Discipline of Pharmacology, School of Medical Sciences, University of Sydney, W300 Blackburn Building, Blackburn Circuit, Camperdown, Sydney, New South Wales 2006, Australia.
Department of Physiology and Pharmacology, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239-3098, USA.
Nat Commun. 2017 Mar 22;8:14611. doi: 10.1038/ncomms14611.
Fear and emotional learning are modulated by endogenous opioids but the cellular basis for this is unknown. The intercalated cells (ITCs) gate amygdala output and thus regulate the fear response. Here we find endogenous opioids are released by synaptic stimulation to act via two distinct mechanisms within the main ITC cluster. Endogenously released opioids inhibit glutamate release through the δ-opioid receptor (DOR), an effect potentiated by a DOR-positive allosteric modulator. Postsynaptically, the opioids activate a potassium conductance through the μ-opioid receptor (MOR), suggesting for the first time that endogenously released opioids directly regulate neuronal excitability. Ultrastructural localization of endogenous ligands support these functional findings. This study demonstrates a new role for endogenously released opioids as neuromodulators engaged by synaptic activity to regulate moment-to-moment neuronal communication and excitability. These distinct actions through MOR and DOR may underlie the opposing effect of these receptor systems on anxiety and fear.
内源性阿片类物质调节恐惧和情绪学习，但这种调节的细胞基础尚不清楚。中间神经元（ITCs）控制杏仁核输出，从而调节恐惧反应。在这里，我们发现内源性阿片类物质通过突触刺激释放，通过主要 ITC 簇内的两种不同机制发挥作用。内源性释放的阿片类物质通过 δ 型阿片受体（DOR）抑制谷氨酸释放，这种作用被 DOR 阳性变构调节剂增强。突触后，阿片类物质通过 μ 型阿片受体（MOR）激活钾电流，这首次表明内源性释放的阿片类物质可直接调节神经元兴奋性。内源性配体的超微结构定位支持这些功能发现。这项研究表明，内源性阿片类物质作为神经调质的新作用，通过突触活动参与，调节神经元间的即时通讯和兴奋性。MOR 和 DOR 的这些不同作用可能是这些受体系统对焦虑和恐惧产生相反影响的基础。
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