Clinically available NMDA antagonist, memantine, attenuates tolerance to analgesic effects of morphine in a mouse...

Converging lines of evidence indicate that N-methyl-D-aspartate (NMDA) receptor antagonists attenuate the development of morphine tolerance tested in antinociception assays in rodents. The present study extends these findings to the effects of clinically available NMDA receptor antagonist, memantine. Male Albino Swiss mice were tested for analgesia using the tail-flick apparatus. Preliminary experiment was designed to find out the optimal dose of morphine and the number of injections that would produce tolerance to its analgesic effects. In the main experiment, during the development of tolerance period (6 days), mice received 10 mg/kg sc b.i.d. morphine injections in the animal room (non-associative tolerance). This treatment resulted in 5.8 fold rightward shift of morphine cumulative dose-response effect from 3.39 mg/kg on day 1 to 16.19 mg/kg on day 8 of the experiment. Memantine pretreatment (5 and 10 mg/kg, but not 2.5 mg/kg), given 30 min prior to each morphine dose during the development of tolerance period, inhibited the rightward shift of morphine cumulative dose-response curve. Thus, pretreatment with memantine at doses of 2.5, 5 and 10 mg/kg resulted in ED50 values of 12.13, 4.74 and 1.95 mg/kg, respectively, corresponding to 3.35, 1.02 and 0.94 fold changes. These data indicate that low affinity, clinically available NMDA receptor antagonist, memantine, may be used to inhibit the development of morphine tolerance.