GV196771A, an NMDA receptor/glycine site antagonist, attenuates mechanical allodynia in neuropathic rats and reduces tolerance induced by morphine in mice

Abstract

The effects of the N-methyl- d-aspartate (NMDA) receptor/glycine site antagonist, GV196771A ( E-4,6-dichloro-3-(2-oxo-1-phenyl-pyrrolidin-3-ylidenemethyl)-1 H-indole-2-carboxylic acid sodium salt), on mechanical allodynia and on tolerance to the antinociceptive effects induced by morphine were evaluated. Its antiallodynic properties were studied in a model of chronic constriction injury applied to rat sciatic nerve. GV196771A (0.3–10 mg/kg, p.o.) dose-dependently inhibited established mechanical allodynia when tested 14 or 21 days after nerve ligation. In the formalin test in mice, GV196771A (10 or 20 mg/kg, p.o.), administered for 8 days together with morphine 10 mg/kg, i.p. inhibited morphine tolerance development in both early and late phases of the test. This finding reinforces the key role of the NMDA receptors in the plastic event, such as allodynia, which develops in some conditions of painful neuropathy. Moreover, the capability to strongly reduce morphine-induced tolerance suggests that GV196771A could be an alternative agent for the treatment of difficult pain states not only when given alone, but also in combination, in order to prolong the analgesic effects of the opiates.