Inhibition of synaptosomal veratridine-induced sodium influx by antidepressants and neuroleptics used in chronic pain

Veratridine-induced (10 mu M) 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 similar to 1-5 mu M), anticonvulsant (lamotrigine, phenytoin IC50 similar to 70-140 mu M), local anaesthetic (lidocaine, procaine IC50 similar to 60-200 mu M) or antiarrhythmic properties (quinidine, disopyramide, amiodarone, mexiletene, propafenone, fleicainide IC50, similar to 2-200 mu M). 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 similar to 1-10 mu M. 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. Copyright (C) 1996 Elsevier Science Ireland Ltd.