title: Functional up-regulation of Nav1.8 sodium channel in Aβ afferent fibers subjected to chronic peripheral inflammation.
abstract: BACKGROUND
  Functional alterations in the properties of Aβ afferent fibers may account for the increased pain sensitivity observed under peripheral chronic inflammation. Among the voltage-gated sodium channels involved in the pathophysiology of pain, Na(v)1.8 has been shown to participate in the peripheral sensitization of nociceptors. However, to date, there is no evidence for a role of Na(v)1.8 in controlling Aβ-fiber excitability following persistent inflammation.
  
  
  METHODS
  Distribution and expression of Na(v)1.8 in dorsal root ganglia and sciatic nerves were qualitatively or quantitatively assessed by immunohistochemical staining and by real time-polymerase chain reaction at different time points following complete Freund's adjuvant (CFA) administration. Using a whole-cell patch-clamp configuration, we further determined both total INa and TTX-R Na(v)1.8 currents in large-soma dorsal root ganglia (DRG) neurons isolated from sham or CFA-treated rats. Finally, we analyzed the effects of ambroxol, a Na(v)1.8-preferring blocker on the electrophysiological properties of Nav1.8 currents and on the mechanical sensitivity and inflammation of the hind paw in CFA-treated rats.
  
  
  RESULTS
  Our findings revealed that Na(v)1.8 is up-regulated in NF200-positive large sensory neurons and is subsequently anterogradely transported from the DRG cell bodies along the axons toward the periphery after CFA-induced inflammation. We also demonstrated that both total INa and Na(v)1.8 peak current densities are enhanced in inflamed large myelinated Aβ-fiber neurons. Persistent inflammation leading to nociception also induced time-dependent changes in Aβ-fiber neuron excitability by shifting the voltage-dependent activation of Na(v)1.8 in the hyperpolarizing direction, thus decreasing the current threshold for triggering action potentials. Finally, we found that ambroxol significantly reduces the potentiation of Na(v)1.8 currents in Aβ-fiber neurons observed following intraplantar CFA injection and concomitantly blocks CFA-induced mechanical allodynia, suggesting that Na(v)1.8 regulation in Aβ-fibers contributes to inflammatory pain.
  
  
  CONCLUSIONS
  Collectively, these findings support a key role for Na(v)1.8 in controlling the excitability of Aβ-fibers and its potential contribution to the development of mechanical allodynia under persistent inflammation.
authors.forename: Mounir
authors.initials: M
authors.lastname: Belkouch
authors.forename: Marc-André
authors.initials: MA
authors.lastname: Dansereau
authors.forename: Pascal
authors.initials: P
authors.lastname: Tétreault
authors.forename: Michael
authors.initials: M
authors.lastname: Biet
authors.forename: Nicolas
authors.initials: N
authors.lastname: Beaudet
authors.forename: Robert
authors.initials: R
authors.lastname: Dumaine
authors.forename: Ahmed
authors.initials: A
authors.lastname: Chraibi
authors.forename: Stéphane
authors.initials: S
authors.lastname: Mélik-Parsadaniantz
authors.affiliation: Department of Physiology and Biophysics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 3001, 12th Avenue North, Sherbrooke, Quebec J1H 5N4, Canada. Philippe.Sarret@USherbrooke.ca.
authors.forename: Philippe
authors.initials: P
authors.lastname: Sarret
mesh_terms: D000551:Ambroxol / Q000627:therapeutic use; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D004195:Disease Models, Animal; D005620:Freund's Adjuvant; D005727:Ganglia, Spinal / Q000166:cytology* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D007249:Inflammation / Q000139:chemically induced / Q000150:complications / Q000473:pathology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D062559:NAV1.8 Voltage-Gated Sodium Channel / Q000378:metabolism*; D009413:Nerve Fibers, Myelinated / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D017288:Pain Threshold / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000378:metabolism*; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D000893:Anti-Inflammatory Agents; D062559:NAV1.8 Voltage-Gated Sodium Channel; C568319:Scn10a protein, rat; D026941:Sodium Channel Blockers; D000551:Ambroxol; D013779:Tetrodotoxin; D005620:Freund's Adjuvant