TOLERANCE DEVELOPS TO THE ANTINOCICEPTIVE AND MOTOR IMPAIRING EFFECTSOF ACEA-1416, A NMDA RECEPTOR ANTAGONIST, IN THE FORMALIN AND ROTARODTESTS IN MICE

Antinociception, disturbances of motor coordination and development of tolerance to these effects were examined following acute and chronic administration of ACEA-1416, a NMDA receptor/glycine site antagonist, in Swiss Webster mice using the formalin and rotarod tests. In the for malin test, mice were injected with either the vehicle (Tris, 0.05 M) or ACEA-1416 (1-10 mg kg(-1)). Fifteen or 60 min later, mice were inje cted with formalin and observed for nociceptive responses (licking and /or biting of the injected paw). In the vehicle-treated control mice a biphasic nociceptive response was observed at 0-5 min (early phase) a nd from 15 to 50 min (late phase) after formalin injections. ACEA-1416 showed a dose-dependent attenuation of the nociceptive responses in b oth phases of the formalin test. In the rotarod test, mice were inject ed with ACEA-1416, placed on a rotating bar at 6 rpm for 2 min and exa mined for motor impairment. ACEA-1416 produced disturbances of motor c oordination in a dose-dependent manner. For tolerance studies, mice we re injected once daily with either the vehicle or ACEA-1416 (30 mg kg( -1)) and tested for antinociception and motor impairment on day 5, 10 and 20. A time-dependent decrease in the antinociceptive effect of the drug was observed in the early but not in the late phase of the forma lin test. Tolerance also developed to the motor impairing effect of th e drug. Taken together, these data suggest that chronic inhibition of NMDA receptors by ACEA-1416 differentially affected the antinociceptiv e effect of the drug in the early and late phase of the formalin test. Furthermore, the antinociceptive and motor impairing effects of the d rug can be separated. (C) 1998 The Italian Pharmacological Society.