The antinociceptive interactions between spinally administered opioids and the alpha2 agonist clonidine were examined in placebo and morphine pellet-implanted mice using the tail flick test. In placebo pellet-implanted animals, coadministered morphine and clonidine produced a synergistic antinociceptive effect. In mice implanted with morphine pellets, the synergism decreased to an additive interaction. The interactions between clonidine and the mu agonist Tyr-D-Ala-Gly-N-Me-Phe-Gly-ol (DAMGO), the delta agonist D-Pen2-D-Pen5-Enkephalin (DPDPE), and the kappa agonist U50-488H were also synergistic in placebo animals. In morphine pellet treated mice the DPDPE/clonidine interaction decreased to an antagonistic interaction, the DAMGO/clonidine remained synergistic and the U50-488H/clonidine interaction decreased to additive. These results support the proposal that the morphine spinal/supraspinal synergism depends upon the interaction between spinal opioid and alpha2 receptors and a decrease in this interaction is a mechanism involved in development of tolerance to morphine. In addition, delta and kappa receptors appeared to be more involved in the morphine/clonidine decreased interaction than did mu opioid receptors.
A recent clinical report suggested that kappa opioids such as nalbuphine and butorphanol produced greater pain relief in women than in men. However, both compounds have been characterized as partial agonists with mixed mu/kappa opioid actions in animal studies. The aim of this study was to evaluate whether there is a sex difference in antinociception caused by nalbuphine and butorphanol as well as more selective kappa opioid agonists including U50,488 and Cl-977 in mice. In the acid-induced writhing assay, all compounds (U50,488: 1-10 mg/kg; Cl-977: 0.01-0.1 mg/kg; nalbuphine: 1-320 mg/kg; butorphanol: 0.032-0.32 mg/kg) dose-dependently inhibited writhing, but there were no sex-related differences found when comparing ED(50) values in male and female mice. In the warm water (48°C) tail withdrawal assay, U50,488 (10-100 mg/kg) and Cl-977 (0.1-3.2 mg/kg) also dose-dependently produced antinociception, although there were no sex-related differences observed. Nalbuphine (10-320 mg/kg) did not have antinociceptive effects under this condition. On the other hand, butorphanol (0.32-32 mg/kg) produced greater antinociception in male (50% MPE) than female mice (20% MPE). Further antagonist studies revealed that butorphanol is a mixed mu/kappa opioid with low efficacy. In summary, there were no sex-related differences in response to more selective kappa opioid agonists on antinociception in mice under these conditions.
