Dysregulation of voltage-gated sodium channels by ubiquitin ligase NEDD4-2 in neuropathic pain
Cédric J. Laedermann, Matthieu Cachemaille, Guylène Kirschmann, Marie Pertin, Romain-Daniel Gosselin, Isabelle Chang, Maxime Albesa, Chris Towne, Bernard L. Schneider, Stephan Kellenberger, Hugues Abriel, Isabelle Decosterd
Cédric J. Laedermann, Matthieu Cachemaille, Guylène Kirschmann, Marie Pertin, Romain-Daniel Gosselin, Isabelle Chang, Maxime Albesa, Chris Towne, Bernard L. Schneider, Stephan Kellenberger, Hugues Abriel, Isabelle Decosterd
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Research Article Neuroscience

Dysregulation of voltage-gated sodium channels by ubiquitin ligase NEDD4-2 in neuropathic pain

Abstract

Peripheral neuropathic pain is a disabling condition resulting from nerve injury. It is characterized by the dysregulation of voltage-gated sodium channels (Navs) expressed in dorsal root ganglion (DRG) sensory neurons. The mechanisms underlying the altered expression of Navs remain unknown. This study investigated the role of the E3 ubiquitin ligase NEDD4-2, which is known to ubiquitylate Navs, 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 Nav1.7-specific inhibitor, ProTxII, allowed the isolation of Nav1.7-mediated currents. SNI decreased NEDD4-2 expression in DRG cells and increased the amplitude of Nav1.7 and Nav1.8 currents. The redistribution of Nav1.7 channels toward peripheral axons was also observed. Similar changes were observed in the nociceptive DRG neurons of Nedd4L knockout mice (SNS-Nedd4L–/–). SNS-Nedd4L–/– 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 Nav1.7 and Nav1.8 current amplitudes, but also alleviated SNI-induced mechanical allodynia. These findings demonstrate that NEDD4-2 is a potent posttranslational regulator of Navs and that downregulation of NEDD4-2 leads to the hyperexcitability of DRG neurons and contributes to the genesis of pathological pain.

Authors

Cédric J. Laedermann, Matthieu Cachemaille, Guylène Kirschmann, Marie Pertin, Romain-Daniel Gosselin, Isabelle Chang, Maxime Albesa, Chris Towne, Bernard L. Schneider, Stephan Kellenberger, Hugues Abriel, Isabelle Decosterd

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Figure 5

SNS-Nedd4L–/– mice show increased thermal sensitivity and an increased second pain phase after formalin injection.

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SNS-Nedd4L–/– mice show increased thermal sensitivity and an increased ...
(A) Significantly higher thermal sensitivity was detected in the hot-plate test at 52°C and 54°C in SNS-Nedd4L–/– mice. P = 0.112 at 49°C, **P = 0.009 at 52°C, and **P = 0.008 at 55°C; Mann-Whitney U test. (B) No differences were observed in the tail-flick test. P = 0.414 at intensity 4 and P = 0.830 at intensity 7 (AU); Mann-Whitney U test. (C) Responses to the tail pressure test were unchanged. P = 0.452, Student’s t test. (D) Basal responses to mechanical stimulation and development of SNI-related mechanical allodynia-like behavior were not different. P > 0.05, 2-way ANOVA on log values with post-hoc Bonferroni’s tests. (E) Higher thermal sensitivity was detected at 52°C in SNS-Nedd4L–/– mice, but this effect was not further increased after SNI. *P < 0.05 between groups using 2-way ANOVA with repeated measures. *P < 0.05 on day 7 with post-hoc Bonferroni’s tests. (F) Plantar test 35 days after SNI. Higher thermal sensitivity was detected in SNS-Nedd4L–/– mice as compared with the noninjured paws of Nedd4Lfl/fl mice (contralateral). SNI induced thermal hyperalgesia in the injured paws of Nedd4Lfl/fl mice compared with noninjured paws. *P = 0.013 and **P = 0.006 at intensity 3 (AU), Student’s t test. (G) Time course of the nocifensive response to formalin injection revealed an increased response in SNS-Nedd4L–/– mice during the second phase of the test. ***P < 0.001, 2-way ANOVA with repeated measures with post-hoc Bonferroni’s tests. Insert shows the bar graph of this effect through AUC quantification. **P = 0.009, Mann-Whitney U test. Data are expressed as the means ± SEM and n = 7– 28 animals per group for all panels.