The N-methyl-D-aspartate antagonistic and opioid components of d-methadoneantinociception in the rat spinal cord

The d-enantiomer of the opioid methadone is a weak opioid with low micromol ar affinity to the N-methyl-D-aspartate (NMDA) receptor. We have investigat ed the antinociception and in vivo NMDA antagonism after systemic administr ation of d-methadone in the rat spinal cord. d-Methadone caused antinocicep tion in the Randall-Selitto model of inflammatory pain and inhibited the re sponses of hindlimb single motor units to noxious electrical and mechanical stimulation (ED50 6.6, 6.8 and 7.2 mg/kg intravenous (i.v.), respectively) ; the wind-up of these responses was only inhibited at the dose almost comp letely abolishing the baseline responses, d-Methadone inhibited the activit y of spinal dorsal horn neurones evoked by both iontophoretic NM DA and (R, S)-alpha -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA, ED50 5 .7 and 8.2 mg/kg i.v., respectively). After pre-treatment with naloxone, d- methadone was unable to inhibit nociception in the Randall-Selitto model, t he NMDA- or AMPA-evoked neuronal activity or the motoneurone wind-up. Thus, in the antinociceptive dose range, the NMDA antagonism does not appear to contribute to the mechanism of d-methadone antinociception. (C) 2000 Elsevi er Science Ireland Ltd. All rights reserved.