BLOCKADE OF MORPHINE-TOLERANCE BY ACEA-1328, A NOVEL NMDA RECEPTOR GLYCINE SITE ANTAGONIST

Recent studies indicate that competitive and non-competitive NMDA rece ptor antagonists can block the development of morphine tolerance. Sinc e glycine is considered to be a co-agonist for activation of NMDA rece ptors we examined the effect of a novel bioavailable NMDA receptor/gly cine site antagonist, itro-6,7-dimethyl-1,4-dihydro-2,3-quinoxalinedio ne (ACEA-1328), on the development of morphine tolerance. Administrati on of ACEA-1328 (20 mg/kg) completely blocked tolerance to morphine-in duced antinociception in the tail flick test in CD-1 mice, without aff ecting the basal nociceptive response or potentiating morphine-induced antinociceptive effects. These data suggest that inhibition of NMDA r eceptor activity via blockade of the glycine co-agonist site is potent ially viable as a therapeutic approach for preventing development of m orphine tolerance.