The effects of majonoside R2 on antinociceptive responses caused by the μ-opioid receptor agonist morphine and the selective κ-opioid receptor agonist U-50,488H were examined by the tail-pinch test in mice. Intraperitoneal (IP) or intracerebroventricular (ICV) injection of majonoside-R2 (3.1-6.2 mg/kg, IP or 5-10 μg/mouse. ICV) and diazepam (0.1- 0.5 mg/kg, IP or 0.5-1.0 μg/mouse, ICV), as well as an opioid receptor antagonist naloxone (2 mg/kg. IP or 5 μg/mouse, ICV), dose-dependently attenuated the antinociception caused by subcutaneously administered morphine and U-50,488H. Moreover, when co-administered ICV or intrathecally (IT) with morphine (4 μg/mouse, ICV) and diazepam (1 μg/mouse, ICV) were reversed by flumazenil (2.5 μg/mouse, ICV), a selective benzodiazepine receptor antagonist and picrotoxin (0.25 μg/mouse, ICV), a GABA-gated chloride channel blocker. These results suggest that majonoside-R2 attenuates the opioid-induced antinociception by acting at the spinal and supraspinal levels, and that the GABA, receptor complex at the supraspinal level is involved in the effect of ICV administered majonoside-R2.
