Gabapentin inhibits high-threshold calcium channel currents in cultured rat dorsal root ganglion neurones

1 This study examined the action of gabapentin (gabapentin,1-(aminomethyl) cyclohexane acetic acid (Neurontin(R))) on voltage-gated calcium (Ca2+) channel influx recorded in cultured rat dorsal root ganglion (DRG) neurones. 2 Voltage-gated Ca2+ influx was monitored using both fura-2 based fluorescence Ca2+ imaging and the whole-cell patch clamp technique. 3 Imaging of intracellular Ca2+ transients revealed that gabapentin inhibited KCl (30 mm)-evoked voltage-dependent Ca2+ influx. Both the duration for 50% of the maximum response (W50) and total Ca2+ influx were significantly reduced by similar to25-30% in the presence of gabapentin (25 muM). 4 Gabapentin potently inhibited the peak whole-cell Ca2+ channel current (I-Ba) in a dose-dependent manner with an estimated IC50 value of 167 rim. Block was incomplete and saturated at a maximal concentration of 25 muM. 5 Inhibition was significantly decreased in the presence of the neutral amino acid L-isoleucine (25 muM) but unaffected by application of the GABA(B) antagonist, saclofen (200 muM), suggesting a direct action on the alpha(2)delta subunit of the Ca2+ channel. 6 Gabapentin inhibition was voltage-dependent, producing an similar to 7 mV hyperpolarizing shift in current voltage properties and reducing a non-inactivating component of whole-cell current activated at relatively depolarized potentials. 7 The use of specific Ca2+ channel antagonists revealed a mixed pharmacology of the gabapentin-sensitive current (N-, L- and P/Q-type), which is dominated by N-type current. 8 The present study is the first to demonstrate that gabapentin directly mediates inhibition of voltage-gated Ca2+ influx in DRG neurones, providing a potential means for gabapentin to effectively mediate spinal anti-nociception.