Ionic mechanisms of post spike excitability changes during high-frequency firing rates

Abstract

Abstract Aims Axonal hyperexcitability in peripheral nerves has been observed in patients with neuropathic pain [1]. The use-dependent propagation of double pulses, recovery cycles, was found to be different in patients relative to healthy controls. Methods We study the mechanisms underlying the recovery cycle phenomenon using a biophysical model of a C-fiber [2]. The model represents the spatial extent of the axon including its passive properties as well as ion channels of Hodgkin-Huxley type. In vitro voltage clamp recordings from dissociated small DRG somata from rat were performed to assess model predictions. Results The model was able to replicate the transitions in excitability from subnormal to supernormal observed experimentally. For 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 of a relative shift in the sodium currents was supported by data from an in vitro preparation of small rat DRG somata showing a relative reduction in the magnitude of TTX-sensitive to TTX-resistant whole cell currents. Conclusions By providing mechanistic explanations of axonal excitability in terms of changes in ion channel activity, we suggest these channel changes can subsequently be used to discuss mechanisms of neuropathic pain.