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

Olga Kopach, Viacheslav Viatchenko-Karpinski, Fidelis E. Atianjoh, Pavel Belan, Yuan Xiang Tao, Nana Voitenko

Research output: Contribution to journalArticle

Abstract

Persistent inflammation promotes internalization of synaptic GluR2-containing, Ca2+-impermeable AMPA receptors (AMPARs) and insertion of GluR1-containing, Ca2+-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 Ca2+-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 Ca2+-permeable AMPARs in tonically firing SG neurons depends on PKCα, and that this PKCα-dependent trafficking may contribute to persistent inflammatory pain maintenance. Perspective: This study shows that PKCα knockdown blocks inflammation-induced upregulation of extrasynaptic Ca2+-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.

Original languageEnglish (US)
Pages (from-to)182-192
Number of pages11
JournalJournal of Pain
Volume14
Issue number2
DOIs
StatePublished - Feb 2013

Fingerprint

Substantia Gelatinosa
Protein Kinase C-alpha
Posterior Horn Cells
AMPA Receptors
Maintenance
Inflammation
Pain
Freund's Adjuvant
Neurons
Spinal Cord
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
Oligodeoxyribonucleotides
Gene Silencing
Genetic Therapy
Hypersensitivity
Up-Regulation
Hot Temperature

Keywords

  • Extrasynaptic AMPA receptors
  • inflammatory pain
  • PKCα
  • substantia gelatinosa neurons

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine
  • Neurology
  • Clinical Neurology

Cite this

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. / Kopach, Olga; Viatchenko-Karpinski, Viacheslav; Atianjoh, Fidelis E.; Belan, Pavel; Tao, Yuan Xiang; Voitenko, Nana.

In: Journal of Pain, Vol. 14, No. 2, 02.2013, p. 182-192.

Research output: Contribution to journalArticle

Kopach, Olga ; Viatchenko-Karpinski, Viacheslav ; Atianjoh, Fidelis E. ; Belan, Pavel ; Tao, Yuan Xiang ; Voitenko, Nana. / 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. In: Journal of Pain. 2013 ; Vol. 14, No. 2. pp. 182-192.
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