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

Abstract

Veratridine-induced (10 μM) 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 ≈1–5 μM), anticonvulsant (lamotrigine, phenytoin IC₅₀ ≈70–140 μM), local anaesthetic (lidocaine, procaine IC₅₀ ≈ 60–200 μM) or antiarrhythmic properties (quinidine, disopyramide, amiodarone, mexiletene, propafenone, fleicainide IC₅₀,≈2–200 μM). 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 ≈1–10 μM. 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.