Aconitum sp. alkaloids: the modulation of voltage-dependent Na+ channels, toxicity and antinociceptive properties

Alkaloids from Aconitum sp., used as analgesics in traditional Chinese medicine, were investigated to elucidate their antinociceptive and toxic properties considering: (1) binding to Na+ channel epitope site 2, (2) alterations in synaptosomal Na+ and Ca2+ concentration ([Na+](i), [Ca2+](i)), (3) arrhythmogenic action of isolated atria, (4) antinociceptive and (5) acute toxic action In mice. The study revealed a high affinity group (K-i 1 mu M) and a low affinity group (K-i 10 mu M) of alkaloids binding to site 2. The compounds of the high affinity group induce an increase in synaptosomal [Na+](i) and [Ca2+](i) (EC50 3 mu M), are antinociceptive (ED50, 25 mu g/kg), provoke tachyarrhythmia and are highly toxic (LD50 70 mu g/kg), whereas low affinity alkaloids reduce [Ca2+](i), induce bradycardia and are less antinociceptive (ED50 20 mg/kg) and less toxic (LD50 30 mg/kg). These results suggest that the alkaloids can be grouped in Na+ channel activating and blocking compounds, but none of the alkaloids seem to be suitable as analgesics because of the low LD50/ED50 values. (C) 1997 Elsevier Science B.V.