPA receptor trafficking and mechanical allodynia were all TNF dependent. Whether phosphorylation of Akt and of GluR1 are in series or in parallel or upstream of pain behavior remains to be determined. Certainly, TNF-mediated GluR1 trafficking appears to play a major role in inflammatory pain and TNF-mediated effects such as these could represent a path by which glia contribute to neuronal sensitization (spinal LTP) and pathological pain.
authors.affiliation: Department of Anesthesiology, University of California, San Diego, La Jolla, CA 92093, USA Department of Anesthesiology and Pain Medicine, Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea Department of Pharmacology, Karolinska Institute, Stockholm, Sweden College of Medicine, University of Arizona, Tucson, AZ, USA.
authors.forename: Jeong Il
authors.initials: JI
authors.lastname: Choi
authors.forename: Camilla I
authors.initials: CI
authors.lastname: Svensson
authors.forename: Fred J
authors.initials: FJ
authors.lastname: Koehrn
authors.forename: Aditi
authors.initials: A
authors.lastname: Bhuskute
authors.forename: Linda S
authors.initials: LS
authors.lastname: Sorkin
mesh_terms: D000818:Animals; D002351:Carrageenan / Q000494:pharmacology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000068800:Etanercept; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D007074:Immunoglobulin G / Q000494:pharmacology; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D018836:Inflammation Mediators / Q000494:pharmacology; D008297:Male; D009619:Nociceptors / Q000187:drug effects / Q000502:physiology; D009836:Oligodendroglia / Q000378:metabolism; D010146:Pain / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D020671:Posterior Horn Cells / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000187:drug effects / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000502:physiology; D013116:Spinal Cord / Q000166:cytology / Q000378:metabolism* / Q000503:physiopathology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D002351:Carrageenan; D004791:Enzyme Inhibitors; D000068800:Etanercept; D007074:Immunoglobulin G; D018836:Inflammation Mediators; D051057:Proto-Oncogene Proteins c-akt; D018091:Receptors, AMPA; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha