title: PKCα is required for inflammation-induced trafficking of extrasynaptic AMPA receptors in tonically firing lamina II dorsal horn neurons during the maintenance of persistent inflammatory pain.
abstract: Persistent inflammation promotes internalization of synaptic GluR2-containing, Ca(2+)-impermeable AMPA receptors (AMPARs) and insertion of GluR1-containing, Ca(2+)-permeable AMPARs at extrasynaptic sites in dorsal horn neurons. Previously we have shown that internalization of synaptic GluR2-containing AMPARs requires activation of spinal cord protein kinase C alpha (PKCα), but molecular mechanisms that underlie altered trafficking of extrasynaptic AMPARs are unclear. Here, using antisense (AS) oligodeoxynucleotides (ODN) that specifically knock down PKCα, we found that a decrease in dorsal horn PKCα expression prevents complete Freund's adjuvant (CFA)-induced increase in functional expression of extrasynaptic Ca(2+)-permeable AMPARs in substantia gelatinosa (SG) neurons of the rat spinal cord. Augmented AMPA-induced currents and associated [Ca(2+)](i) transients were abolished, and the current rectification 1 day post-CFA was reversed. These changes were observed specifically in SG neurons characterized by intrinsic tonic firing properties, but not in those that exhibited strong adaptation. Finally, dorsal horn PKCα knockdown produced an antinociceptive effect on CFA-induced thermal and mechanical hypersensitivity during the maintenance period of inflammatory pain, indicating a role for PKCα in persistent inflammatory pain maintenance. Our results indicate that inflammation-induced trafficking of extrasynaptic Ca(2+)-permeable AMPARs in tonically firing SG neurons depends on PKCα, and that this PKCα-dependent trafficking may contribute to persistent inflammatory pain maintenance.
  
  
  CONCLUSIONS
  This study shows that PKCα knockdown blocks inflammation-induced upregulation of extrasynaptic Ca(2+)-permeable AMPARs in dorsal horn neurons and produces an antinociceptive effect during the maintenance period of inflammatory pain. These findings have potential implications for use of PKCα gene-silencing therapy to prevent and/or treat persistent inflammatory pain.
authors: State Key Laboratory of Molecular and Cellular Biology, Bogomoletz Institute of Physiology, Kiev, Ukraine.
authors: Olga
authors: O
authors: Kopach
authors: Viacheslav
authors: V
authors: Viatchenko-Karpinski
authors: Fidelis E
authors: FE
authors: Atianjoh
authors: Pavel
authors: P
authors: Belan
authors: Yuan-Xiang
authors: YX
authors: Tao
authors: Nana
authors: N
authors: Voitenko
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D005620:Freund's Adjuvant; D007091:Image Processing, Computer-Assisted; D007249:Inflammation / Q000150:complications / Q000201:enzymology* / Q000378:metabolism*; D007278:Injections, Spinal; D008297:Male; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000494:pharmacology; D010146:Pain / Q000139:chemically induced / Q000209:etiology / Q000503:physiopathology*; D018408:Patch-Clamp Techniques; D020671:Posterior Horn Cells / Q000502:physiology*; D051571:Protein Kinase C-alpha / Q000235:genetics / Q000502:physiology*; D051381:Rats; D018091:Receptors, AMPA / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology
chemical_list: D009838:Oligodeoxyribonucleotides; D018091:Receptors, AMPA; D005620:Freund's Adjuvant; D051571:Protein Kinase C-alpha; D002118:Calcium
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