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

Gabapentin (Neurontin) (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 whole-cell patch recording technique to study the effects of GBP on N-methyl-D-aspartate (NMDA)-evoked currents in single dorsal horn neurons isolated from normal rats and from rats with inflammation induced by the injection of complete 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 these cells. The enhancement resulted from an increase in the affinity of glycine 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 GBP exerts its effects only on those cells affected by inflammatory injuries. Thus, the effects of GBP on NMDA receptors are plastic; they depend on the phosphorylation states of cells or receptors. These observations point to a new strategy for drug design. A chemical whose action depends on the state of cells would maximize its effectiveness while keeping its side-effects to a minimum.