D-METHADONE IS ANTINOCICEPTIVE IN THE RAT FORMALIN TEST

The l-isomer of methadone possesses opioid activity, whereas the d-iso mer is weak or inactive as an opioid. Both d- and l-methadone have bee n shown to bind to the N-methyl-D-aspartate (NMDA) receptor. To determ ine whether d-methadone has functional, in vivo NMDA receptor antagoni st activity, the antinociceptive effects of d-methadone were evaluated in the rat tail-flick and formalin tests. Cumulative dose-response an alysis in the tail-flick test revealed an ED50 value far intrathecal ( spinal) l-methadone of 15.6 mu g/rat. In contrast, spinal d-methadone produced no antinociception at a cumulative dose of 460 mu g/rat. d-Me thadone in a dose range from 32 to 320 mu g/rat dose-dependently reduc ed formalin-induced flinching behavior during phase 2 but not during p hase 1 of the formalin test. These antinociceptive effects of d-methad one were not blocked by a spinal dose of naloxone that effectively ant agonized an antinociceptive (tail-flick test) dose of l-methadone. d-M ethadone at an intrathecal dose of 250 mu g shifted the ED50 value for NMDA-induced nociceptive behaviors more than 3-fold to the right, whi ch indicates an antagonism of these NMDA receptor-mediated effects. Th ese results indicate that d-methadone is antinociceptive as a result o f its NMDA receptor antagonist activity.