Chung Paul Chu Sin, Boehrer Annie, Stephan Aline, Matifas Audrey, Scherrer Grégory, Darcq Emmanuel, Befort Katia, Kieffer Brigitte L
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/Université de Strasbourg, 1 rue Laurent Fries, 67404 Illkirch, France.
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.
Behav Brain Res. 2015 Feb 1;278:429-34. doi: 10.1016/j.bbr.2014.10.029. Epub 2014 Oct 30.
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.
δ阿片受体（DOR）在新型治疗药物的研发方面引发了诸多关注，尤其是用于治疗患有情绪障碍和慢性疼痛的患者。不幸的是，典型的DOR激动剂SNC80在啮齿动物中会诱发轻度癫痫发作。尽管最近开发的激动剂似乎没有显示出惊厥特性，但支持DOR介导的癫痫发作的机制和神经回路仍有待阐明。DOR在整个神经系统中均有表达。在本研究中，我们测试了以下假设：SNC80诱发的癫痫发作源于前脑GABA能传递水平上的DOR活性，已知抑制该传递会促进癫痫发作的发展。我们构建了一个条件性DOR基因敲除小鼠品系，专门在前脑的GABA能神经元中靶向受体基因（Dlx-DOR）。我们测量了给予SNC80（4.5、9、13.5和32mg/kg）、ARM390（10、30和60mg/kg）或ADL5859（30、100和300mg/kg）对Dlx-DOR小鼠及其对照同窝小鼠（Ctrl小鼠）记录的脑电图（EEG）的影响。SNC80在Ctrl小鼠中产生了剂量依赖性的癫痫发作事件，但在Dlx-DOR小鼠中未检测到这些效应。正如预期的那样，ARM390和ADL5859在两种基因型的小鼠中均未引发任何可检测到的变化。这些结果首次证明，SNC80诱导的DOR激活通过直接抑制前脑GABA能神经元诱发癫痫发作，并支持了第一代和第二代DOR激动剂之间存在差异活性的观点。
