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

Abstract

This study examined the action of gabapentin (gabapentin,1‐(aminomethyl) cyclohexane acetic acid (Neurontin®)) on voltage‐gated calcium (Ca 2+) channel influx recorded in cultured rat dorsal root ganglion (DRG) neurones. Voltage‐gated Ca 2+ influx was monitored using both fura‐2 based fluorescence Ca 2+ imaging and the whole‐cell patch clamp technique. Imaging of intracellular Ca 2+ transients revealed that gabapentin inhibited KCl (30 m M)‐evoked voltage‐dependent Ca 2+ influx. Both the duration for 50% of the maximum response (W50) and total Ca 2+ influx were significantly reduced by ∼25‐30% in the presence of gabapentin (25 μ M). Gabapentin potently inhibited the peak whole‐cell Ca 2+ channel current (I Ba) in a dose‐dependent manner with an estimated IC 50 value of 167 n M. Block was incomplete and saturated at a maximal concentration of 25 μ M. Inhibition was significantly decreased in the presence of the neutral amino acid L‐isoleucine (25 μ M) but unaffected by application of the GABA B antagonist, saclofen (200 μ M), suggesting a direct action on the α 2 δ subunit of the Ca 2+ channel. Gabapentin inhibition was voltage‐dependent, producing an ∼7 mV hyperpolarizing shift in current voltage properties and reducing a non‐inactivating component of whole‐cell current activated at relatively depolarized potentials. The use of specific Ca 2+ channel antagonists revealed a mixed pharmacology of the gabapentin‐sensitive current (N‐, L‐ and P/Q‐type), which is dominated by N‐type current. The present study is the first to demonstrate that gabapentin directly mediates inhibition of voltage‐gated Ca 2+ influx in DRG neurones, providing a potential means for gabapentin to effectively mediate spinal anti‐nociception. British Journal of Pharmacology (2002) 135, 257–265; doi:10.1038/sj.bjp.0704439