Abstract

Graded doses of naltrexone (0.31, 1.125, 5.0, 20.0 and 80.0 micrograms/kg) were administered to five beagle-type dogs dependent on increasingly large stabilization doses of morphine (0.5, 1.0, 2.0, 4.0, 8.0, 16.0 and 24.0 mg/kg/day) and the intensity of precipitated abstinence (PAS) was determined by a previously developed scoring system. A complete crossover design was executed with all dogs receiving all doses of both naltrexone and morphine. The data were analyzed using a two-way analysis of variance (dogs and treatments). Treatment variance was partitioned into a regression and residual component. A mathematical model for relating the intensity of abstinence (PAS) to the concentrations of morphine and naltrexone was developed using the law of mass action and assuming that the degree of morphine physical dependence is related directly to the number of mu receptors occupied by morphine and the intensity of PAS is proportional to the number of receptors from which morphine is displaced by the antagonist. Using the mathematical model the deviations of the observed values from the calculated values were minimized using an iterative curve-fitting procedure which varied the values of the dissociation constants of morphine (KA) and naltrexone (KB) and the activity coefficient for morphine (alpha). The analysis of variance showed that the treatment effect was significant and that the regression accounted for most of this variance. The values which provided the best fit were: KA, 1.58 mg/kg; KB, 0.95 microgram/kg; and alpha, 245.(ABSTRACT TRUNCATED AT 250 WORDS)