1. Propofol (2,6 di-isopropylphenol), an intravenous general anaesthetic, blocks voltage-dependent Na+ channels (Na+ channels). In this study the interaction between propofol and Na+ channels was analysed by examining its effects on neurotoxin binding to various receptor sites of the Na+ channel in rat cerebrocortical synaptosomes. 2. Propofol (10-200 microM) exhibited concentration-dependent inhibition of equilibrium binding of [3H]-batrachotoxinin-A 20-alpha-benzoate ([3H]-BTX-B) to receptor site 2 of the Na+ channel (mean IC50 = 26 microM; 6.5 microM free). Scatchard analysis revealed that propofol significantly increased the KD without affecting the Bmax for [3H]-BTX-B binding. 3. Kinetic studies of [3H]-BTX-B binding in the presence of various concentrations (25-200 microM) of propofol showed no significant changes in the association rate of [3H]-BTX-B. However, propofol at 200 microM significantly increased the rate of dissociation of [3H]-BTX-B, consistent with an indirect allosteric competitive mechanism of inhibition. 4. [3H]-saxitoxin binding to receptor site 1 and [3H]-brevetoxin-3 binding to receptor site 5 of the Na+ channel were not inhibited by propofol (10-200 microM). 5. Propofol (10-100 microM) exhibited concentration-dependent inhibition of veratridine-evoked Na+ influx either in the absence or presence of scorpion toxin with IC50 values of 46 microM (8.8 microM free) and 44 microM (8.5 microM free), respectively. 6. These results suggest that propofol inhibits voltage-dependent Na+ channels due to a preferential interaction with the inactivated state of the channel. Blockade of Na+ channels by propofol, which is known to inhibit glutamate release from synaptosomes, may contribute to its anaesthetic, anticonvulsant and neuroprotective properties.