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Investigation of the Mechanisms of Tramadol-Induced Seizures in Overdose in the Rat
Tramadol overdose is frequently associated with the onset of seizures, usually considered as serotonin syndrome manifestations. Recently, the serotoninergic mechanism of tramadol-attributed seizures has been questioned. This study’s aim was to identify the mechanisms involved in tramadol-induced sei...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9607071/ https://www.ncbi.nlm.nih.gov/pubmed/36297366 http://dx.doi.org/10.3390/ph15101254 |
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author | Lagard, Camille Vodovar, Dominique Chevillard, Lucie Callebert, Jacques Caillé, Fabien Pottier, Géraldine Liang, Hao Risède, Patricia Tournier, Nicolas Mégarbane, Bruno |
author_facet | Lagard, Camille Vodovar, Dominique Chevillard, Lucie Callebert, Jacques Caillé, Fabien Pottier, Géraldine Liang, Hao Risède, Patricia Tournier, Nicolas Mégarbane, Bruno |
author_sort | Lagard, Camille |
collection | PubMed |
description | Tramadol overdose is frequently associated with the onset of seizures, usually considered as serotonin syndrome manifestations. Recently, the serotoninergic mechanism of tramadol-attributed seizures has been questioned. This study’s aim was to identify the mechanisms involved in tramadol-induced seizures in overdose in rats. The investigations included (1) the effects of specific pretreatments on tramadol-induced seizure onset and brain monoamine concentrations, (2) the interaction between tramadol and γ-aminobutyric acid (GABA)(A) receptors in vivo in the brain using positron emission tomography (PET) imaging and (11)C-flumazenil. Diazepam abolished tramadol-induced seizures, in contrast to naloxone, cyproheptadine and fexofenadine pretreatments. Despite seizure abolishment, diazepam significantly enhanced tramadol-induced increase in the brain serotonin (p < 0.01), histamine (p < 0.01), dopamine (p < 0.05) and norepinephrine (p < 0.05). No displacement of (11)C-flumazenil brain kinetics was observed following tramadol administration in contrast to diazepam, suggesting that the observed interaction was not related to a competitive mechanism between tramadol and flumazenil at the benzodiazepine-binding site. Our findings do not support the involvement of serotoninergic, histaminergic, dopaminergic, norepinephrine or opioidergic pathways in tramadol-induced seizures in overdose, but they strongly suggest a tramadol-induced allosteric change of the benzodiazepine-binding site of GABA(A) receptors. Management of tramadol-poisoned patients should take into account that tramadol-induced seizures are mainly related to a GABAergic pathway. |
format | Online Article Text |
id | pubmed-9607071 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-96070712022-10-28 Investigation of the Mechanisms of Tramadol-Induced Seizures in Overdose in the Rat Lagard, Camille Vodovar, Dominique Chevillard, Lucie Callebert, Jacques Caillé, Fabien Pottier, Géraldine Liang, Hao Risède, Patricia Tournier, Nicolas Mégarbane, Bruno Pharmaceuticals (Basel) Article Tramadol overdose is frequently associated with the onset of seizures, usually considered as serotonin syndrome manifestations. Recently, the serotoninergic mechanism of tramadol-attributed seizures has been questioned. This study’s aim was to identify the mechanisms involved in tramadol-induced seizures in overdose in rats. The investigations included (1) the effects of specific pretreatments on tramadol-induced seizure onset and brain monoamine concentrations, (2) the interaction between tramadol and γ-aminobutyric acid (GABA)(A) receptors in vivo in the brain using positron emission tomography (PET) imaging and (11)C-flumazenil. Diazepam abolished tramadol-induced seizures, in contrast to naloxone, cyproheptadine and fexofenadine pretreatments. Despite seizure abolishment, diazepam significantly enhanced tramadol-induced increase in the brain serotonin (p < 0.01), histamine (p < 0.01), dopamine (p < 0.05) and norepinephrine (p < 0.05). No displacement of (11)C-flumazenil brain kinetics was observed following tramadol administration in contrast to diazepam, suggesting that the observed interaction was not related to a competitive mechanism between tramadol and flumazenil at the benzodiazepine-binding site. Our findings do not support the involvement of serotoninergic, histaminergic, dopaminergic, norepinephrine or opioidergic pathways in tramadol-induced seizures in overdose, but they strongly suggest a tramadol-induced allosteric change of the benzodiazepine-binding site of GABA(A) receptors. Management of tramadol-poisoned patients should take into account that tramadol-induced seizures are mainly related to a GABAergic pathway. MDPI 2022-10-12 /pmc/articles/PMC9607071/ /pubmed/36297366 http://dx.doi.org/10.3390/ph15101254 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Lagard, Camille Vodovar, Dominique Chevillard, Lucie Callebert, Jacques Caillé, Fabien Pottier, Géraldine Liang, Hao Risède, Patricia Tournier, Nicolas Mégarbane, Bruno Investigation of the Mechanisms of Tramadol-Induced Seizures in Overdose in the Rat |
title | Investigation of the Mechanisms of Tramadol-Induced Seizures in Overdose in the Rat |
title_full | Investigation of the Mechanisms of Tramadol-Induced Seizures in Overdose in the Rat |
title_fullStr | Investigation of the Mechanisms of Tramadol-Induced Seizures in Overdose in the Rat |
title_full_unstemmed | Investigation of the Mechanisms of Tramadol-Induced Seizures in Overdose in the Rat |
title_short | Investigation of the Mechanisms of Tramadol-Induced Seizures in Overdose in the Rat |
title_sort | investigation of the mechanisms of tramadol-induced seizures in overdose in the rat |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9607071/ https://www.ncbi.nlm.nih.gov/pubmed/36297366 http://dx.doi.org/10.3390/ph15101254 |
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