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d-Methadone Blocks Morphine Tolerance and N-Methyl-DAspartate- Induced Hyperalgesia

d-Methadone Blocks Morphine Tolerance and N-Methyl-DAspartate- Induced Hyperalgesia

  1. davestate
    The American Society for Pharmacology and Experimental Therapeutics 289:1048–1053, 1999
    ANTONIA M. DAVIS and CHARLES E. INTURRISI

    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 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 mg/rat. A decrease in thermal paw withdrawal latency induced by the i.t. administration of 1.64 mg/rat NMDA was completely blocked by
    pretreatment with 160 mg/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.
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