Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents

This Article Full Text PDF (Full Text) Alert me when this article is cited Citation Map Services Email this article Similar articles in this journal Similar articles in PubMed Alert me to new content in the JGP Download to citation manager Citing Articles Citing Articles via CrossRef Google Scholar Articles by Maingret, F. Articles by Delmas, P. PubMed PubMed Citation Articles by Maingret, F. Articles by Delmas, P. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB HISTAMINE TETRODOTOXIN Social Bookmarking                      What's this?

¹ CRN2M, CNRS, Université de la Méditerranée, 13916 Marseille Cedex 20, France
² Laboratory of Biophysics and Bioelectronics, Dniepropetrovsk National University, 49050 Dniepropetrovsk, Ukraine

Correspondence to Patrick Delmas: patrick.delmas{at}univmed.fr

Altered function of Na⁺ channels is responsible for increased hyperexcitability of primary afferent neurons that may underlie pathological pain states. Recent evidence suggests that the Nav1.9 subunit is implicated in inflammatory but not acute pain. However, the contribution of Nav1.9 channels to the cellular events underlying nociceptor hyperexcitability is still unknown, and there remains much uncertainty as to the biophysical properties of Nav1.9 current and its modulation by inflammatory mediators. Here, we use gene targeting strategy and computer modeling to identify Nav1.9 channel current signature and its impact on nociceptors' firing patterns. Recordings using internal fluoride in small DRG neurons from wild-type and Nav1.9-null mutant mice demonstrated that Nav1.9 subunits carry the TTX-resistant "persistent" Na⁺ current called NaN. Nav1.9^–/– nociceptors showed no significant change in the properties of the slowly inactivating TTX-resistant SNS/Nav1.8 current. The loss in Nav1.9-mediated Na⁺ currents was associated with the inability of small DRG neurons to generate a large variety of electrophysiological behaviors, including subthreshold regenerative depolarizations, plateau potentials, active hyperpolarizing responses, oscillatory bursting discharges, and bistable membrane behaviors. We further investigated, using CsCl- and KCl-based pipette solutions, whether G-protein signaling pathways and inflammatory mediators upregulate the NaN/Nav1.9 current. Bradykinin, ATP, histamine, prostaglandin-E2, and norepinephrine, applied separately at maximal concentrations, all failed to modulate the Nav1.9 current. However, when applied conjointly as a soup of inflammatory mediators they rapidly potentiated Nav1.9 channel activity, generating subthreshold amplification and increased excitability. We conclude that Nav1.9 channel, the molecular correlate of the NaN current, is potentiated by the concerted action of inflammatory mediators that may contribute to nociceptors' hyperexcitability during peripheral inflammation.

Abbreviations used in this paper: BK, bradykinin; DRG, dorsal root ganglion; NaN, novel and nociceptive; Nav, Na⁺ channel subunits; SNS, sensory neuron specific; TTX, tetrodotoxin.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents