Delta opioid receptors expressed in forebrain GABAergic neurons are responsible for SNC80-induced seizures.

TitleDelta opioid receptors expressed in forebrain GABAergic neurons are responsible for SNC80-induced seizures.
Publication TypeJournal Article
Year of Publication2015
AuthorsChung PChu Sin, Boehrer A, Stephan A, Matifas A, Scherrer G, Darcq E, Befort K, Kieffer BL
JournalBehav Brain Res
Volume278
Pagination429-34
Date Published2015 Feb 1
ISSN1872-7549
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.

DOI10.1016/j.bbr.2014.10.029
Alternate JournalBehav. Brain Res.
PubMed ID25447299
PubMed Central IDPMC4382405
Grant List05010 / / PHS HHS / United States
16658 / / PHS HHS / United States
P50 DA005010 / DA / NIDA NIH HHS / United States
U01 AA016658 / AA / NIAAA NIH HHS / United States