Opioids and non-opioid enantiomers selectively attenuate N-methyl-D-aspartate neurotoxicity on cortical neurons.
Addition of 1 microM-1 mM methadone to the bathing medium produced a concentration-dependent reduction in the neurotoxicity of exogenously applied N-methyl-D-aspartate (NMDA) in murine cortical cell culture (EC50 about 100 microM); the reduction persisted at intense NMDA exposure, consistent with non-competitive inhibition. Methadone also protected against exposure to quinolinate but not quisqualate or kainate. Concentrations (100 microM-3 mM) of several other opioids - morphine, fentanyl, codeine, meperidine, dextropropoxyphene, and naltrexone - were additionally found to produce concentration-dependent reductions in NMDA neurotoxicity. This novel neuron-protective effect of opioids was not mediated by conventional opioid receptors: the non-opioid enantiomer of methadone and morphine exhibited a potency equal to or greater than that of the opioid enantiomer, and 1 mM naloxone did not act as an antagonist. The possibility that opioids, or especially non-opioid enantiomers of opioids, might provide a useful therapeutic approach in diseases states involving NMDA receptor-mediated neurotoxicity, warrants further study.
Choi
D W
DW
Department of Neurology, Stanford University Medical Center, CA 94305.
Viseskul
V
V
D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000633:toxicity; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D007202:Indicators and Reagents; D008691:Methadone / Q000494:pharmacology; D051379:Mice; D009020:Morphine / Q000494:pharmacology; D016202:N-Methylaspartate; D009270:Naloxone / Q000494:pharmacology; D009294:Narcotics / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects*; D013237:Stereoisomerism
D000596:Amino Acids; D007202:Indicators and Reagents; D009294:Narcotics; D001224:Aspartic Acid; D009270:Naloxone; D016202:N-Methylaspartate; D009020:Morphine; D008691:Methadone