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Vol. 289, Issue 2, 1048-1053, May 1999
Department of Pharmacology, Cornell University Medical College, New
York, New York
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 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.
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