The proposed hypothesis considers that it is possible to influence the anesthetic effect of benzodiazepines by allosterically modulating the benzodiazepine receptor component of the postsynaptic GABA receptor macromolecular complex. We hypothesize that sedative-hypnotic agents which allosterically enhance the binding of benzodiazepines to the benzodiazepine receptor provide supra-additive (synergistic) anesthetic interactions with benzodiazepines, and therefore, synergistic anesthetic interactions can be achieved when benzodiazepine administration is combined with either one of two types of allosteric modulators of the benzodiazepine receptor: those acting via the GABA domain (aminooxyacetic acid) and those acting via the chloride channel domain of the GABA macromolecular complex (barbiturates, etomidate). Hence, it is further hypothesized that because the synergistic action of the GABA and barbiturate type modulators is exerted from two different sites of the GABA macromolecular complex combinations of a benzodiazepine with two modulators of the different types (triple combination) may provide a greater degree of synergism regarding anesthetic action than the combination of the benzodiazepine with only one of the respective modulators (binary combination). To examine and assess the anesthetic interactions of benzodiazepines with sedative-hypnotic agents that modulate the benzodiazepine receptor we will perform experiments in rats using two indices of anesthesia: loss of the righting reflex and blockade of movement response to noxious stimulation. Dose- response curves for midazolam, diazepam, various barbiturates and GABA agonists given separately and in combinations will be determined with a probit procedure. Graphic and algebraic methods for analysis of two and three agent interactions (including isobolographic technique) will be used. These experiments will not only test our hypothesis that several sedative-hypnotic agents have a powerful modulatory effect on the anesthetic action of benzodiazepines, but they will also produce new and detailed quantitative estimates of the respective interactions under scrutiny. It is readily apparent that these interactions might represent an important mechanism responsible for the potentiation of the anesthetic effect of benzodiazepines.
| DeLorey, T M; Kissin, I; Brown, P et al. (1993) Barbiturate-benzodiazepine interactions at the gamma-aminobutyric acidA receptor in rat cerebral cortical synaptoneurosomes. Anesth Analg 77:598-605 |
| DeLorey, T M; Brown, G B (1992) gamma-Aminobutyric acidA receptor pharmacology in rat cerebral cortical synaptoneurosomes. J Neurochem 58:2162-9 |
