Inhibitory effect of gabapentin on N-methyl-D-aspartate receptors expressed in Xenopus oocytes.

BACKGROUND: Gabapentin (GBP) is a prescription drug used for the treatment of neuropathic and post-operative pain. However, the mechanism by which it exerts its analgesic action is not well understood. Because intrathecal administration of GBP has been shown to exert antinociceptive effects in animal studies, we hypothesized that the spinal cord may be a plausible action site.

METHODS: We examined the effects of GBP on neurotransmitter-gated ion channels and G protein-coupled inwardly rectifying potassium (GIRK) channels distributed in the spinal cord and involved in pain modulation. Recombinant human NR1/NR2A N-methyl-D-aspartate (NMDA), alpha(1)beta(2)gamma(2S)gamma-aminobutyric acid type A (GABA(A)) or alpha(1) glycine receptors, or GIRK1/GIRK2 channels were expressed in Xenopus laevis oocytes and the effects of GBP (0.1-1000 microM) on them were assessed using a two-electrode, voltage-clamp system.

RESULTS: GABA(A) and glycine receptors and GIRK channels were not affected by GBP, even at the highest concentrations. Conversely, NMDA receptors were inhibited by GBP in a concentration-dependent manner, with significant inhibition observed at 10 microM. At 30 microM, GBP inhibited the glutamate-concentration response curve without changing the half-maximal effective concentration or the Hill coefficient, indicating a non-competitive inhibition. Glycine decreased the inhibitory effect in a concentration-dependent manner.

CONCLUSIONS: These findings suggest that the inhibitory effect of GBP on NMDA receptors may play an important role in the antinociceptive property of GBP; however, it does not appear that GABA(A) and glycine receptors or GIRK channels contribute to the pharmacological properties of GBP.