Impact of gabapentin on neuronal high voltage-activated Ca2+ channel properties of injured-side axotomized and adjacent uninjured dorsal root ganglions in a rat model of spinal nerve ligation.

Abstract

The density and properties of ion channels in the injured axon and dorsal root ganglion (DRG) neuronal soma membrane change following nerve injury, which may result in the development of neuropathic pain. Gabapentin (GBP) is a drug for the first-line treatment of neuropathic pain. One of its therapeutic targets is the voltage-activated calcium channel (VACC). In the present study, the whole-cell patch clamp technique was used to examine the changes of high voltage-activated Ca2+ (HVA-Ca2+) channels in DRG neurons from sham and neuropathic rats in the absence and presence of GBP. The results demonstrated a reduction in peak current density and the ‘window current’ between activation and inactivation in adjacent and axotomized neurons from rats that had undergone L5 spinal nerve ligation, thus attenuating the total inward Ca2+ current. Following the use of the specific channel blockers nifedipine, ω-conotoxin MVIIC and ω-conotoxin MVIIA, increased HVA-Ca2+ channels as well as an increased proportion of N-type Ca2+ currents were observed in axotomized neurons. GBP inhibited HVA calcium channel currents in a dose-dependent manner. The activation and steady-state inactivation curves for HVA channels were shifted in a hyperpolarizing direction by 100 µmol/l GBP. Following the application of GBP, a reduction in the ‘window current’ was observed in control and axotomized neurons, whereas the ‘window current’ was unchanged in adjacent neurons. This indicates that the inhibitory effects of GBP may be dependent on particular neuropathological or inflammatory conditions. The proportion of N-type Ca2+ currents and sensitivity to GBP were increased in axotomized neurons, which indicated the involvement of N-type Ca2+ currents in the inhibitory effect of GBP.