Depression of spinal network activity by thiopental: Shift from phasic to tonic GABAA receptor-mediated inhibition

Interneuronal networks in the spinal ventral horn are plausible substrates for mediating anesthetic-induced immobility. Here, we investigated how their activity is affected by clinically relevant concentrations of thiopental, a barbiturate in clinical use. In cultured spinal cord slices from mice, thiopental reduced action potential activity with an EC50 of 16.6 +/- 2.4 mu M. Recordings of GABA(A) and glycine receptor-mediated inhibitory currents indicated that the effect was largely mediated by GABAA receptors and that glycine receptors were not relevant targets. Specifically, 20 mu M thiopental prolonged the decay time of spontaneous GABAergic inhibitory postsynaptic currents (sIPSCs) more than twofold. Although this prolongation of decay time increased the inhibitory charge per slPSC the concomitant strong reduction of sIPSC frequency resulted in less inhibitory current entering the neurons via this route. However, 20 mu M thiopental also induced a tonic current of 30 +/- 10 pA, mediated by GABAA receptors; 50 mu M thiopental nearly abolished sIPSC activity but augmented tonic currents to 69 +/- 14 pA. Furthermore, at this concentration, activity-depressing mechanisms independent of GABAA receptors came into play. The results suggest that in the spinal ventral horn thiopental acts mostly, but not exclusively, via GABAA receptors. With increasing concentrations of the drug, inhibition via sIPSCs is limited by negative feedback on interneuronal firing whereas action potential-independent GABAergic inhibition due to tonic currents gains progressively in impact. (c) 2008 Elsevier Ltd. All rights reserved.