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Vol. 283, Issue 2, 648-652, 1997
Department of Pharmacology, Cornell University Medical College, New
York, New York and Pain and Palliative Care Service, Department of
Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York
The l-isomer of methadone possesses opioid activity,
whereas the d-isomer is weak or inactive as an opioid.
Both d- and l-methadone have been shown
to bind to the N-methyl-D-aspartate (NMDA) receptor. To
determine whether d-methadone has functional, in
vivo NMDA receptor antagonist activity, the antinociceptive
effects of d-methadone were evaluated in the rat
tail-flick and formalin tests. Cumulative dose-response analysis in the
tail-flick test revealed an ED50 value for intrathecal
(spinal) l-methadone of 15.6 µg/rat. In contrast,
spinal d-methadone produced no antinociception at a cumulative dose of 460 µg/rat. d-Methadone in a dose
range from 32 to 320 µg/rat dose-dependently reduced formalin-induced
flinching behavior during phase 2 but not during phase 1 of the
formalin test. These antinociceptive effects of
d-methadone were not blocked by a spinal dose of
naloxone that effectively antagonized an antinociceptive (tail-flick
test) dose of l-methadone. d-Methadone at
an intrathecal dose of 250 µg shifted the ED50 value for
NMDA-induced nociceptive behaviors more than 3-fold to the right, which
indicates an antagonism of these NMDA receptor-mediated effects. These
results indicate that d-methadone is antinociceptive as
a result of its NMDA receptor antagonist activity.
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