In our initial study we hypothesized that the combination of an intravenous anesthetic with an opioid might give different outcomes for different components of anesthesia. We confirmed this assumption with the most striking results being observed when using the diazepam-morphine combination which produced synergism with respect to the hypnotic action but antagonism with regard to the antinociceptive action. In this renewal application we propose investigations that will be devoted to a comprehensive analysis of the mechanisms of the benzodiazepine-opioid interactions. We hypothesize that the synergistic midazolam-morphine hypnotic interaction is pharmacodynamic in nature and that it is based on the interaction of opioid and benzodiazepine receptor systems in the mediation of the hypnotic effect, possibly to the degree when the hypnotic action of benzodiazepines has an underlying mechanism involving opioid receptors and vice versa for the hypnotic action of morphine. It is also hypothesized that the wide individual variability in response to the hypnotic action of benzodiazepines is largely due to pharmacodynamic factors and that it may be reduced by the addition of morphine. Finally, our hypothesis also considers that the antagonistic effect of midazolam on morphine analgesia is mediated by benzodiazepine receptors and associated with a benzodiazepine-induced depression of an inhibitory descending pain control system activated by morphine. To analyze the interactions between benzodiazepines (midazolam) and opioids (morphine) we will perform experiments in rats using the following basis tests: loss of the righting reflex, suppression of spontaneous locomotor activity, and increase in reaction threshold to noxious stimulation. Quantal dose-response curves for midazolam, morphine and their combinations concerned with the above test will be determined and the effects of various specific receptor antagonists on these curves will be investigated. Algebraic and isobolographic methods for analysis of agent interactions will be used. These experiments will test our hypotheses and produce new and detailed quantitative analysis of the mechanisms involved in hypnotic and analgesic interactions of benzodiazepines and opioids which are commonly used now in anesthesiological practice.
