title: Neuronal expression of the ubiquitin ligase Nedd4-2 in rat dorsal root ganglia: modulation in the spared nerve injury model of neuropathic pain.
abstract: Neuronal hyperexcitability following peripheral nerve lesions may stem from altered activity of voltage-gated sodium channels (VGSCs), which gives rise to allodynia or hyperalgesia. In vitro, the ubiquitin ligase Nedd4-2 is a negative regulator of VGSC α-subunits (Na(v)), in particular Na(v)1.7, a key actor in nociceptor excitability. We therefore studied Nedd4-2 in rat nociceptors, its co-expression with Na(v)1.7 and Na(v)1.8, and its regulation in pathology. Adult rats were submitted to the spared nerve injury (SNI) model of neuropathic pain or injected with complete Freund's adjuvant (CFA), a model of inflammatory pain. L4 dorsal root ganglia (DRG) were analyzed in sham-operated animals, seven days after SNI and 48 h after CFA with immunofluorescence and Western blot. We observed Nedd4-2 expression in almost 50% of DRG neurons, mostly small and medium-sized. A preponderant localization is found in the non-peptidergic sub-population. Additionally, 55.7 ± 2.7% and 55.0 ± 3.6% of Nedd4-2-positive cells are co-labeled with Na(v)1.7 and Na(v)1.8 respectively. SNI significantly decreases the proportion of Nedd4-2-positive neurons from 45.9 ± 1.9% to 33.5 ± 0.7% (p<0.01) and the total Nedd4-2 protein to 44% ± 0.13% of its basal level (p<0.01, n=4 animals in each group, mean ± SEM). In contrast, no change in Nedd4-2 was found after peripheral inflammation induced by CFA. These results indicate that Nedd4-2 is present in nociceptive neurons, is downregulated after peripheral nerve injury, and might therefore contribute to the dysregulation of Na(v)s involved in the hyperexcitability associated with peripheral nerve injuries.
authors.affiliation: Pain Center, Department of Anesthesiology, University Hospital Center (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland. Matthieu.Cachemaille@chuv.ch
authors.forename: M
authors.initials: M
authors.lastname: Cachemaille
authors.forename: C J
authors.initials: CJ
authors.lastname: Laedermann
authors.forename: M
authors.initials: M
authors.lastname: Pertin
authors.forename: H
authors.initials: H
authors.lastname: Abriel
authors.forename: R-D
authors.initials: RD
authors.lastname: Gosselin
authors.forename: I
authors.initials: I
authors.lastname: Decosterd
mesh_terms: D051700:Activating Transcription Factor 3 / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D002452:Cell Count; D004195:Disease Models, Animal; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism*; D005620:Freund's Adjuvant / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000378:metabolism / Q000473:pathology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000378:metabolism; D062559:NAV1.8 Voltage-Gated Sodium Channel / Q000378:metabolism; D000075702:Nedd4 Ubiquitin Protein Ligases; D009437:Neuralgia / Q000473:pathology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D051700:Activating Transcription Factor 3; C497108:Atf3 protein, rat; D056827:Endosomal Sorting Complexes Required for Transport; D062556:NAV1.7 Voltage-Gated Sodium Channel; D062559:NAV1.8 Voltage-Gated Sodium Channel; C568319:Scn10a protein, rat; C503480:Scn9a protein, rat; D005620:Freund's Adjuvant; C000618479:NEDD4L protein, rat; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618484:Nedd4 protein, rat; D044767:Ubiquitin-Protein Ligases