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

Abstract

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_v1.8 and Na_v1.9 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 <i>Na_v1.8</i>, <i>Na_v1.9</i>, <i>TNF-α</i>, and <i>COX-2</i> was evaluated by Real-Time PCR in dorsal root ganglia (DRG). Knockdown mice for Na_v1.8 and Na_v1.9 were produced by antisense oligodeoxynucleotides intrathecal treatments. Local levels of TNF-α and PGE₂ were immunoenzymatically determined. Incised mice exhibited hypernociception and upregulated expression of <i>Na_v1.8</i> and <i>Na_v1.9</i> in DRG. Antisense oligodeoxynucleotides reduced hypernociception and downregulated <i>Na_v1.8</i> and <i>Na_v1.9</i>. TNF-α and <i>COX-2</i>/PGE₂ were upregulated in DRG and plantar skin. Inhibition of TNF-α and COX-2 reduced hypernociception, but only TNF-α inhibition downregulated <i>Na_v1.8</i> and <i>Na_v1.9</i>. Antagonizing NF-κB and p38 mitogen-activated protein kinase (MAPK), but not ERK or JNK, reduced both hypernociception and hyperexpression of <i>Na_v1.8</i> and <i>Na_v1.9</i>. This study proposes the contribution of the TNF-α/p38/NF-κB/Na_v1.8 and Na_v1.9 pathways to the pathophysiology of the mouse model of incisional pain.