d-Methadone blocks morphine tolerance and N-methyl-D-aspartate-induced hyperalgesia

Previous in vitro and in vivo studies have determined that the d isomer of methadone has N-methyl-D-aspartate (NMDA) receptor antagonist activity. The present studies examined the ability of d-methadone to attenuate the devel opment of morphine tolerance in mice and rats and to modify NMDA-induced hy peralgesia in rats. A decrease in the percentage of mice analgesic (tail-fl ick response) after 5 days of once-daily morphine (7 mg/kg s,c.) was comple tely blocked by coadministration of d-methadone given s.c. at 10 mg/kg. Mor phine given s.c, to mice on an escalating three times per day dosing schedu le resulted in a nearly 3-fold increase in the tail-flick ED50 dose of morp hine which was prevented by s.c, coadministered d-methadone at 15 mg/kg, In rats, intrathecal (i.t.) morphine produced a 38-fold increase in the ED50, which was completely prevented by the coadministration of i.t. d-methadone at 160 mu g/rat. A decrease in thermal paw withdrawal latency induced by t he i.t. administration of 1.64 mu g/rat NMDA was completely blocked by pret reatment with 160 mu g/rat d-methadone. Thus, systemically coadministered d -methadone prevents systemically induced morphine tolerance in mice, i.t. d -methadone attenuates tolerance produced by i.t. morphine in rats, and i.t. d-methadone, at the same dose which modulates morphine tolerance, blocks N MDA-induced hyperalgesia. These results support the conclusion that d-metha done affects the development of morphine tolerance and NMDA-induced hyperal gesia by virtue of its NMDA receptor antagonist activity.