title: Delta opioid receptors expressed in forebrain GABAergic neurons are responsible for SNC80-induced seizures.
abstract: The delta opioid receptor (DOR) has raised much interest for the development of new therapeutic drugs, particularly to treat patients suffering from mood disorders and chronic pain. Unfortunately, the prototypal DOR agonist SNC80 induces mild epileptic seizures in rodents. Although recently developed agonists do not seem to show convulsant properties, mechanisms and neuronal circuits that support DOR-mediated epileptic seizures remain to be clarified. DORs are expressed throughout the nervous system. In this study we tested the hypothesis that SNC80-evoked seizures stem from DOR activity at the level of forebrain GABAergic transmission, whose inhibition is known to facilitate the development of epileptic seizures. We generated a conditional DOR knockout mouse line, targeting the receptor gene specifically in GABAergic neurons of the forebrain (Dlx-DOR). We measured effects of SNC80 (4.5, 9, 13.5 and 32 mg/kg), ARM390 (10, 30 and 60 mg/kg) or ADL5859 (30, 100 and 300 mg/kg) administration on electroencephalograms (EEGs) recorded in Dlx-DOR mice and their control littermates (Ctrl mice). SNC80 produced dose-dependent seizure events in Ctrl mice, but these effects were not detected in Dlx-DOR mice. As expected, ARM390 and ADL5859 did not trigger any detectable change in mice from both genotypes. These results demonstrate for the first time that SNC80-induced DOR activation induces epileptic seizures via direct inhibition of GABAergic forebrain neurons, and supports the notion of differential activities between first and second-generation DOR agonists.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/Université de Strasbourg, 1 rue Laurent Fries, 67404 Illkirch, France.
authors.forename: Paul Chu Sin
authors.initials: PC
authors.lastname: Chung
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/Université de Strasbourg, 1 rue Laurent Fries, 67404 Illkirch, France.
authors.forename: Annie
authors.initials: A
authors.lastname: Boehrer
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/Université de Strasbourg, 1 rue Laurent Fries, 67404 Illkirch, France.
authors.forename: Aline
authors.initials: A
authors.lastname: Stephan
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/Université de Strasbourg, 1 rue Laurent Fries, 67404 Illkirch, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Matifas
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Department of Molecular and Cellular Physiology, Department of Neurosurgery, Stanford Neurosciences Institute, Stanford University, Palo Alto, CA 94304, USA.
authors.forename: Grégory
authors.initials: G
authors.lastname: Scherrer
authors.affiliation: Douglas Hospital Research Center, Department of Psychiatry, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Darcq
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/Université de Strasbourg, 1 rue Laurent Fries, 67404 Illkirch, France.
authors.forename: Katia
authors.initials: K
authors.lastname: Befort
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/Université de Strasbourg, 1 rue Laurent Fries, 67404 Illkirch, France; Douglas Hospital Research Center, Department of Psychiatry, Faculty of Medicine, McGill University, Montreal, Quebec, Canada. Electronic address: brigitte.kieffer@douglas.mcgill.ca.
authors.forename: Brigitte L
authors.initials: BL
authors.lastname: Kieffer
mesh_terms: D000701:Analgesics, Opioid / Q000633:toxicity*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology / Q000633:toxicity*; D001578:Benzopyrans / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography; D059330:GABAergic Neurons / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D010879:Piperazines / Q000633:toxicity*; D016548:Prosencephalon / Q000187:drug effects / Q000473:pathology*; D011930:Reaction Time / Q000187:drug effects; D017465:Receptors, Opioid, delta / Q000235:genetics / Q000378:metabolism*; D012640:Seizures / Q000139:chemically induced / Q000235:genetics / Q000473:pathology
chemical_list: D000701:Analgesics, Opioid; D001549:Benzamides; D001578:Benzopyrans; C532570:N,N-diethyl-4-(5-hydroxyspiro(chromene-2,4'-piperidine)-4-yl)benzamide; D010879:Piperazines; D017465:Receptors, Opioid, delta; C088464:4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide
keywords: Biased agonism; Conditional knockout; Delta agonist; Delta opioid receptor; Epileptic seizure; In vivo