Preclinical Animal Models to Investigate the Role of Na_v1.7 Ion Channels in Pain

Chronic pain is a maladaptive neurological disease that remains a major global healthcare problem. Voltage-gated sodium channels (Na_vs) are major drivers of the excitability of sensory neurons, and the Na_v subtype 1.7 (Na_v1.7) has been shown to be critical for the transmission of pain-related signaling. This is highlighted by demonstrations that gain-of-function mutations in the Na_v1.7 gene SCN9A result in various pain pathologies, whereas loss-of-function mutations cause complete insensitivity to pain. A substantial body of evidence demonstrates that chronic neuropathy and inflammation result in an upregulation of Na_v1.7, suggesting that this channel contributes to pain transmission and sensation. As such, Na_v1.7 is an attractive human-validated target for the treatment of pain. Nonetheless, a lack of subtype selectivity, insufficient efficacy, and adverse reactions are some of the issues that have hindered Na_v1.7-targeted drug development. This review summarizes the pain behavior profiles mediated by Na_v1.7 reported in multiple preclinical models, outlining the current knowledge of the biophysical, physiological, and distribution properties required for a Na_v1.7 inhibitor to produce analgesia.