Modulation of presynaptic beta3-containing GABAA receptors limits the immobilizing actions of GABAergic anesthetics.
Intravenous GABAergic anesthetics are potent hypnotics but are rather ineffective in depressing movements. Immobility is mediated, in part, by the ventral horn of the spinal cord. We hypothesized that the efficacy of these anesthetics in producing immobility is compromised by the activation of GABA(A) receptors located presynaptically, which modulate GABA release onto neurons in the ventral horn. Because anesthetics acting by modulation of GABA(A) receptor function require GABA to be present at its binding site, a decrease in GABA release would abate their efficacy in reducing neuronal excitability. Here we report that in organotypic spinal cord slices, the efficacy of the intravenous anesthetic etomidate to depress network activity of ventral horn neurons is limited to approximately 60% at concentrations greater than 1 microM that produce immobility. Depression of spinal network activity was almost abolished in spinal slices from beta3(N265M) knock-in mice. In the wild type, etomidate prolonged decay times of GABA(A) receptor-mediated inhibitory postsynaptic currents (IPSCs) and concomitantly reduced the frequency of action potential-dependent IPSCs. Etomidate prolonged the decay time of GABA(A) receptors at all tested concentrations. At concentrations greater than 1.0 microM, anesthetic-induced decrease of GABA release via modulation of presynaptic GABA(A) receptors and enhancement of postsynaptic GABA(A) receptor-function compensated for each other. The results suggest that the limited immobilizing efficacy of these agents is probably due to a presynaptic mechanism and that GABAergic agents with a specificity for post-versus presynaptic receptors would probably have much stronger immobilizing actions, pointing out novel avenues for drug development.
Grasshoff
Christian
C
Experimental Anesthesiology Section, Department of Anesthesiology and Intensive Care, Eberhard-Karls-University, Tuebingen, Germany. christian.grasshoff@uni-tuebingen.de
Jurd
Rachel
R
Rudolph
Uwe
U
Antkowiak
Bernd
B
D019943:Amino Acid Substitution; D018686:Anesthetics, Intravenous / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000870:Anterior Horn Cells / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D004622:Embryo, Mammalian; D005045:Etomidate / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D006720:Homozygote; D046353:Immobility Response, Tonic / Q000187:drug effects*; D007395:Interneurons / Q000187:drug effects; D008715:Methionine / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D010477:Perfusion; D011247:Pregnancy; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D017661:Receptors, Presynaptic / Q000187:drug effects*; D013116:Spinal Cord / Q000187:drug effects
D018686:Anesthetics, Intravenous; C546270:Gabrb3 protein, mouse; D011963:Receptors, GABA-A; D017661:Receptors, Presynaptic; D008715:Methionine; D005045:Etomidate