Depression of spinal network activity by thiopental: shift from phasic to tonic GABA(A) 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 EC(50) of 16.6+/-2.4microM. Recordings of GABA(A) and glycine receptor-mediated inhibitory currents indicated that the effect was largely mediated by GABA(A) receptors and that glycine receptors were not relevant targets. Specifically, 20microM 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 sIPSC the concomitant strong reduction of sIPSC frequency resulted in less inhibitory current entering the neurons via this route. However, 20microM thiopental also induced a tonic current of 30+/-10pA, mediated by GABA(A) receptors; 50microM thiopental nearly abolished sIPSC activity but augmented tonic currents to 69+/-14pA. Furthermore, at this concentration, activity-depressing mechanisms independent of GABA(A) receptors came into play. The results suggest that in the spinal ventral horn thiopental acts mostly, but not exclusively, via GABA(A) 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.
Grasshoff
C
C
Department of Anesthesiology and Intensive Care, Eberhard-Karls-University, Schaffhausenstrasse 113, D-72072 Tuebingen, Germany.
Netzhammer
N
N
Schweizer
J
J
Antkowiak
B
B
Hentschke
H
H
D000200:Action Potentials / Q000187:drug effects; D000704:Analysis of Variance; D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D018756:GABA Antagonists / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology*; D018684:Glycine Agents / Q000494:pharmacology; D051379:Mice; D009415:Nerve Net / Q000166:cytology / Q000187:drug effects*; D009433:Neural Inhibition / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques / Q000379:methods; D011963:Receptors, GABA-A / Q000502:physiology*; D013116:Spinal Cord / Q000033:anatomy & histology / Q000502:physiology*; D013331:Strychnine / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D013874:Thiopental / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D000779:Anesthetics, Local; D018756:GABA Antagonists; D018757:GABA Modulators; D018684:Glycine Agents; D011963:Receptors, GABA-A; D013779:Tetrodotoxin; D005680:gamma-Aminobutyric Acid; D013331:Strychnine; D013874:Thiopental; D001640:Bicuculline