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

摘要

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 an activation of spinal cord protein kinase C alpha (PKCα), but molecular mechanisms that underlie altered trafficking of extrasynaptic AMPARs are still unclear. By utilizing the antisence oligodeoxynucleotides that specifically knockdown PKCα, we have found that a decrease in dorsal horn PKCα expression prevents complete Freund’s adjuvant (CFA)-induced increase in a functional expression of extrasynaptic Ca²⁺-permeable AMPARs in substantia gelatinosa (SG) neurons of the rat spinal cord. This was manifested as an abolishment of augmented AMPA-induced currents and associated [Ca²⁺]i transients, and as a reverse of the current rectification 1 d post-CFA. These changes were observed specifically in SG neurons characterized by intrinsic tonic firing properties, but not in those exhibiting strong adaptation. Finally, dorsal horn PKCα knockdown produced anti-nociceptive 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. Altogether, our results indicate that inflammation-induced trafficking of extrasynaptic Ca²⁺-permeable AMPARs in tonically firing SG neurons depends on PKCα, and suggest that this PKCα-dependent trafficking may contribute to the persistent inflammatory pain maintenance.