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

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.