The improvement of the anti-hyperalgesic effect of ketamine and of its isomers by the administration of ifenprodil

Abstract

Intrathecal or epidural administration of NMDA (N-methyl- d-aspartate) receptors antagonists, in special ketamine and ifenprodil are used to control moderate to severe hyperalgesia in humans. Activation of NMDA receptor usually requires binding of two agonists, glutamate and glycine, in different receptor subunits. Ketamine is a NMDA receptor antagonist and acts at phencyclidine site in NR1 subunit while ifenprodil is a selective NR2B subunit antagonist of NMDA receptor. The aim of this study was to investigate the pharmacological interactions between ketamine or its isomers and ifenprodil, when intrathecally co-administrated, to reduce prostaglandin E 2-induced hyperalgesia in rat's hind paw. The intrathecal administration of ketamine, its isomers R(−) or S(+), or ifenprodil-induced anti-hyperalgesic effects in a dose-related manner. Ifenprodil, in a dose that did not induce significant effect when administrated alone, significantly improved the anti-hyperalgesic effect of ketamine or its isomers. The other way round, ketamine or S(+) ketamine, but not R(−) ketamine, in a dose that did not induce significant effect when administrated alone, improved the anti-hyperalgesic effect of ifenprodil. However, by comparing ED 50s (half maximal effective doses), ifenprodil-induced potentiation of ketamine was significantly greater than ketamine-induced potentiation of ifenprodil. The findings of this present study suggest that intrathecal administration of very small doses of ifenprodil, just before and ketamine significantly improves its anti-hyperalgesic effect and this association could be useful to control inflammatory pain with less undesirable effects.