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

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 (PKC alpha), but molecular mechanisms that underlie altered trafficking of extrasynaptic AMPARs are unclear. Here, using antisense (AS) oligodeoxynucleotides (ODN) that specifically knock down PKC alpha, we found that a decrease in dorsal horn PKC alpha 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 [Ca2+](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 PKC alpha knockdown produced an antinociceptive effect on CFA-induced thermal and mechanical hypersensitivity during the maintenance period of inflammatory pain, indicating a role for PKC alpha in persistent inflammatory pain maintenance. Our results indicate that inflammation-induced trafficking of extrasynaptic Ca2+-permeable AMPARs in tonically firing SG neurons depends on PKC alpha, and that this PKC alpha-dependent trafficking may contribute to persistent inflammatory pain maintenance. Perspective: This study shows that PKC alpha 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 PKC alpha gene-silencing therapy to prevent and/or treat persistent inflammatory pain. (C) 2013 by the American Pain Society