Effects of noribogaine on the development of tolerance to antinociceptive action of morphine in mice.

The effects of noribogaine, a metabolite of ibogaine, on the development of tolerance to the antinociception action of morphine was determined in male Swiss-Webster mice. Ibogaine is an alkaloid isolated from the bark of the African shrub, Tabernanthe iboga. Morphine tolerance in mice was developed by two different methods. Mice were rendered tolerant to morphine either by subcutaneous implantation of a pellet containing 25 mg morphine free base for 4 days or by injecting morphine (20 mg/kg, s.c.) twice a day for 4 days. Placebo pellet implanted mice or vehicle injected mice served as controls. To determine the effect of intraperitoneally administered noribogaine on tolerance development, the drug was injected in the appropriate dose twice a day. In pellet implanted mice, a dose of 20 mg/kg of noribogaine attenuated the tolerance to morphine whereas lower doses had no effect. Similarly, in mice given multiple injections of morphine, noribogaine attenuated tolerance development at 20 and 40 mg/kg doses. Previous studies from this laboratory had shown that ibogaine at 40 and 80 mg/kg doses inhibited tolerance to morphine. Because noribogaine could attenuate morphine tolerance at lower doses than ibogaine, it is concluded that the attenuating effect of ibogaine on morphine tolerance may be mediated by its conversion to noribogaine, a more active metabolite.