Antinociceptive effect in mice of intraperitoneal N-methyl- d-aspartate receptor antagonists in the formalin test

Abstract

Although the antinociceptive effect of NMDA antagonists in the formalin test is well recognised, these compounds can induce adverse motor effects. The aim of this study was to identify the systemic doses of NMDA antagonists that induce analgesia without causing side effects. Male Swiss mice (30–40 g) received a subcutaneous (sc) injection of 1.25% formalin ( 50 μl ) in the dorsal surface of the right hind-paw and, 15 min before or after formalin, an ip injection of one of the following NMDA receptor antagonists: MK 801 (0.01, 0.025, and 0.05 mg/kg), memantine (0.1, 0.5, and 1 mg/kg), ketamine (0.125, 0.25, and 0.5 mg/kg), dextromethorphan (5, 10, and 20 mg/kg), and CGP 37849 (4, 6, and 8 mg/kg). Pain-related behaviour (licking, lifting, favouring, shaking, and flinching of the treated paw) was recorded at 5-min intervals for 60 min. The NMDA receptor antagonists significantly ( p<0.01) and dose-dependently reduced, versus controls, nociceptive activity during the second phase of the formalin test (from the 20th to the 60th min): at the highest doses, 97.6±0.1% with MK 801; 90.4±0.2% with memantine; 74.7±0.3% with ketamine; 92.8±0.4% with dextromethorphan; and 80.7±0.3% with CGP 37849, without affecting coordination. The rank order potency of antinociceptive activity of NMDA antagonists was: MK 801 > memantine> ketamine> dextromethorphan> CGP37849 . The NMDA antagonists administered after formalin (during the analgesic interval) did not affect the late phase of the formalin test. In conclusion, systemic administration of NMDA receptor antagonists decreases the nociception observed during the late phase of the formalin test.