TY - JOUR
T1 - 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
AU - Kopach, Olga
AU - Viatchenko-Karpinski, Viacheslav
AU - Atianjoh, Fidelis E.
AU - Belan, Pavel
AU - Tao, Yuan Xiang
AU - Voitenko, Nana
PY - 2013/2
Y1 - 2013/2
N2 - 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.
AB - 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.
KW - Extrasynaptic AMPA receptors
KW - PKCα
KW - inflammatory pain
KW - substantia gelatinosa neurons
UR - http://www.scopus.com/inward/record.url?scp=84873297041&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84873297041&partnerID=8YFLogxK
U2 - 10.1016/j.jpain.2012.10.015
DO - 10.1016/j.jpain.2012.10.015
M3 - Article
C2 - 23374940
AN - SCOPUS:84873297041
SN - 1526-5900
VL - 14
SP - 182
EP - 192
JO - Journal of Pain
JF - Journal of Pain
IS - 2
ER -