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Article Dans Une Revue Pharmaceuticals Année : 2022

Investigation of the mechanisms of tramadol-induced seizures in overdose in the rat

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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 $\gamma$-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.
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hal-03858021 , version 1 (18-11-2022)

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Camille Lagard, Dominique Vodovar, Lucie Chevillard, Jacques Callebert, Fabien Caillé, et al.. Investigation of the mechanisms of tramadol-induced seizures in overdose in the rat. Pharmaceuticals, 2022, 15, pp.1254. ⟨10.3390/ph15101254⟩. ⟨hal-03858021⟩
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