Synergistic effect between intrathecal non-NMDA antagonist and gabapentin on allodynia induced by spinal nerve ligation in rats

Background: Glutamate and non-N-methyl-D-aspartate (NMDA) receptors have been implicated in the development of neuroplasticity in the spinal cord in neuropathic pain. The spinal cord has been identified as one of the sites of the analgesic action of gabapentin. In the current study, the authors determined the antiallodynic effect of intrathecal 6-cyano-7- nitroquinoxaline-2,3-dione (CNQX) in a rat model of neuropathic pain. Also tested was a hypothesis that intrathecal injection of CNQX and gabapentin produces a synergistic effect on allodynia in neuropathic rats. Methods: Allodynia was produced in rats by ligation of the left L5 and L6 spinal nerves. Allodynia was determined by application of yon Frey filaments to the left hind paw. Through an implanted intrathecal catheter, 10-100 μg gabapentin or 0.5-8 μg CNQX disodium (a water-soluble formulation of CNQX) was injected in conscious rats. Isobolographic analysis was performed comparing the interaction of intrathecal gabapentin and CNQX using the ED₅₀ dose ratio of 15:1. Results: Intrathecal treatment with gabapentin or CNQX produced a dose-dependent increase in the withdrawal threshold to mechanical stimulation. The ED₅₀ for gabapentin and CNQX was 45.9 ± 4.65 and 3.4 ± 0.22 μg, respectively. Intrathecal injection of a combination of CNQX and gabapentin produced a strong synergistic antiallodynic effect in neuropathic rats. Conclusions: This study shows that intrathecal administration of CNQX exhibits an antiallodynic effect in this rat model of neuropathic pain. Furthermore, CNQX and gabapentin, when combined intrathecally, produce a potent synergistic antiallodynic effect on neuropathic pain in spinal nerve- ligated rats.