Gabapentin actions on N-methyl-D-aspartate receptor channels are protein kinase C-dependent

Gabapentin (Neurontin((R))) (GBP) is a widely prescribed analgesic used in treating pain patients with peripheral nerve injuries, diabetic neuropathy and cancer. To understand the mechanism of its action, we used the H whole- cell patch recording technique to study the effects of GBP on N-methyl-D-as partate (NMDA)-evokcd currents in single dorsal horn neurons isolated From normal rats and from rats with inflammation induced by the injection of com plete Freund adjuvant (CFA) to the hindpaw. We found that GBP enhanced NMDA currents in normal neurons only when protein kinase C (PKC) was added to t hese cells. The enhancement resulted from an increase in the affinity of gl ycine for NMDA receptors by GBP. In contrast, in neurons isolated from CFA- treated rats. GBP enhanced NMDA responses without any PKC treatment. Since endogenous PKC in inflamed tissue is elevated. these results suggest that G BP exerts its. effects only on those cells affected by inflammatory injurie s. Thus, the effects of GBP on NMDA receptors are plastic: they depend on t he phosphorylation states uf cells or receptors. These observations point t o a new strategy for drug design. A chemical whose action depends on the st ate of cells would maximize its effectiveness while keeping its side-effect s to a minimum. (C) 2001 International Association fur the Study of Pain. P ublished by Elsevier Science B.V. All rights reserved.