title: d-Methadone blocks morphine tolerance and N-methyl-D-aspartate-induced hyperalgesia.
abstract: Previous in vitro and in vivo studies have determined that the d isomer of methadone has N-methyl-D-aspartate (NMDA) receptor antagonist activity. The present studies examined the ability of d-methadone to attenuate the development of morphine tolerance in mice and rats and to modify NMDA-induced hyperalgesia in rats. A decrease in the percentage of mice analgesic (tail-flick response) after 5 days of once-daily morphine (7 mg/kg s.c.) was completely blocked by coadministration of d-methadone given s.c. at 10 mg/kg. Morphine given s.c. to mice on an escalating three times per day dosing schedule resulted in a nearly 3-fold increase in the tail-flick ED50 dose of morphine which was prevented by s.c. coadministered d-methadone at 15 mg/kg. In rats, intrathecal (i.t.) morphine produced a 38-fold increase in the ED50, which was completely prevented by the coadministration of i.t. d-methadone at 160 micrograms/rat. A decrease in thermal paw withdrawal latency induced by the i.t. administration of 1.64 micrograms/rat NMDA was completely blocked by pretreatment with 160 micrograms/rat d-methadone. Thus, systemically coadministered d-methadone prevents systemically induced morphine tolerance in mice, i.t. d-methadone attenuates tolerance produced by i.t. morphine in rats, and i.t. d-methadone, at the same dose which modulates morphine tolerance, blocks NMDA-induced hyperalgesia. These results support the conclusion that d-methadone affects the development of morphine tolerance and NMDA-induced hyperalgesia by virtue of its NMDA receptor antagonist activity.
authors.affiliation: Department of Pharmacology, Cornell University Medical College, New York, New York, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Davis
authors.forename: C E
authors.initials: CE
authors.lastname: Inturrisi
mesh_terms: D000701:Analgesics, Opioid / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D006930:Hyperalgesia / Q000139:chemically induced / Q000517:prevention & control*; D007278:Injections, Spinal; D008297:Male; D008691:Methadone / Q000494:pharmacology*; D051379:Mice; D009020:Morphine / Q000494:pharmacology*; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors* / Q000633:toxicity; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism
chemical_list: D000701:Analgesics, Opioid; D018690:Excitatory Amino Acid Agonists; D016202:N-Methylaspartate; D009020:Morphine; D008691:Methadone