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Front Cell Neurosci. 2018 Sep 27;12:319. doi: 10.3389/fncel.2018.00319. eCollection 2018.

Activation of Astrocytic μ-opioid Receptor Elicits Fast Glutamate Release Through TREK-1-Containing K2P Channel in Hippocampal Astrocytes.

Woo DH1,2, Bae JY3, Nam MH1,4, An H1,5, Ju YH1,6, Won J1,7, Choi JH1,6, Hwang EM1,6, Han KS1,6, Bae YC3, Lee CJ1,5,6.

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Center for Neural Science and Center for Functional Connectomics, Korea Institute of Science and Technology (KIST), Seoul, South Korea.
Animal Model Research Center, Korea Institute of Toxicology, Korea Research Institute of Chemical Technology, Daejeon, South Korea.
Department of Anatomy and Neurobiology, School of Dentistry, Kyungpook National University, Daegu, South Korea.
Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul, South Korea.
KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, South Korea.
Division of Bio-Medical Science & Technology, Korea Institute of Science and Technology (KIST) School, Korea University of Science and Technology, Seoul, South Korea.
Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, South Korea.


Recently, μ-opioid receptor (MOR), one of the well-known Gi-protein coupled receptors (Gi-GPCR), was reported to be highly expressed in the hippocampal astrocytes. However, the role of astrocytic MOR has not been investigated. Here we report that activation of astrocytic MOR by [D-Ala2,N-MePhe4,Gly-ol]-enkephalin (DAMGO), a selective MOR agonist, causes a fast glutamate release using sniffer patch technique. We also found that the DAMGO-induced glutamate release was not observed in the astrocytes from MOR-deficient mice and MOR-short hairpin RNA (shRNA)-expressed astrocytes. In addition, the glutamate release was significantly reduced by gene silencing of the TREK-1-containing two-pore potassium (K2P) channel, which mediates passive conductance in astrocytes. Our findings were consistent with the previous study demonstrating that activation of Gi-GPCR such as cannabinoid receptor CB1 and adenosine receptor A1 causes a glutamate release through TREK-1-containing K2P channel from hippocampal astrocytes. We also demonstrated that MOR and TREK-1 are significantly co-localized in the hippocampal astrocytes. Furthermore, we found that both MOR and TREK-1-containing K2P channels are localized in the same subcellular compartments, soma and processes, of astrocytes. Our study raises a novel possibility that astrocytic MOR may participate in several physiological and pathological actions of opioids, including analgesia and addiction, through astrocytically released glutamate and its signaling pathway.


TREK-1; astrocyte; glutamate; hippocampus; μ-opioid receptor

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