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Simulation in Sensory Neurons Reveals a Key Role for Delayed Na⁺ Current in Subthreshold Oscillations and Ectopic Discharge: Implications for Neuropathic Pain

Department of Cell and Developmental Biology, Institute of Life Sciences and Center for Research on Pain, The Hebrew University of Jerusalem, Jerusalem, Israel

Submitted 5 January 2009; accepted in final form 25 June 2009

Abstract

Somata of primary sensory neurons are thought to contribute to the ectopic neural discharge that is implicated as a cause of some forms of neuropathic pain. Spiking is triggered by subthreshold membrane potential oscillations that reach threshold. Oscillations, in turn, appear to result from reciprocation of a fast active tetrodotoxin-sensitive Na⁺ current (I_Na⁺) and a passive outward I_K⁺ current. We previously simulated oscillatory behavior using a transient Hodgkin–Huxley-type voltage-dependent I_Na⁺ and ohmic leak. This model, however, diverged from oscillatory parameters seen in live cells and failed to produce characteristic ectopic discharge patterns. Here we show that use of a more complete set of Na⁺ conductances—which includes several delayed components—enables simulation of the entire repertoire of oscillation-triggered electrogenic phenomena seen in live dorsal root ganglion (DRG) neurons. This includes a physiological window of induction and natural patterns of spike discharge. An I_Na⁺ component at 2–20 ms was particularly important, even though it represented only a tiny fraction of overall I_Na⁺ amplitude. With the addition of a delayed rectifier I_K⁺ the singlet firing seen in some DRG neurons can also be simulated. The model reveals the key conductances that underlie afferent ectopia, conductances that are potentially attractive targets in the search for more effective treatments of neuropathic pain.