Morphine tolerance and dependence in mice with history of repeated exposures to NMDA receptor channel blockers

Mice were subjected to two successive treatment protocols: first with NMDA receptor channel blockers (14 days, once a day) and second with morphine (5 mg/kg, 8 days, once a day). Treatment with the higher doses of dizocilpine (1 mg/kg), memantine (30 mg/kg), and MRZ 2/576 (30 mg/kg) upon discontinua tion revealed only minor behavioral abnormalities attributable to the state of withdrawal. Following repeated administration of low-dose morphine, tol erance to morphine analgesia developed in mice preexposed to dizocilpine (1 mg/kg but not 0.3 mg/kg) but not memantine (10 and 30 mg/kg), MRZ 2/579 (1 0 and 30 mg/kg), or saline. There were no signs of morphine dependence in a ny treatment group. Overall, the present study found only minor effects of the subchronic administration of high doses of NMDA receptor channel blocke rs, suggesting that clinical use of NMDA receptor channel blockers such as memantine will not be accompanied by increased propensity to induction of m orphine tolerance and dependence. (C) 1999 Elsevier Science Inc.