The time-course of the development and disappearance of physical dependence to morphine was studied in rats using the implantation method of Huidobro and Contreras (8). Groups of 12 rats were challenged with 10 mg/kg of levallorphan tartrate at various times from 3 to 96 h after implantation and the intensity of abstinence gauged by the behavioral reaction to a battery of graded mechanical stimuli. Physical dependence develops exponentially with a time-constant of 12 h, becoming 95 % complete at 48 h. The time-course of withdrawal abstinence was studied following the removal of the morphine tablets 96 h after implantation in a group of 13 rats. It requires 12 h for the intensity of abstinence to reach a maximum and the intensity at this time is comparable to that obtained with levallorphan challenge in the presence of morphine. This was confirmed in a third study of four groups of 18 rats each in which the tablets were removed 48, 72, 84 and 92 h after implantation and the animals challenged at the 96th h. In the 84 and 92 h groups, levallorphan enhanced the intensity of abstinence, whereas in the 48 and 72 h groups it did not, although the prechallenge irritability scores of these animals were still significantly greater than normal control scores. Rats implanted with levallorphan or pentazocine tablets are refractory to subsequent injections of morphine (D’Amour-Smith test) (3) and of levallorphan. The implantation of morphine simultaneously with or subsequent to levallorphan implantation neither produces signs of analgesic depression nor causes physical dependence to develop. Implantation of levallorphan 96 h after the implantation of morphine produces signs of abstinence lasting 96 h at which time the animals are similar behaviorally to those in whom the implantations were made simultaneously. A second implant of morphine at 96 h is without further effect in morphine-implanted rats.

Keywords:
Continuous precipitated abstinence, Morphine dependence, Physical dependence, Precipitated abstinence, Withdrawal abstinence
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© 1974 S. Karger AG, Basel
1974
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