Unveiling Targets for Treating Postoperative Pain: The Role of the TNF-α/p38 MAPK/NF-κB/Nav1.8 and Nav1.9 Pathways in the Mouse Model of Incisional Pain

Although the mouse model of incisional pain is broadly used, the mechanisms underlying plantar incision-induced nociception are not fully understood. This work investigates the role of Na(v)1.8 and Na(v)1.9 sodium channels in nociceptive sensitization following plantar incision in mice and the signaling pathway modulating these channels. A surgical incision was made in the plantar hind paw of male Swiss mice. Nociceptive thresholds were assessed by von Frey filaments. Gene expression of Na(v)1.8, Na(v)1.9, TNF-α, and COX-2 was evaluated by Real-Time PCR in dorsal root ganglia (DRG). Knockdown mice for Na(v)1.8 and Na(v)1.9 were produced by antisense oligodeoxynucleotides intrathecal treatments. Local levels of TNF-α and PGE(2) were immunoenzymatically determined. Incised mice exhibited hypernociception and upregulated expression of Na(v)1.8 and Na(v)1.9 in DRG. Antisense oligodeoxynucleotides reduced hypernociception and downregulated Na(v)1.8 and Na(v)1.9. TNF-α and COX-2/PGE(2) were upregulated in DRG and plantar skin. Inhibition of TNF-α and COX-2 reduced hypernociception, but only TNF-α inhibition downregulated Na(v)1.8 and Na(v)1.9. Antagonizing NF-κB and p38 mitogen-activated protein kinase (MAPK), but not ERK or JNK, reduced both hypernociception and hyperexpression of Na(v)1.8 and Na(v)1.9. This study proposes the contribution of the TNF-α/p38/NF-κB/Na(v)1.8 and Na(v)1.9 pathways to the pathophysiology of the mouse model of incisional pain.