The NMDA antagonist Memantine blocks pain behavior in a rat model of formalin-induced facial pain

Abstract

Recent studies have provided evidence that excitatory amino acid antagonists can exert analgesic effects in animals. These studies, however, have focused primarily on phasic pain or hyperalgesia rather than tonic pain. The present study evaluates the effects of systemic administration of Memantine (1-amino-3,5-dimethyl-adamantane), a clinically used N-methyl-D-aspartate (NMDA) receptor antagonist, on formalin-induced phasic and tonic pain behavior in the rat. Memantine (2.5, 5.0, 10.0 and 20.0 mg/kg) or normal saline was injected i.p. 1 h prior to a s.c. injection of formalin (5%, 50 microliters) into the vibrissal pad of adult rats (n = 5/group). Pain behavior was measured by the number of seconds of formalin-induced face grooming during a 42-min post-injection observation period. Saline-injected animals displayed a biphasic face-grooming response, consisting of an early, phasic phase (0-6 min) and a delayed, prolonged tonic phase (12-42 min). Memantine at doses of 2.5-10 mg/kg produced a significant dose-related inhibition of the second phase (65-93%) and a much smaller inhibition of the first phase (up to 52%). A higher dose (20 mg/kg) further inhibited both phases but also produced other motor effects (increased exploratory and decreased freezing behavior, hind-paw weakness and gait ataxia) which were not observed at the lower doses. These results suggest that the NMDA receptor antagonist Memantine can block formalin-induced tonic and, to a lesser extent, phasic pain, at doses that do not alter observed motor behaviors.