Differential interaction of anaesthetics and antiepileptic drugs with neuronal Na+ channels, Ca2+ channels, and GABAA receptors

Abstract

Current theories favour multiple agent-specific neuronal actions for both general anaesthetics and antiepileptic drugs, but the pharmacological properties that distinguish them are poorly understood. We compared the interactions of representative agents from each class on their putative targets using well-characterized radioligand binding assays. Synaptosomes or membranes prepared from rat cerebral cortex were used to analyse drug effects on [(35)S]t-butyl bicyclophosphorothionate ([(35)S]TBPS) binding to the picrotoxinin site of GABA(A) receptors, [(3)H]batrachotoxinin A 20-alpha benzoate ([(3)H]BTX-B) binding to site 2 of voltage-gated Na(+) channels, (+)-[methyl-(3)H]isopropyl 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-methoxycarboxyl-2,6-dimethyl-3-pyridinecarboxylate ([(3)H]PN200-110; isradipine) binding to L-type Ca(2+) channels, and [cyclohexyl-2,3-(3)H](N)glibenclamide ([(3)H]GB) binding to K(ATP) channels. I.V. anaesthetics other than ketamine preferentially inhibited [(35)S]TBPS binding (etomidate approximately equal alphaxalone > propofol > thiopental > pentobarbital). Volatile anaesthetics inhibited both [(35)S]TBPS and [(3)H]BTX-B binding with comparable potencies (halothane approximately equal isoflurane approximately equal enflurane). Antiepileptic drugs preferentially antagonized either [(35)S]TBPS (diazepam > phenobarbital) or [(3)H]BTX-B (phenytoin > carbamazepine) binding. Local anaesthetics (lidocaine, tertracaine) selectively antagonized [(3)H]BTX-B binding. None of the drugs tested were potent antagonists of [(3)H]PN200-110 or [(3)H]GB binding. Comparative radioligand binding assays identified distinct classes of general anaesthetic and antiepileptic drugs based on their relative specificities for a defined target set. I.V. anaesthetics interacted preferentially with GABA(A) receptors, while volatile anaesthetics were essentially equipotent at Na(+) channels and GABA(A) receptors. Antiepileptic drugs could be classified by preferential actions at either Na(+) channels or GABA(A) receptors. Anaesthetics and antiepileptic drugs have agent-specific effects on radioligand binding. Both general anaesthetics and antiepileptic drugs interact with Na(+) channels and GABA(A) receptors at therapeutic concentrations, in most cases with little selectivity.