Veratridine-induced (10 microM) increases in intracellular sodium ([Na+]int) or calcium ([Ca2+]int) in rat cortical synaptosomes, measured with the fluorescent dyes SBFI or FLUO-3 were blocked by tetrodotoxin (IC50 Na+ 14 nM; Ca2+ 20 nM) and by a series of reference sodium channel blockers with neuroprotective (riluzole, lifarizine IC50 approximately 1-5 microM), anticonvulsant (lamotrigine, phenytoin IC50 approximately 70-140 micro M), local anaesthetic (lidocaine, procaine IC50 approximately 60-200 microM) or antiarrhythmic properties (quinidine, disopyramide, amiodarone, mexiletene, propafenone, fleicainide IC50, approximately 2-200 microM). Potencies for inhibition of veratridine-induced sodium and calcium entry were closely matched. These agents did not, or only weakly blocked, potassium evoked (50 mM) increases in [Ca2+]int. A number of antidepressant monoamine uptake inhibitors (amitriptyline, fluoxetine, clomipramine, desipramine, imipramine) or neuroleptics (pimozide, cinnarizine, haloperidol) were also potent inhibitors of veratridine-induced increases in [Na+]int or [Ca2+]int with affinities ranging from approximately 1-10 microM. A number of these drugs, from diverse chemical and pharmacological classes, are used for the treatment of chronic pain and their mechanism of action could perhaps be related to their common effects on a particular species of neuronal sodium channel.