title: Favouring inhibitory synaptic drive mediated by GABA(A) receptors in the basolateral nucleus of the amygdala efficiently reduces pain symptoms in neuropathic mice.
abstract: Pain is an emotion and neuropathic pain symptoms are modulated by supraspinal structures such as the amygdala. The central nucleus of the amygdala is often called the 'nociceptive amygdala', but little is known about the role of the basolateral amygdala. Here, we monitored the mechanical nociceptive thresholds in a mouse model of neuropathic pain and infused modulators of the glutamate/GABAergic transmission in the basolateral nucleus of the amygdala (BLA) via chronically-implanted cannulas. We found that an N-methyl-D-aspartate-type glutamate receptor antagonist (MK-801) exerted a potent antiallodynic effect, whereas a transient allodynia was induced after perfusion of bicuculline, a GABA(A) receptor antagonist. Potentiating GABA(A) receptor function using diazepam or etifoxine (a non-benzodiazepine anxiolytic) fully but transiently alleviated mechanical allodynia. Interestingly, the antiallodynic effect of etifoxine disappeared in animals that were incapable of producing 3α-steroids. Diazepam had a similar effect but of shorter duration. As indicated by patch-clamp recordings of BLA neurons, these effects were mediated by a potentiation of GABA(A) receptor-mediated synaptic transmission. Together with a presynaptic elevation of miniature inhibitory postsynaptic current frequency, the duration and amplitude of GABA(A) miniature inhibitory postsynaptic currents were also increased (postsynaptic effect). The analgesic contribution of endogenous neurosteroid seemed to be exclusively postsynaptic. This study highlights the importance of the BLA and the local inhibitory/excitatory neuronal network activity while setting the mechanical nociceptive threshold. Furthermore, it appears that promoting inhibition in this specific nucleus could fully alleviate pain symptoms. Therefore, the BLA could be a novel interesting target for the development of pharmacological or non-pharmacological therapies.
authors.affiliation: Institut des Neurosciences Cellulaires et Intégratives (INCI), UPR 3212 CNRS, Centre National de la Recherche Scientifique and University of Strasbourg, 5 rue Blaise Pascal, F-67084, Strasbourg Cedex, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Zeitler
authors.affiliation: Institut des Neurosciences Cellulaires et Intégratives (INCI), UPR 3212 CNRS, Centre National de la Recherche Scientifique and University of Strasbourg, 5 rue Blaise Pascal, F-67084, Strasbourg Cedex, France.
authors.forename: Nisrine
authors.initials: N
authors.lastname: Kamoun
authors.affiliation: Institut des Neurosciences Cellulaires et Intégratives (INCI), UPR 3212 CNRS, Centre National de la Recherche Scientifique and University of Strasbourg, 5 rue Blaise Pascal, F-67084, Strasbourg Cedex, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Goyon
authors.affiliation: Institut des Neurosciences Cellulaires et Intégratives (INCI), UPR 3212 CNRS, Centre National de la Recherche Scientifique and University of Strasbourg, 5 rue Blaise Pascal, F-67084, Strasbourg Cedex, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Wahis
authors.affiliation: Institut des Neurosciences Cellulaires et Intégratives (INCI), UPR 3212 CNRS, Centre National de la Recherche Scientifique and University of Strasbourg, 5 rue Blaise Pascal, F-67084, Strasbourg Cedex, France.|University of Strasbourg Institute for Advanced Study (USIAS), Strasbourg, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Charlet
authors.affiliation: Institut des Neurosciences Cellulaires et Intégratives (INCI), UPR 3212 CNRS, Centre National de la Recherche Scientifique and University of Strasbourg, 5 rue Blaise Pascal, F-67084, Strasbourg Cedex, France.
authors.forename: Pierrick
authors.initials: P
authors.lastname: Poisbeau
authors.affiliation: Institut des Neurosciences Cellulaires et Intégratives (INCI), UPR 3212 CNRS, Centre National de la Recherche Scientifique and University of Strasbourg, 5 rue Blaise Pascal, F-67084, Strasbourg Cedex, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Darbon
mesh_terms: D000818:Animals; D066272:Basolateral Nuclear Complex / Q000378:metabolism* / Q000502:physiology; D016291:Dizocilpine Maleate / Q000494:pharmacology / Q000627:therapeutic use; D058785:GABA-A Receptor Agonists / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D053444:Inhibitory Postsynaptic Potentials; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009437:Neuralgia / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D011963:Receptors, GABA-A / Q000378:metabolism*
chemical_list: D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D011963:Receptors, GABA-A; D016291:Dizocilpine Maleate
keywords: etifoxine; neuronal network; neurosteroid