TOLERANCE DEVELOPS TO THE ANTINOCICEPTIVE AND MOTOR IMPAIRING EFFECTS OF ACEA-1416, A NMDA RECEPTOR ANTAGONIST, IN THE FORMALIN AND ROTAROD TESTS IN MICE

Abstract

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 formalin 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 injected 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) and from 15 to 50 min (late phase) after formalin injections. ACEA-1416 showed a dose-dependent attenuation of the nociceptive responses in both phases of the formalin test. In the rotarod test, mice were injected with ACEA-1416, placed on a rotating bar at 6 rpm for 2 min and examined for motor impairment. ACEA-1416 produced disturbances of motor coordination in a dose-dependent manner. For tolerance studies, mice were 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 formalin test. Tolerance also developed to the motor impairing effect of the drug. Taken together, these data suggest that chronic inhibition of NMDA receptors by ACEA-1416 differentially affected the antinociceptive effect of the drug in the early and late phase of the formalin test. Furthermore, the antinociceptive and motor impairing effects of the drug can be separated.