title: Nav1.9 channel contributes to mechanical and heat pain hypersensitivity induced by subacute and chronic inflammation.
abstract: Inflammation is known to be responsible for the sensitization of peripheral sensory neurons, leading to spontaneous pain and invalidating pain hypersensitivity. Given its role in regulating neuronal excitability, the voltage-gated Nav1.9 channel is a potential target for the treatment of pathological pain, but its implication in inflammatory pain is yet not fully described. In the present study, we examined the role of the Nav1.9 channel in acute, subacute and chronic inflammatory pain using Nav1.9-null mice and Nav1.9 knock-down rats. In mice we found that, although the Nav1.9 channel does not contribute to basal pain thresholds, it plays an important role in heat pain hypersensitivity induced by subacute paw inflammation (intraplantar carrageenan) and chronic ankle inflammation (complete Freund's adjuvant-induced monoarthritis). We showed for the first time that Nav1.9 also contributes to mechanical hypersensitivity in both models, as assessed using von Frey and dynamic weight bearing tests. Consistently, antisense-based Nav1.9 gene silencing in rats reduced carrageenan-induced heat and mechanical pain hypersensitivity. While no changes in Nav1.9 mRNA levels were detected in dorsal root ganglia (DRGs) during subacute and chronic inflammation, a significant increase in Nav1.9 immunoreactivity was observed in ipsilateral DRGs 24 hours following carrageenan injection. This was correlated with an increase in Nav1.9 immunolabeling in nerve fibers surrounding the inflamed area. No change in Nav1.9 current density could be detected in the soma of retrolabeled DRG neurons innervating inflamed tissues, suggesting that newly produced channels may be non-functional at this level and rather contribute to the observed increase in axonal transport. Our results provide evidence that Nav1.9 plays a crucial role in the generation of heat and mechanical pain hypersensitivity, both in subacute and chronic inflammatory pain models, and bring new elements for the understanding of its regulation in those models.
authors.affiliation: Clermont Université, Laboratoire de Pharmacologie Fondamentale et Clinique de la Douleur, Clermont-Ferrand, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Lolignier
authors.forename: Muriel
authors.initials: M
authors.lastname: Amsalem
authors.forename: François
authors.initials: F
authors.lastname: Maingret
authors.forename: Françoise
authors.initials: F
authors.lastname: Padilla
authors.forename: Mélanie
authors.initials: M
authors.lastname: Gabriac
authors.forename: Eric
authors.initials: E
authors.lastname: Chapuy
authors.forename: Alain
authors.initials: A
authors.lastname: Eschalier
authors.forename: Patrick
authors.initials: P
authors.lastname: Delmas
authors.forename: Jérôme
authors.initials: J
authors.lastname: Busserolles
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000503:physiopathology; D002351:Carrageenan; D002908:Chronic Disease; D004487:Edema / Q000139:chemically induced / Q000503:physiopathology; D005552:Forelimb / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D005727:Ganglia, Spinal / Q000378:metabolism; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006614:Hindlimb / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D006930:Hyperalgesia / Q000503:physiopathology*; D007150:Immunohistochemistry; D007249:Inflammation / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D062558:NAV1.9 Voltage-Gated Sodium Channel; D010146:Pain / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D011984:Sensory Receptor Cells / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013997:Time Factors
chemical_list: D062558:NAV1.9 Voltage-Gated Sodium Channel; C491885:Scn11a protein, mouse; C113705:Scn11a protein, rat; D015222:Sodium Channels; D002351:Carrageenan