Papers of the Week

Chronic pain and addiction are a significant global health challenge. Voltage-gated sodium channel Na 1.8, a pivotal driver of pain signaling, is a clinically validated target for the development of novel, non-addictive pain therapeutics. Small molecule inhibitors against Na 1.8 have shown promise in acute pain indications, but large clinical effect sizes have not yet been demonstrated and efficacy in chronic pain indications are lacking. An alternative strategy to target Na 1.8 channels for analgesia is to reduce the number of channels that are present on nociceptor membranes. We generated a therapeutic heterobifunctional protein, named UbiquiNa , that contains a Na 1.8-selective binding module and the catalytic subunit of the NEDD4 E3 Ubiquitin ligase. We show that UbiquiNav significantly reduces channel expression in the plasma membrane and reduces Na 1.8 currents in rodent sensory neurons. We demonstrate that UbiquiNa is selective for Na 1.8 over other Na isoforms and other components of the sensory neuronal electrogenisome. We then show that UbiquiNa normalizes the distribution of Na 1.8 protein to distal axons, and that UbiquiNa normalizes the neuronal hyperexcitability in models of inflammatory and chemotherapy-induced neuropathic pain. Our results serve as a blueprint for the design of therapeutics that leverage the selective ubiquitination of Na 1.8 channels for analgesia.