Vol. 298, Issue 1, 15-24, July 2001

The Anticonvulsant, Antihyperalgesic Agent Gabapentin Is an Agonist at Brain -Aminobutyric Acid Type B Receptors Negatively Coupled to Voltage-Dependent Calcium Channels

Sandrine Bertrand¹ , Gordon Y. K. Ng¹ , Maya Gadhvi Purisai, Shannyn E. Wolfe, Mathew W. Severidt, Dominique Nouel, Richard Robitaille, Malcolm J. Low, Gary P. O'Neill, Kathleen Metters, Jean-Claude Lacaille, Bibie M. Chronwall and Stephen J. Morris

Centre de Recherche en Sciences Neurologiques et Département de Physiologie, Université de Montréal, Montréal, Province of Québec, Canada (S.B., D.N., R.R., J.-C.L.); Merck Frosst Center for Therapeutic Research, Kirkland, Province of Québec, Canada (G.N., G.P.O., K.M.); School of Biological Sciences, University of Missouri-Kansas City, Kansas City, Missouri (M.G.P., B.M.C., S.E.W., M.W.S.); Stowers Institute for Medical Research, Kansas City, Missouri (S.J.M.); and Vollum Institute, Oregon Health Sciences University, Portland, Oregon (M.J.L.)

Gabapentin (Neurontin, Pfizer Global R & D) is a novel anticonvulsant, antihyperalgesic, and antinociceptive agent with a poorly understood mechanism of action. In this study, we show that gabapentin (EC₅₀ 2 µM) inhibited up to 70 to 80% of the total K⁺-evoked Ca²⁺ influx via voltage-dependent calcium channels (VD-CCs) in a mouse pituitary intermediate melanotrope clonal mIL-tsA58 (mIL) cell line. mIL cells endogenously express only -aminobutyric acid type B (GABA_B) gb1a-gb2 receptors. Moreover, activity of the agonist gabapentin was dose dependently and completely blocked with the GABA_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 control 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 cell recording and multiphoton Ca²⁺ imaging in hippocampal neurons in situ, gabapentin significantly inhibited in a dose-dependent manner subthreshold soma depolarizations and Ca²⁺ responses evoked by somatic current injection. Furthermore, gabapentin almost completely blocked Ca²⁺ action potentials and Ca²⁺ responses elicited by suprathreshold current injection. However, larger current injection overcame this inhibition of Ca²⁺ action potentials suggesting that gabapentin did not predominantly affect L-type Ca²⁺ channels. The depressant effect of gabapentin on Ca²⁺ responses was coupled to the activation of neuronal GABA_B receptors since they were blocked by CGP55845, and baclofen produced similar effects. Thus gabapentin activation of neuronal GABA_B gb1a-gb2 receptors negatively coupled to VD-CCs can be a potentially important therapeutic mechanism of action of gabapentin that may be linked to inhibition of neurotransmitter release in some systems.