Benzodiazepines potentiate morphine antinociception at the spinal level via GABAergic mechanisms. At the supraspinal level, the inhibitory effect of midazolam on morphine antinociception cannot be easily explained by GABAA receptor activation. Since excitatory amino acids play a role in central transmission, we investigated the effect of dizocilpine (MK 801) on this interaction in spinal cord and brain. 2. In rats with an intrathecal or intracerebroventricular catheter, the mechanisms of the antinociceptive effect of benzodiazepine-morphine combinations were tested during thermal nociceptive tests. 3. The principal findings of this study were that at the spinal level, midazolam potentiation of morphine antinociception can be antagonized by the NMDA antagonist, MK 801 (10 micrograms), as assessed by hot-plate and tail-flick tests. When drugs were administered supraspinally, midazolam inhibited morphine antinociception only in the hot-plate test, an effect also inhibited by MK 801. In the tail-flick assay, midazolam failed to influence the morphine response. 4. The NMDA antagonist significantly affected midazolam antinociception at the spinal level, but was not effective following i.c.v. administration of the drugs. MK 801 had no effect on morphine antinociception after i.t. and i.c.v. administration of the drugs. 5. The paradoxical effect of midazolam on morphine antinociception and its reversal by MK 801 might be due to modulation at various levels of the neuraxis and/or modulation of different pathways mediated via both GABAA and NMDA receptor mechanisms.
