Allopregnanolone Enhances GABAergic Inhibition in Spinal Motor Networks
The neurosteroid allopregnanolone (ALLO) causes unconsciousness by allosteric modulation of γ-aminobutyric acid type A (GABA<sub>A</sub>) receptors, but its actions on the spinal motor networks are unknown. We are therefore testing the hypothesis that ALLO attenuates the action potential...
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MDPI AG
2020-10-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/21/19/7399 |
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| author | Berthold Drexler Julia Grenz Christian Grasshoff Bernd Antkowiak |
| author_facet | Berthold Drexler Julia Grenz Christian Grasshoff Bernd Antkowiak |
| author_sort | Berthold Drexler |
| collection | DOAJ |
| description | The neurosteroid allopregnanolone (ALLO) causes unconsciousness by allosteric modulation of γ-aminobutyric acid type A (GABA<sub>A</sub>) receptors, but its actions on the spinal motor networks are unknown. We are therefore testing the hypothesis that ALLO attenuates the action potential firing of spinal interneurons and motoneurons predominantly via enhancing tonic, but not synaptic GABAergic inhibition. We used video microscopy to assess motoneuron-evoked muscle activity in organotypic slice cultures prepared from the spinal cord and muscle tissue. Furthermore, we monitored GABA<sub>A</sub> receptor-mediated currents by performing whole-cell voltage-clamp recordings. We found that ALLO (100 nM) reduced the action potential firing of spinal interneurons by 27% and that of α-motoneurons by 33%. The inhibitory effects of the combination of propofol (1 µM) and ALLO on motoneuron-induced muscle contractions were additive. Moreover, ALLO evoked a tonic, GABA<sub>A</sub> receptor-mediated current (amplitude: 41 pA), without increasing phasic GABAergic transmission. Since we previously showed that at a clinically relevant concentration of 1 µM propofol enhanced phasic, but not tonic GABAergic inhibition, we conclude that ALLO and propofol target distinct subpopulations of GABA<sub>A</sub> receptors. These findings provide first evidence that the combined application of ALLO and propofol may help to reduce intraoperative movements and undesired side effects that are frequently observed under total intravenous anesthesia. |
| first_indexed | 2024-03-10T15:47:36Z |
| format | Article |
| id | doaj.art-2966b55bd3c34aa6b413d9959b5eb4fc |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T15:47:36Z |
| publishDate | 2020-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-2966b55bd3c34aa6b413d9959b5eb4fc2023-11-20T16:18:10ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-10-012119739910.3390/ijms21197399Allopregnanolone Enhances GABAergic Inhibition in Spinal Motor NetworksBerthold Drexler0Julia Grenz1Christian Grasshoff2Bernd Antkowiak3Experimental Anesthesiology Section, Department of Anesthesiology and Intensive Care Medicine, Eberhard-Karls-University, Waldhörnlestrasse 22, 72072 Tübingen, GermanyExperimental Anesthesiology Section, Department of Anesthesiology and Intensive Care Medicine, Eberhard-Karls-University, Waldhörnlestrasse 22, 72072 Tübingen, GermanyExperimental Anesthesiology Section, Department of Anesthesiology and Intensive Care Medicine, Eberhard-Karls-University, Waldhörnlestrasse 22, 72072 Tübingen, GermanyExperimental Anesthesiology Section, Department of Anesthesiology and Intensive Care Medicine, Eberhard-Karls-University, Waldhörnlestrasse 22, 72072 Tübingen, GermanyThe neurosteroid allopregnanolone (ALLO) causes unconsciousness by allosteric modulation of γ-aminobutyric acid type A (GABA<sub>A</sub>) receptors, but its actions on the spinal motor networks are unknown. We are therefore testing the hypothesis that ALLO attenuates the action potential firing of spinal interneurons and motoneurons predominantly via enhancing tonic, but not synaptic GABAergic inhibition. We used video microscopy to assess motoneuron-evoked muscle activity in organotypic slice cultures prepared from the spinal cord and muscle tissue. Furthermore, we monitored GABA<sub>A</sub> receptor-mediated currents by performing whole-cell voltage-clamp recordings. We found that ALLO (100 nM) reduced the action potential firing of spinal interneurons by 27% and that of α-motoneurons by 33%. The inhibitory effects of the combination of propofol (1 µM) and ALLO on motoneuron-induced muscle contractions were additive. Moreover, ALLO evoked a tonic, GABA<sub>A</sub> receptor-mediated current (amplitude: 41 pA), without increasing phasic GABAergic transmission. Since we previously showed that at a clinically relevant concentration of 1 µM propofol enhanced phasic, but not tonic GABAergic inhibition, we conclude that ALLO and propofol target distinct subpopulations of GABA<sub>A</sub> receptors. These findings provide first evidence that the combined application of ALLO and propofol may help to reduce intraoperative movements and undesired side effects that are frequently observed under total intravenous anesthesia.https://www.mdpi.com/1422-0067/21/19/7399allopregnanolonespinal networkselectrophysiologyorganotypic culturesneuro-muscular junctionpropofol |
| spellingShingle | Berthold Drexler Julia Grenz Christian Grasshoff Bernd Antkowiak Allopregnanolone Enhances GABAergic Inhibition in Spinal Motor Networks International Journal of Molecular Sciences allopregnanolone spinal networks electrophysiology organotypic cultures neuro-muscular junction propofol |
| title | Allopregnanolone Enhances GABAergic Inhibition in Spinal Motor Networks |
| title_full | Allopregnanolone Enhances GABAergic Inhibition in Spinal Motor Networks |
| title_fullStr | Allopregnanolone Enhances GABAergic Inhibition in Spinal Motor Networks |
| title_full_unstemmed | Allopregnanolone Enhances GABAergic Inhibition in Spinal Motor Networks |
| title_short | Allopregnanolone Enhances GABAergic Inhibition in Spinal Motor Networks |
| title_sort | allopregnanolone enhances gabaergic inhibition in spinal motor networks |
| topic | allopregnanolone spinal networks electrophysiology organotypic cultures neuro-muscular junction propofol |
| url | https://www.mdpi.com/1422-0067/21/19/7399 |
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