Neurochemical action of the general anaesthetic propofol on the chloride ion channel coupled with GABA A receptors

Abstract

The effect of propofol, a novel short acting anaesthetic, on the function of the GABA A/ionophore receptor complex was studied in vitro in cortical membrane preparations from rat cerebral cortex and was compared with the action of pentobarbital and alphaxalone, two general anaesthetics known to enhance GABAergic transmission. Propofol, mimicking the action of pentobarbital and alphaxalone, increased [ 3H]GABA binding, reduced [ 35S]TBPS binding and enhanced muscimol-stimulated 36CI − uptake in a concentration-dependent manner. While the efficacy of the drugs in affecting these biochemical parameters was similar, they differed markedly in potency being alphaxalone > propofol > pentobarbital. However, separate sites of action or different mechanisms for these drugs can be suggested by the result that the concomitant addition of propofol either with alphaxalone or pentobarbital or diazepam produced a simple additive inhibition of [ 35S]TBPS binding as well as an addictive enhancement of [ 3H]GABA binding and muscimol-stimulated 36CI − uptake. The effect of propofol at the level of the GABA/ionophore receptor complex seems to be strictly dependent on the interaction of GABA with its recognition site. In fact, the specific GABA A receptor antagonist bicuculline antagonized the decrease of [ 35S]TBPS binding as well as the enhancement of [ 3H]GABA binding and muscimol-stimulated 36CI − uptake induced by propofol. On the other hand, propofol was able to enhance [ 3]GABA binding in membranes previously incubated with the specific chloride channel blocker picrotoxin.Finally, the finding that propofol fails to affect [ 3H]flunitrazepam binding together with the failure of Ro 15–1788 and PK 11195 to antagonize its effect on [ 35S]TBPS binding excludes a direct interaction at the level of benzodiazepine recognition sites. Taken together these results strongly suggest that an enhancement in the function of the GABA A/ionophore receptor complex may have a relevant role in mediating the anaesthetic effect of propofol as well as those of other general anaesthetics.