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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 (1–20μM) administration inhibited the persistent sodium currents in dose-dependent manner, while the changes of K+ and Ca2+ 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. [Copyright &y& Elsevier]

Ectopic spontaneous discharges play a critical role for both initiation and maintenance of the neuropathic pain state. Gabapentin (GBP) has been shown to be effective in animal models of neuropathic pain as well as in chronic pain patients. To investigate the peripheral mechanisms of GBP, the effects of GBP on spontaneous discharges and subthreshold membrane potential oscillation (SMPO) of chronically compressed dorsal root ganglion (DRG) were examined electrophysiolocally in vitro. The rate of spontaneous discharges was transitorily enhanced when GBP was applied to the DRG. When the concentration was under 5microM, only enhanced effect was observed, while spontaneous discharges were completely suppressed when the concentration of GBP was beyond 5microM. The similar doses of GBP blocking the spontaneous discharges failed to block the propagation of impulses by electrical nerve stimulation. Furthermore, we found that the SMPO of injured DRG cells can be selectively abolished by GBP without interrupting spike propagation. The results suggest that the inhibitory effect of GBP on SMPO might be one of the membrane mechanisms of action of GBP. This may partially explain the antinociceptive action of GBP by directly suppression nociceptive afferent input to the spinal cord. [ABSTRACT FROM AUTHOR]