Synergistic Inhibition of Nav1.7 and NCX1: A Novel Strategy for Treating Cancer-Induced Bone Pain by Modulating Pain Sensitization and Neuronal Inflammation

Abstract

Aims

Cancer-induced bone pain (CIBP) is a chronic and refractory pain condition characterized by neuronal hyperexcitability, calcium dysregulation, and neuroinflammation. Voltage-gated sodium channels (VGSCs) and sodium/calcium exchangers (NCXs) are crucial in regulating sensory neuron sodium–calcium homeostasis, influencing nociceptive signaling and neuroinflammatory responses. This study focused on exploring how Nav1.7 from the VGSC family and NCX1 from the NCX family influence nociceptive signaling and neuroinflammation in CIBP.

Methods

CIBP was induced in mice. Nav1.7 and NCX1 expression and colocalization in DRG neurons were analyzed by qPCR, western blotting, and immunofluorescence. Calcium overload and neuronal excitability were assessed using calcium imaging and electrophysiological recordings. Neuroinflammation markers were detected by qPCR and western blotting.

Results

Among the VGSC and NCX subtypes, Nav1.7 and NCX1 were notably upregulated and colocalized in the DRG neurons of CIBP mice. Combined inhibition of these channels demonstrated a synergistic analgesic effect and markedly reduced neuronal calcium overload and hyperexcitability. Furthermore, the combined inhibition substantially alleviated neuroinflammation by inhibiting the p38 MAPK/NF-κB pathway and lowering proinflammatory cytokine levels.

Conclusions

The combined inhibition of Nav1.7 and NCX1 enhances analgesic effects and reduces neuroinflammation, presenting a potential therapeutic approach for CIBP and other cancer-associated pain disorders.