d-Methadone is antinociceptive in the rat formalin test.
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 microg/rat. In contrast, spinal d-methadone produced no antinociception at a cumulative dose of 460 microg/rat. d-Methadone in a dose range from 32 to 320 microg/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 microg 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.
Shimoyama
N
N
Department of Pharmacology, Cornell University Medical College, New York, New York 10021, USA.
Shimoyama
M
M
Elliott
K J
KJ
Inturrisi
C E
CE
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D005557:Formaldehyde; D008297:Male; D008691:Methadone / Q000494:pharmacology*; D016202:N-Methylaspartate / Q000494:pharmacology; D009270:Naloxone / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D013237:Stereoisomerism
D000701:Analgesics, Opioid; D016194:Receptors, N-Methyl-D-Aspartate; D005557:Formaldehyde; D009270:Naloxone; D016202:N-Methylaspartate; D008691:Methadone