Preclinical Animal Models to Investigate the Role of Nav1.7 Ion Channels in Pain
Abstract
Chronic pain is a maladaptive neurological disease that remains a major global healthcare problem. Voltage-gated sodium channels (Navs) are major drivers of the excitability of sensory neurons, and the Nav subtype 1.7 (Nav1.7) 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 Nav1.7 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 Nav1.7, suggesting that this channel contributes to pain transmission and sensation. As such, Nav1.7 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 Nav1.7-targeted drug development. This review summarizes the pain behavior profiles mediated by Nav1.7 reported in multiple preclinical models, outlining the current knowledge of the biophysical, physiological, and distribution properties required for a Nav1.7 inhibitor to produce analgesia.
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