The anticonvulsant, antihyperalgesic agent gabapentin is an agonist at brain gamma-aminobutyric acid type B receptors negatively coupled to voltage-dependent calcium channels

Gabapentin (Neurontin, Pfizer Global R & D) is a novel anticonvulsant, anti hyperalgesic, and antinociceptive agent with a poorly understood mechanism of action. In this study, we show that gabapentin (EC50 2 muM) inhibited up to 70 to 80% of the total K+-evoked Ca2+ influx via voltage-dependent calc ium channels (VD-CCs) in a mouse pituitary intermediate melanotrope clonal mIL-tsA58 (mIL) cell line, mIL cells endogenously express only gamma -amino butyric acid type B (GABA(B)) gb1a-gb2 receptors. Moreover, activity of the agonist gabapentin was dose dependently and completely blocked with the GA BA(B) antagonist CGP55845 and was nearly identical to the prototypic GABA(B ) agonist baclofen in both extent and potency. Antisense knockdown of gb1a also completely blocked gabapentin activity, while gb1b antisense and contr ol oligonucleotides had no effect, indicating that gabapentin inhibition of membrane Ca2+ mobilization in mIL cells was dependent on a functional GABA (B) (gb1a-gb2) heterodimer receptor. In addition, during combined whole cel l recording and multiphoton Ca2+ imaging in hippocampal neurons in situ, ga bapentin significantly inhibited in a dose-dependent manner subthreshold so ma depolarizations and Ca2+ responses evoked by somatic current injection. Furthermore, gabapentin almost completely blocked Ca2+ action potentials an d Ca2+ responses elicited by suprathreshold current injection. However, lar ger current injection overcame this inhibition of Ca2+ action potentials su ggesting that gabapentin did not predominantly affect L-type Ca2+ channels. The depressant effect of gabapentin on Ca2+ responses was coupled to the a ctivation of neuronal GABA(B) receptors since they were blocked by CGP55845 , and baclofen produced similar effects. Thus gabapentin activation of neur onal GABA(B) gb1a-gb2 receptors negatively coupled to VD-CCs can be a poten tially important therapeutic mechanism of action of gabapentin that may be linked to inhibition of neurotransmitter release in some systems.