Pharmacologically enabling the degradation of Na_V1.8 channels to reduce neuropathic pain

In phase II clinical trials, Na_V1.8 channels were identified as viable targets to treat acute pain. Results were modest, however, and Na_V1.8 pore blockers must be given systemically, potentially leading to adverse effects, especially during prolonged use. A local, long-lasting approach is desirable, yet local anesthetics are neither specific nor long-lasting. In lieu of a pore blocker approach, we show a pharmacological method targeting the scaffolding and degradation of Na_V1.8 channels, which attenuated neuropathic pain behavior in mice. Na_V1.8 channels interact with the WW domain–containing scaffold protein called Magi-1. WW domains are typically found in ubiquitin ligases, and Na_V1.8 channels are susceptible to degradation by ubiquitin ligases. Here, we show Na_V1.8 and MAGI-1 colocalized in human tissues. We demonstrate that a lipidated peptide derived from the Na_V1.8 WW binding domain, at sub-micromolar concentrations, inhibited rodent dorsal root ganglion neuronal firing. The peptide reduced Na_V1.8 channel immunoreactivity and tetrodotoxin-resistant currents in human dorsal root ganglion neurons. We found that the lipidated peptide attenuated neuropathic pain behaviors in mice for multiple weeks after a single injection. Our results reveal that the Na_V1.8-targeted lipidated peptide provides local and sustained analgesia, serving as a viable alternative to Na_V1.8 pore blockers.