Analysis of Interaction between Intrathecal Gabapentin with MK801, 5,7-DKA or NBQX in the Rat Formalin Test

Kim, Mi Kyoung; Ki, Hyoung Gon; Choi, Jeong Il; Yoon, Myung Ha; Jeong, Chang Young

Abstract

Spinal NMDA receptor and AMPA receptor are involved in the modulation of nociceptive transmission. It has been known that the antinociception of gabapentin is linked to these sites. We evaluated the effect of intrathecal gabapentin, NMDA receptor ion channel blocker (MK801), antagonist of glycine site of NMDA receptor (5,7-DKA) and AMPA antagonist (NBQX) in the formalin test and further assessed the interactions between gabapentin and MK801, 5,7-DKA or NBQX. Male Sprague-Dawley rats were implanted with intrathecal catheters. For the formalin test, 50microliter of 5% formalin solution was injected into the hindpaw. The interaction of drugs was investigated by a fixed dose analysis or an isobolographic analysis. Intrathecal MK801, 5,7-DKA and NBQX suppressed the flinching responses of phase 1 and phase 2 of the formalin test, while intrathecal gabapentin had little effect on phase 1. All four agents decreased the phase 2 flinching response. A fixed dose analysis, in phase 1, showed that gabapentin potentiated the antinociceptive effect of MK801 and NBQX. Isobolographic analysis, in phase 2, revealed a synergistic interaction after intrathecal co-administration of gabapentin-MK801 or gabapentin-NBQX. However, neither addition of gabapentin to 5,7-DKA in phase 1 nor gabapentin-5,7-DKA combination in phase 2 increased the antinociception of 5,7-DKA. Gabapentin increased the analgesia of NMDA ion channel blocker or AMPA receptor antagonists. Conclusively, combination of gabapentin with NMDA or AMPA receptor antagonists may be useful in the management of pain. Further, the antinociception of gabapentin may be mediated by glycine sites rather than NMDA ion channel or AMPA receptors at the spinal level.