Signaling mechanisms of μ-opioid receptor (MOR) in the hippocampus: disinhibition versus astrocytic glutamate regulation

Abstract

μ-opioid receptor (MOR) is a class of opioid receptors that is critical for analgesia, reward, and euphoria. MOR is distributed in various brain regions, including the hippocampus, where traditionally, it is believed to be localized mainly at the presynaptic terminals of the GABAergic inhibitory interneurons to exert a strong disinhibitory effect on excitatory pyramidal neurons. However, recent intensive research has uncovered the existence of MOR in hippocampal astrocytes, shedding light on how astrocytic MOR participates in opioid signaling via glia-neuron interaction in the hippocampus. Activation of astrocytic MOR has shown to cause glutamate release from hippocampal astrocytes and increase the excitability of presynaptic axon fibers to enhance the release of glutamate at the Schaffer Collateral-CA1 synapses, thereby, intensifying the synaptic strength and plasticity. This novel mechanism involving astrocytic MOR has been shown to participate in hippocampus-dependent conditioned place preference. Furthermore, the signaling of hippocampal MOR, whose action is sexually dimorphic, is engaged in adult neurogenesis, seizure, and stress-induced memory impairment. In this review, we focus on the two profoundly different hippocampal opioid signaling pathways through either GABAergic interneuronal or astrocytic MOR. We further compare and contrast their molecular and cellular mechanisms and their possible roles in opioid-associated conditioned place preference and other hippocampus-dependent behaviors.

Keywords: Astrocyte; Disinhibition; Glutamate; Hippocampus; LTP; μ-opioid receptor.

Fig. 1

Schematic diagrams of the MOR distribution in hippocampus region (CA1, CA3, and DG). Color of cell indicates cell types: gold, inhibitory neuron; green, pyramidal neuron; blue, granule cell; yellow, astrocyte. MOR is indicated in brown. DG dentate gyrus, SO stratum oriens, SP stratum pyramidale, SR stratum radiatum, SLM stratum lacunosum-moleculare, Slu stratum lucidum, ML molecular layer, GCL granule cell layer

Fig. 2

Cellular mechanisms underlying how hippocampal MOR activation enhances synaptic transmission and plasticity. a Schematic diagram of hippocampal synapses. b Schematic diagram of interneuronal MOR signaling through disinhibition via membrane hyperpolarization of GABAergic interneuron. MOR activation in the interneurons dissociates G_βγ from heterotrimeric G-protein complex, leading to the opening of GIRK by G_βγ binding. Potassium efflux through GIRK causes hyperpolarization of the interneurons, which decreases GABA release and causes GABAergic disinhibition. c Schematic diagram of astrocytic MOR signaling through glutamate release. MOR activation in the astrocytes dissociates G_βγ from heterotrimeric G-protein complex, leading to the opening of TREK-1 by G_βγ binding. Glutamate release through TREK-1 binds to mGluR1, which is localized in the axonal process of presynaptic neurons, causing glutamatergic axonal excitability. d Schematic diagram of the alteration of glutamatergic synaptic transmission at SC-CA1 synapses. CA1 cornu ammonis 1, CA3 cornu ammonis 3, DG dentate gyrus, SC Schaffer collateral, MF mossy fiber, MOR μ-opioid receptor, G_αi G-protein alpha I subunit. G_βγ G-protein beta gamma complex, GIRK G-protein-coupled inwardly-rectifying potassium channel, GABA_A GABAA receptor, GABA_B GABAB receptor, Glu glutamate, mGluR1 metabotropic glutamate receptor 1, TREK-1 TWIK-related potassium channel, AMPAR α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, NMDAR N-methyl-D-aspartate receptor

Fig. 3

DAMGO enhances eEPSC at SC-CA1 synapse, which is not mediated by GABAergic disinhibition. DAMGO-mediated enhancement of eEPSC amplitude was not further increased by treatment with bicuculline and CGP55845, which are blockers against GABA_A and GABA_B receptors, respectively. Orange trace is originated from Nam et al. Cell Reports (2019). DAMGO [D-Ala2, N-MePhe4, Gly-ol]-enkephalin, Bic bicuculline, CGP CGP55845, EPSC excitatory post-synaptic current, ns non-significant