Opioid antinociception, tolerance and dependence: interactions with the N-methyl-D-aspartate system in mice

This study explored the involvement of N-methyl-D-aspartate (NMDA) in the effects of mu opioid agonists. A hot plate procedure was used to assess antinociception and tolerance in mice in which the NR1 subunit of the NMDA receptor was reduced (knocked down, KD) to approximately 10% and in mice treated with the NMDA antagonist, LY235959 [(−)-6-phosphonomethyl-deca-hydroisoquinoline-3-carboylic acid]. The mu opioid agonists, morphine, l-methadone and fentanyl, were approximately 3-fold less potent in the NR1 KD mice than in wild type (WT) controls; however, the development of morphine tolerance and dependence did not differ markedly in the NR1 KD and WT mice. Acute administration of the NMDA antagonist, LY235959 produced dose-dependent, leftward shifts in the morphine dose-effect curve in WT mice, but not in the NR1 KD mice. Chronic administration of LY235959 during the morphine tolerance regimen did not attenuate the development of tolerance in the NR1 KD nor the WT mice. These results indicate that the NR1 subunit of the NMDA receptor does not play a prominent role in mu opioid tolerance