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Peripheral neuropathic pain is a disabling condition resulting from nerve injury. It is characterized by the dysregulation of voltage-gated sodium channels (Na^sub v^s) expressed in dorsal root ganglion (DRG) sensory neurons. The mechanisms underlying the altered expression of Na^sub v^s remain unknown. This study investigated the role of the E3 ubiquitin ligase NEDD4-2, which is known to ubiquitylate Na^sub v^s, in the pathogenesis of neuropathic pain in mice. The spared nerve injury (SNI) model of traumatic nerve injury-induced neuropathic pain was used, and an Na^sub v^1.7-specific inhibitor, ProTxII, allowed the isolation of Na^sub v^1.7-mediated currents. SNI decreased NEDD4-2 expression in DRG cells and increased the amplitude of Na^sub v^1.7 and Na^sub v^1.8 currents. The redistribution of Na^sub v^1.7 channels toward peripheral axons was also observed. Similar changes were observed in the nociceptive DRG neurons of Nedd4L knockout mice (SNS-Nedd4L^sup -/-^). SNS-Nedd4L^sup -/-^ mice exhibited thermal hypersensitivity and an enhanced second pain phase after formalin injection. Restoration of NEDD4-2 expression in DRG neurons using recombinant adenoassociated virus (rAAV2/6) not only reduced Na^sub v^1.7 and Na^sub v^1.8 current amplitudes, but also alleviated SNI-induced mechanical allodynia. These findings demonstrate that NEDD4-2 is a potent posttranslational regulator of Na^sub v^s and that downregulation of NEDD4-2 leads to the hyperexcitability of DRG neurons and contributes to the genesis of pathological pain.
Introduction
Neuropathic pain is a direct consequence of alterations in the somatosensory system. It affects approximately 7% of the general population and is insufficiently treated with currently available drugs (1). Following nerve injury, there is ectopic spontaneous activity of afferent neurons due to the increased expression of voltage-gated sodium channels (Navs) (2, 3). This hyperexcitabil- ity mediates enduring changes in the nervous system, contrib- uting to both peripheral and central sensitization (4). Navs are heteromeric glycosylated protein complexes composed of a large pore-forming a subunit and auxiliary ? subunits (5, 6). Nine genes encode for distinct channel isoforms (Navl.l to Nav1.9), each displaying specific properties. They are classified according to their sensitivity to tetrodotoxin (TTX). All isoforms, except Nav1.4 and Nav1.5, are expressed in the dorsal root ganglia (DRG) and trigeminal ganglia (TG) nociceptive neurons, with Nav1.8 and Nav1.9 being expressed almost exclusively in DRG/ TG neurons and Nav1.7 in DRG/TG and sympathetic ganglion neurons (7). Nav1.7 is...