Sedative and Hypnotic Midazolam-Morphine Interactions in Rats

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Abstract
The midazolam-morphine interactions in relation to the sedative effect and in relation to the hypnotic effect were studied in rats. Two series of experiments (sedative and hypnotic) were performed. In the sedative series, doses that inhibited locomotor activity to 10% or more of the control level were determined when the agents were given singly or in combination. Dose-response curves were determined with a probit procedure. The ED50 values of both agents and their combination were compared with algebraic (fractional) and isobolographic analyses in one subseries of experiments. The effect of a small fixed dose of morphine (1/10 of ED50 value for the sedative effect) on the slope of the sedative dose-response curve for midazolam was determined in the other subseries. In the hypnotic series of experiments, doses (ED50) that blocked the righting reflex with drugs given separately and in combination were determined by a probit procedure and, as in the sedative series, compared with algebraic (fractional) and isobolographic analyses. Sedative interaction between midazolam and morphine was found to have a tendency for synergism (interaction coefficient of 1.56, P > 0.05) with decreased individual variability in the sedative response to the combination. Hypnotic midazolam-morphine interaction was highly synergistic with the interaction coeficient of 3.70 (P < 0.0001). A difference in the outcomes of rnidazolam-morphine interaction regarding sedation and hypnosis suggests that underlying mechanisms for these two effects are different; therefore, they should not be regarded as only increasing depths of the same action.

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