Abstract
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 ofd-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.
Footnotes
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Send reprint requests to: Charles E. Inturrisi, Ph.D., Department of Pharmacology, Rm. LC524, Cornell University Medical College, 1300 York Avenue, New York, NY 10021.
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↵1 The research was supported by National Institute on Drug Abuse (NIDA) grants DA01457 (C.E.I.) and DA00255 (K.J.E.) and by the VZV Foundation (K.J.E.). C.E.I. is a recipient of a Research Scientist Award from NIDA (DA00198).
- Abbreviations:
- NMDA
- N-methyl-d-aspartate
- d
- dextrorotatory
- l
- levorotatory
- IT
- intrathecal
- ED50
- median effective dose
- Received March 25, 1997.
- Accepted July 23, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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