Gabapentin decreases membrane calcium currents in injured as well as in control mammalian primary afferent neurons

Abstract

Background and objectives: Neuropathic pain following injury to peripheral sensory neurons is a common clinical problem and frequently difficult to treat. Gabapentin (GBP), a novel anticonvulsant, has significant analgesic effects in clinical neuropathic states and in relevant preclinical models, but its mechanism of action remains unclear. Because calcium currents play a significant role in neuronal function, this study was designed to assess the effect of GBP on the membrane voltage-activated inward calcium currents (I(Ca)) in dorsal root ganglia (DRG) primary afferent neurons of neuropathic versus control rats.

Methods: Male rats were prepared according to the chronic constriction injury (CCI) model. The L4 and L5 dorsal root ganglia of those selected as CCI or control after appropriate behavioral testing were removed, and neurons were enzymatically dissociated. Fluorescent dye (DiI) placed at the injury site allowed identification of neurons projecting to that site. These were acutely studied using whole-cell, perforated (with beta-escin) patch-clamp recordings. Additionally, neurons from sham or nonoperated rats were also studied.

Results: Although there was marked variability among cells, concentrations of GBP ranging from 0.1 to 300 micromol/L decreased neuronal peak ICa in midsized neurons (30 to 40 microm) of both sham and neuropathic rats, in a fast, reversible, and concentration-dependent manner. Intergroup differences were not significant, however the concentration-response EC50s were 2.7 micromol/L for the sham and 16.5 micromol/L for the CCI neurons. The drug suppressed I(Ca) in nonoperated rats to a lesser degree, but changes did not differ significantly from the operated groups. Calcium currents in either small or large diameter neurons were also variably decreased by 10 micromol/L of GBP in sham and CCI neurons. Current inhibition by GBP was partly voltage dependent.

Conclusions: GBP, at clinically relevant concentrations, results in significant reduction of I(Ca) in both sham and neuropathic neurons, while in nonoperated rats reduced I(Ca) to a smaller degree. Sensitivity to drug was not affected by neuropathy. This current inhibition is partly voltage dependent. Depression of I(Ca) may be partly related to the binding of the drug to the alpha(2)delta modulatory subunit of the voltage activated calcium channels (VACC). Analgesia may be due to diminished release of neurotransmitter by sensory neurons, a Ca(2+)-dependent process.