title: Dissecting the role of sodium currents in visceral sensory neurons in a model of chronic hyperexcitability using Nav1.8 and Nav1.9 null mice.
abstract: Tetrodotoxin-resistant (TTX-R) sodium currents have been proposed to underlie sensory neuronal hyperexcitability in acute inflammatory models, but their role in chronic models is unknown. Since no pharmacological tools to separate TTX-R currents are available, this study employs Na(v)1.8 and Na(v)1.9 null mice to evaluate these currents roles in a chronic hyperexcitability model after the resolution of an inflammatory insult. Transient jejunitis was induced by infection with Nippostrongylus brasiliensis (Nb) in Na(v)1.9 and Na(v)1.8 null, wild-type and naïve mice. Retrogradely labelled dorsal root ganglia (DRG) neurons were harvested on day 20-24 post-infection for patch clamp recording. Rheobase and action potential (AP) parameters were recorded as measures of excitability, and Na(v)1.9 and Na(v)1.8 currents were recorded. DRG neuronal excitability was significantly increased in post-infected mice compared to sham animals, despite the absence of ongoing inflammation (sham = 1.9 +/- 0.3, infected = 3.6 +/- 0.7 APs at 2x rheobase, P = 0.02). Hyperexcitability was associated with a significantly increased amplitude of TTX-R currents. Hyperexcitability was maintained in Na(v)1.9(-/-) mice, but hyperexcitability was absent and APs were blunted in Na(v)1.8(-/-) mice. This study identifies a critical role for Na(v)1.8 in chronic post-infectious visceral hyperexcitability, with no contribution from Na(v)1.9. Nb infection-induced hyperexcitability is not observed in Na(v)1.8(-/-) mice, but is still present in Na(v)1.9(-/-) mice. It is not clear whether hyperexcitability is due to a change in the function of Na(v)1.8 channels or a change in the number of Na(v)1.8 channels.
authors.affiliation: Holburn Group, 1100 Bennett Road, Bowmanville, Canada ON L1C 3K5.
authors.forename: Kirk
authors.initials: K
authors.lastname: Hillsley
authors.forename: Jia-Hui
authors.initials: JH
authors.lastname: Lin
authors.forename: Andre
authors.initials: A
authors.lastname: Stanisz
authors.forename: David
authors.initials: D
authors.lastname: Grundy
authors.forename: Jeroen
authors.initials: J
authors.lastname: Aerssens
authors.forename: Pieter J
authors.initials: PJ
authors.lastname: Peeters
authors.forename: Diederik
authors.initials: D
authors.lastname: Moechars
authors.forename: Bernard
authors.initials: B
authors.lastname: Coulie
authors.forename: Ronald H
authors.initials: RH
authors.lastname: Stead
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000595:Amino Acid Sequence; D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D004594:Electrophysiology; D005727:Ganglia, Spinal / Q000378:metabolism / Q000473:pathology / Q000502:physiology* / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D062559:NAV1.8 Voltage-Gated Sodium Channel; D062558:NAV1.9 Voltage-Gated Sodium Channel; D009475:Neurons, Afferent / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D009479:Neuropeptides / Q000032:analysis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D009559:Nippostrongylus; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015222:Sodium Channels / Q000032:analysis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D017206:Strongylida Infections / Q000473:pathology / Q000503:physiopathology; D013779:Tetrodotoxin / Q000494:pharmacology; D014781:Viscera / Q000294:innervation*
chemical_list: D000779:Anesthetics, Local; D062559:NAV1.8 Voltage-Gated Sodium Channel; D062558:NAV1.9 Voltage-Gated Sodium Channel; D009479:Neuropeptides; D012333:RNA, Messenger; C568318:Scn10a protein, mouse; C491885:Scn11a protein, mouse; D015222:Sodium Channels; D013779:Tetrodotoxin