title: C-fiber recovery cycle supernormality depends on ion concentration and ion channel permeability.
abstract: Following each action potential, C-fiber nociceptors undergo cyclical changes in excitability, including a period of superexcitability, before recovering their basal excitability state. The increase in superexcitability during this recovery cycle depends upon their immediate firing history of the axon, but also determines the instantaneous firing frequency that encodes pain intensity. To explore the mechanistic underpinnings of the recovery cycle phenomenon a biophysical model of a C-fiber has been developed. The model represents the spatial extent of the axon including its passive properties as well as ion channels and the Na/K-ATPase ion pump. Ionic concentrations were represented inside and outside the membrane. The model was able to replicate the typical transitions in excitability from subnormal to supernormal observed empirically following a conducted action potential. In the model, supernormality depended on the degree of conduction slowing which in turn depends upon the frequency of stimulation, in accordance with experimental findings. In particular, we show that activity-dependent conduction slowing is produced by the accumulation of intraaxonal sodium. We further show that the supernormal phase results from a reduced potassium current Kdr as a result of accumulation of periaxonal potassium in concert with a reduced influx of sodium through Nav1.7 relative to Nav1.8 current. This theoretical prediction was supported by data from an in vitro preparation of small rat dorsal root ganglion somata showing a reduction in the magnitude of tetrodotoxin-sensitive relative to tetrodotoxin -resistant whole cell current. Furthermore, our studies provide support for the role of depolarization in supernormality, as previously suggested, but we suggest that the basic mechanism depends on changes in ionic concentrations inside and outside the axon. The understanding of the mechanisms underlying repetitive discharges in recovery cycles may provide insight into mechanisms of spontaneous activity, which recently has been shown to correlate to a perceived level of pain.
authors.affiliation: Department of Computational Biology, School of Computer Science and Communication, KTH Royal Institute of Technology, Stockholm, Sweden; Stockholm Brain Institute, KTH Royal Institute of Technology, Stockholm, Sweden.
authors.forename: Jenny
authors.initials: J
authors.lastname: Tigerholm
authors.affiliation: Department of Computational Biology, School of Computer Science and Communication, KTH Royal Institute of Technology, Stockholm, Sweden; Stockholm Brain Institute, KTH Royal Institute of Technology, Stockholm, Sweden.
authors.forename: Marcus E
authors.initials: ME
authors.lastname: Petersson
authors.affiliation: Anaesthesiology, Universitaetsmedizin Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Otilia
authors.initials: O
authors.lastname: Obreja
authors.affiliation: Institute of Physiology and Pathophysiology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Esther
authors.initials: E
authors.lastname: Eberhardt
authors.affiliation: Department of Anesthesiology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Namer
authors.affiliation: Department of Anesthesiology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Weidner
authors.affiliation: Institute of Physiology and Pathophysiology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Institute of Physiology, RWTH Aachen University, Aachen, Germany.
authors.forename: Angelika
authors.initials: A
authors.lastname: Lampert
authors.affiliation: Anaesthesiology, Universitaetsmedizin Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Carr
authors.affiliation: Anaesthesiology, Universitaetsmedizin Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Schmelz
authors.affiliation: Department of Computational Biology, School of Computer Science and Communication, KTH Royal Institute of Technology, Stockholm, Sweden; Stockholm Brain Institute, KTH Royal Institute of Technology, Stockholm, Sweden. Electronic address: erikf@csc.kth.se.
authors.forename: Erik
authors.initials: E
authors.lastname: Fransén
mesh_terms: D000200:Action Potentials; D001369:Axons / Q000378:metabolism; D002463:Cell Membrane Permeability; D006801:Humans; D008959:Models, Neurological; D036421:Nerve Fibers, Unmyelinated / Q000378:metabolism* / Q000502:physiology; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D061566:Voltage-Gated Sodium Channels / Q000378:metabolism*
chemical_list: D015221:Potassium Channels; D061566:Voltage-Gated Sodium Channels; D012964:Sodium; D000254:Sodium-Potassium-Exchanging ATPase; D011188:Potassium