Modulation of peripheral inflammation in sensory ganglia by nuclear factor κB decoy oligodeoxynucleotide: involvement of SRC kinase pathway

Nuclear factor kappa B (NFκB) transcription factor plays a key role in the expression of many genes involved in the inflammatory process. We used the Freund's Complete Adjuvant (FCA)-induced model of peripheral inflammation to investigate the anti-inflammatory effects of double stranded oligodeoxynucleotides (ODN) with consensus NFκB sequence as transcription factor decoys to inhibit NFκB activation in the dorsal root ganglia (DRG). Local administration of the wild-type-, but not mutant-ODN decoy, dose-dependently inhibited edema formation and paw withdrawal latency as a measure of hyperalgesic response induced by FCA in rat paw. Biochemical assays performed in ipsilateral L4/L5 dorsal root ganglia obtained following FCA/wild-type ODN treatment showed: (1) an inhibition of the activity of c-Src kinase, a member of the non-receptor tyrosine kinase super family, (2) a decreased level of p65 NFκB subunit, and (3) an inhibition of cyclooxygenase-2 (COX-2) protein expression, a major pro-inflammatory enzyme transcriptionally controlled by NFκB. The present results indicate that the wild-type ODN decoy may act as a competitor for NFκB binding to its cognate recognition sequence as well as a modulator of c-Src activity in the DRG. The NFκB/c-Src interaction may represent a novel pathway for further exploring the molecular mechanism of inflammatory pain.