ISOBOLOGRAPHIC SUPERADDITIVITY BETWEEN DELTA-OPIOID AND MU-OPIOID AGONISTS IN THE RAT DEPENDS ON THE RATIO OF COMPOUNDS, THE MU-AGONIST AND THE ANALGESIC ASSAY USED

The present study was designed to test rigorously, using isobolographic analysis, whether there was a potentiative interaction between delta and mu agonists administered i.c.v. to rats. Factors such as the specific fixed ratio of compounds, the analgesic assay and the mu agonist were varied to determine the generality of the results. Male rats were implanted with i.c.v. cannulas and were tested in the cold (-3-degrees-C) or hot (+50-degrees-C) water tail-flick test. Full dose-effect curves were generated for the mu agonists, morphine and [N-MePhe3,D-Pro4]morphiceptin and the delta-selective agonist, DPDPE. Each agonist induced dose-related analgesia in the cold water test (ED50 values were 12, 0.79 and 75 mug, respectively). In the hot water test, morphine induced analgesia with an ED50 value of 4.4 mug, whereas DPDPE failed to produce a full effect at doses up to 200 mug. Full dose-effect curves were also generated for various fixed-ratio combinations of DPDPE and morphine in both analgesic assays. Fixed ratios were chosen such that the amount of DPDPE in each dose of the combinations tested was itself subanalgesic. The combination with 20% DPDPE and 80% morphine (by weight) was significantly superadditive in the cold water test as determined by isobolographic analysis, whereas a second combination of the same drugs (40% DPDPE) was not. However, in the hot water test, the 20% DPDPE combination was not superadditive and neither were two other combinations of DPDPE and morphine. No combination of DPDPE and [N-MePhe3,D-Pro4]morphiceplin differed significantly from additivity when tested in the cold water test. Thus, potentiative delta-mu interactions were shown to depend on the ratio of compounds, on the analgesic assay and on the mu agonist used.