Interactions between an N-methyl-D-aspartate antagonist and low-efficacy opioid receptor agonists in assays of schedule-controlled responding and thermal nociception.

A growing body of literature has implicated N-methyl-d-aspartate (NMDA) receptor mechanisms in the acute antinociceptive effects of morphine; however, the nature of this interaction has not been thoroughly quantified. Moreover, it is not clear whether NMDA/morphine interactions extend to less efficacious opioids. Therefore, the present study examined the effects of morphine and various low-efficacy opioid agonists in combination with the NMDA antagonist (-)-6-phosphonomethyl-deca-hydroisoquinoline-3-carboxylic acid (LY235959) in two different assays: schedule-controlled responding and thermal nociception. Data were examined with dose-addition analysis to provide a quantitative assessment of the drug interactions. LY235959 and the opioid agonists morphine, buprenorphine, butorphanol, and nalbuphine all decreased rates of schedule-controlled responding. LY235959/morphine and LY235959/buprenorphine mixtures produced additive or subadditive effects in this assay, whereas LY235959/butorphanol and LY235959/nalbuphine mixtures produced additive or supra-additive effects, depending on the relative proportions of each drug in mixture. Morphine, buprenorphine, butorphanol, and nalbuphine also produced dose-dependent antinociception in the assay of thermal nociception, whereas LY235959 failed to produce an effect. In this assay, LY235959 potentiated the antinociceptive effects of morphine and each of the low-efficacy opioids tested. These results suggest that LY235959 may selectively increase the antinociceptive effects of morphine and some low-efficacy opioid receptor agonists without increasing their rate-altering effects. In addition, these data confirm that the behavioral effects of drug mixtures depend on the relative concentrations of the drugs in the mixture and on the endpoint under study.