Gabapentin selectively reduces persistent sodium current in injured type-A dorsal root ganglion neurons

Abstract

It has been confirmed that the voltage-gated persistent sodium currents mediate the generation of subthreshold membrane potential oscillations (SMPOs) and contribute to shaping repetitive firing. Our previous study indicated that gabapentin (GBP) administration induced a dose-dependent inhibition of SMPO in chronically compressed dorsal root ganglion (CCD) neurons. To investigate the mechanisms and possible site(s) of action of GBP, the persistent sodium currents (I(NaP)) were measured and the effects of GBP on I(NaP) were examined in CCD neurons electrophysiologically in vitro. DRG neurons possess slow TTX-sensitive inactivating sodium currents that significantly contribute to the generation of membrane oscillations by amplifying the resonance behavior. GBP reduced the resonant amplitude of DRG neurons as well as inhibiting the firing and SMPO induced by injection current, which was strongly due to the inhibitory effect on persistent sodium currents. Furthermore, we found that GBP (1-20 microM) administration inhibited the persistent sodium currents in dose-dependent manner, while the changes of K(+) and Ca(2+) current minimally contributed to the effect of GBP on oscillation and resonant behavior of DRG neurons. In contrast, the amplitude and voltage-dependence of transient sodium current were unchanged by GBP. The results suggest that GBP decreased the amplitude of resonance and abolished the SMPO of A-type DRG neurons through the inhibition of I(NaP), and thus inhibited the SMPO dependent repetitive and bursting firings.

Pacemaker Neurons and Neuronal Networks in Health and Disease

“…These intrinsic bursters exhibit an increase in the density of the INap and the HCN [70], which may offer therapeutic targets to treat chronic pain [71,72]. In fact, several blockers of the INap have shown very promising effects against acute and chronic pain [73][74][75]. Finally, I will review the role of pacemaker neurons in the activity of a vital network: the preBötzinger Complex (preBötC).…”

The role of negative conductances in neuronal subthreshold properties and synaptic integration

“…It has been observed that I NaP increases the impedance of neurons (Boehlen et al 2012;Curti et al 2008;Economo et al 2014;Gutfreund and Segev 1995;Hu et al 2002;Hutcheon et al 1996a;Hutcheon et al 1996b;Jacobson et al 2005;Klink and Alonso 1997;Manuel et al 2007;Pape and Driesang 1998;Saint Mleux and Moore 2000;Sun et al 2014;Wu et al 2001;Wu et al 2005;Yang et al 2009;Yaron-Jakoubovitch et al 2008). This increase in the membrane impedance is thus a function of membrane voltage, increasing as the neuron is depolarized towards the spike threshold.…”

Electrical resonance with voltage-gated ion channels: perspectives from biophysical mechanisms and neural electrophysiology

“…Electrical resonance contributes to the network oscillation in the immature neocortex and temporally tunes the integration of synaptic inputs within a specific range of frequencies in developing cortical neurons [68] . In addition, persistent Na + currents could amplify the electrical resonance in neurons [1,7,16] and may play an important role in the nervous system [69][70][71][72] .…”