Targeting Supramolecular Active Complexes of Na_v1.7/Na_v1.8 to Relieve Chronic Neuropathic Pain

Neuropathic pain (NP) affects 7%-10% of population, with current treatments often proving inadequate. Here we show that Na_v1.7 and Na_v1.8 form supramolecular active complexes (SMACs) with polygonal lattice structure in dorsal root ganglion (DRG) neurons of mouse models and patients with severe chronic NP. TrkB signaling facilitates the formation of Na_v1.7/Na_v1.8 SMACs. Targeting these SMACs with combined Na_v1.7 and Na_v1.8 blockers inhibits action potentials of both human and mouse pathological DRG neurons and synergistically alleviates chronic NP in spared nerve injury (SNI) and diabetic mouse models. The SMAC formation is promoted by five cytoskeletal proteins (SPTAN1, DSP, AHNAK, MPZ and PRX). Functional study demonstrates that these SMACs create a Na⁺ potential difference to amplify sodium currents, promoting DRG neuron hyperexcitability. Moreover, knockdown of these five cytoskeletal proteins prevents action potential generation in DRG neurons and eliminates NP in SNI mice. Our findings support that SMACs can be a potential pathological hallmark and novel promising therapeutic target for severe chronic NP.