TNF-α is a major pro-inflammatory cytokine that sensitizes nociceptors by modulating voltage-gated sodium channels, including NaV1.7, which is crucial for pain sensation. This study shows that acute exposure to TNF-α increases the excitability of sensory neurons by upregulating NaV1.7 current density. This effect is mediated by p38 MAPK, which phosphorylates serine 110 in the N-terminal region of NaV1.7, promoting channel insertion into the somatic membrane. However, this process is compartment-specific, with NaV1.7 channels accumulating in axonal endings but not inserting into the axonal membrane. The study also demonstrates that the N-terminal region of NaV1.7 is sufficient to mediate this effect. These findings highlight the role of TNF-α in regulating NaV1.7 channel insertion in sensory neurons and suggest that compartment-specific regulation of ion channels may be a key mechanism in inflammatory pain. The results provide insights into the molecular mechanisms underlying TNF-α- mediated regulation of NaV1.7 and its implications for pain pathogenesis.TNF-α is a major pro-inflammatory cytokine that sensitizes nociceptors by modulating voltage-gated sodium channels, including NaV1.7, which is crucial for pain sensation. This study shows that acute exposure to TNF-α increases the excitability of sensory neurons by upregulating NaV1.7 current density. This effect is mediated by p38 MAPK, which phosphorylates serine 110 in the N-terminal region of NaV1.7, promoting channel insertion into the somatic membrane. However, this process is compartment-specific, with NaV1.7 channels accumulating in axonal endings but not inserting into the axonal membrane. The study also demonstrates that the N-terminal region of NaV1.7 is sufficient to mediate this effect. These findings highlight the role of TNF-α in regulating NaV1.7 channel insertion in sensory neurons and suggest that compartment-specific regulation of ion channels may be a key mechanism in inflammatory pain. The results provide insights into the molecular mechanisms underlying TNF-α- mediated regulation of NaV1.7 and its implications for pain pathogenesis.