This study investigates the acute effects of tumor necrosis factor α (TNF-α) on sodium channel Nav1.7 in sensory neurons. TNF-α is a major pro-inflammatory cytokine that sensitizes nociceptors and contributes to inflammatory pain. The research demonstrates that TNF-α rapidly increases the current density of Nav1.7 channels and enhances neuronal excitability in dorsal root ganglion (DRG) neurons. This effect is mediated by the phosphorylation of a specific serine residue (S110) in the N terminus of Nav1.7 by p38 MAPK. The study also reveals that while TNF-α increases the accumulation of Nav1.7-carrying vesicles at axonal endings, it does not significantly increase channel insertion into the axonal membrane. Instead, the channel insertion occurs preferentially in the somatic membrane. These findings highlight the compartment-specific regulation of Nav1.7 channels by TNF-α and provide insights into the molecular mechanisms underlying acute inflammatory pain. The results suggest that targeting the S110 residue or the p38 MAPK pathway could be potential therapeutic strategies for managing acute inflammatory pain.This study investigates the acute effects of tumor necrosis factor α (TNF-α) on sodium channel Nav1.7 in sensory neurons. TNF-α is a major pro-inflammatory cytokine that sensitizes nociceptors and contributes to inflammatory pain. The research demonstrates that TNF-α rapidly increases the current density of Nav1.7 channels and enhances neuronal excitability in dorsal root ganglion (DRG) neurons. This effect is mediated by the phosphorylation of a specific serine residue (S110) in the N terminus of Nav1.7 by p38 MAPK. The study also reveals that while TNF-α increases the accumulation of Nav1.7-carrying vesicles at axonal endings, it does not significantly increase channel insertion into the axonal membrane. Instead, the channel insertion occurs preferentially in the somatic membrane. These findings highlight the compartment-specific regulation of Nav1.7 channels by TNF-α and provide insights into the molecular mechanisms underlying acute inflammatory pain. The results suggest that targeting the S110 residue or the p38 MAPK pathway could be potential therapeutic strategies for managing acute inflammatory pain.