The N-methyl-D-aspartate antagonistic and opioid components of d-methadone antinociception in the rat spinal cord.
The d-enantiomer of the opioid methadone is a weak opioid with low micromolar affinity to the N-methyl-D-aspartate (NMDA) receptor. We have investigated the antinociception and in vivo NMDA antagonism after systemic administration of d-methadone in the rat spinal cord. d-Methadone caused antinociception in the Randall-Selitto model of inflammatory pain and inhibited the responses of hindlimb single motor units to noxious electrical and mechanical stimulation (ED(50) 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 completely abolishing the baseline responses. d-Methadone inhibited the activity of spinal dorsal horn neurones evoked by both iontophoretic NMDA and (R, S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA, ED(50) 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, the 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.
Chizh
B A
BA
Grünenthal GmbH, Research Centre, Zieglerstrasse 6, 52078, Aachen, Germany. boris.chizh@grunenthal.de
Schlütz
H
H
Scheede
M
M
Englberger
W
W
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000698:Analgesia / Q000379:methods; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008297:Male; D008691:Methadone / Q000494:pharmacology*; D016202:N-Methylaspartate / Q000494:pharmacology; D009270:Naloxone / Q000494:pharmacology; D009619:Nociceptors / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010146:Pain / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D020671:Posterior Horn Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
D000701:Analgesics, Opioid; D016194:Receptors, N-Methyl-D-Aspartate; D009270:Naloxone; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D008691:Methadone