TY - JOUR T1 - <em>d</em>-Methadone Blocks Morphine Tolerance and<em>N</em>-Methyl-<span class="sc">d-</span>Aspartate-Induced Hyperalgesia JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 1048 LP - 1053 VL - 289 IS - 2 AU - Antonia M. Davis AU - Charles E. Inturrisi Y1 - 1999/05/01 UR - http://jpet.aspetjournals.org/content/289/2/1048.abstract N2 - Previous in vitro and in vivo studies have determined that thed isomer of methadone hasN-methyl-d-aspartate (NMDA) receptor antagonist activity. The present studies examined the ability ofd-methadone to attenuate the development of morphine tolerance in mice and rats and to modify NMDA-induced hyperalgesia in rats. A decrease in the percentage of mice analgesic (tail-flick response) after 5 days of once-daily morphine (7 mg/kg s.c.) was completely blocked by coadministration of d-methadone given s.c. at 10 mg/kg. Morphine given s.c. to mice on an escalating three times per day dosing schedule resulted in a nearly 3-fold increase in the tail-flick ED50 dose of morphine 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 μg/rat. A decrease in thermal paw withdrawal latency induced by the i.t. administration of 1.64 μg/rat NMDA was completely blocked by pretreatment with 160 μg/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 NMDA-induced hyperalgesia. These results support the conclusion that d-methadone affects the development of morphine tolerance and NMDA-induced hyperalgesia by virtue of its NMDA receptor antagonist activity. The American Society for Pharmacology and Experimental Therapeutics ER -