Peripheral inflammation alters AMPA receptor (AMPAR) subunit trafficking and increases AMPAR Ca2+ permeability at synapses of dorsal horn neurons by internalized GluR2-containing Ca2+-impermeable AMPARs (Park et al., 2009). However, whether and how AMPAR trafficking at extrasynaptic sites of these neurons changed under persistent inflammation and which molecular mechanisms underlie these changes are still unclear. Persistent peripheral inflammation was induced by complete Freund’s adjuvant (CFA, 100 μl), injected subcutaneously into the plantar side of one hind paw of the rats, anesthetized with isoflurane (1.5-2% depending on age and verified by toe pinch). The animals were used in accordance with protocols that were approved by the Animal Care and Use Committee at the Bogomoletz Institute of Physiology and Johns Hopkins University and were consistent with the ethical guidelines of the National Institutes of Health and the International Association for the Study of Pain. Using patch-clamp recording combined with Ca2+ imaging we showed that under normal conditions extrasynaptic AMPARs in rat substantia gelatinosa (SG) neurons consists predominantly of GluR2-containing Ca2+-impermeable receptors. Peripheral inflammation induces a dramatic increase in functional expression of GluR1-containing Ca2+-permeable AMPARs in the extrasynaptic plasma membrane of SG neurons, manifested as augmented AMPA-induced current and associated Ca2+ influx in neurons 1d post-CFA, an increased sensitivity to selective inhibition of Ca2+-permeable AMPARs and inward rectification of the currents (Kopach et al., 2011). These changes occurred only in SG neurons characterized by tonic firing properties, but not in those exhibiting a strong adaptation. By utilizing the oligonucleotides (ODNs) that specifically knockdown spinal cord protein kinase C alpha (PKCα), we found that a decrease in dorsal horn PKCα expression prevents CFA-induced upregulation of extrasynaptic Ca2+-permeable AMPARs in tonically firing SG neurons, 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. Finally, dorsal horn PKCα knockdown produced anti-nociceptive effect on CFA-induced thermal and mechanical hypersensitivity during the maintenance period of inflammatory pain. Thus, persistent inflammation dramatically increases functional expression of extrasynaptic GluR1-containing Ca2+-permeable AMPARs and their proportion in total AMPAR pool in tonically firing SG neurons that depends on PKCα. A significant anti-nociceptive effect of spinal cord PKCα knockdown may inspire the possible implications of PKCα gene-silencing therapy for preventing and/or treating persistent inflammatory pain.