KETOBEMIDONE, METHADONE AND PETHIDINE ARE NONCOMPETITIVE N-METHYL-D-ASPARTATE (NMDA) ANTAGONISTS IN THE RAT CORTEX AND SPINAL-CORD

The opiate agonists, ketobemidone, methadone and pethidine, were evalu ated as N-methyl-D-aspartate (NMDA) receptor antagonists using the rat cortical wedge preparation and the neonatal rat spinal cord preparati on for electrophysiological studies and 5-methyl-10,11-dihydro-5H-dibe nzo[a,d]cyclohepten- 5,10-imine ([3H]MK-801) binding experiments using rat forebrain homogenates. Ketobemidone, methadone and pethidine were inhibitors of [H-3]MK-801 binding with K-i values of 26 mu M, 0.85 mu M and 47 mu M, respectively. In the cortex, 1 mM ketobemidone and 1 m M methadone reduced NMDA responses, but not amino-3-(3-hydroxy-5-methy lisoxazol-4-yl)propionic acid (AMPA) or kainate responses in an use-de pendent manner, whereas 1 mM pethidine was devoid of antagonist activi ty. In the spinal cord preparation, the activities of ketobemidone and methadone were weaker than in cortex. In contrast, pethidine was equi potent with ketobemidone in the spinal cord. These results suggest tha t ketobemidone and methadone may be useful therapeutic agents in condi tions where a combined opiate agonist and NMDA antagonist treatment is desired.