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μ-Opioid Receptor–Mediated Enteric Glial Activation Is Involved in Morphine-Induced Constipation

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A Correction to this article was published on 03 November 2021

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Abstract

Among all the side effects, opioid-induced constipation (OIC) has the highest incidence rate in people who take chronic opioid therapy. Increasing evidence shows that enteric glial cells (EGCs) play a pivotal role in the modulation of gastrointestinal motility. We aim to investigate whether EGCs are involved in OIC and possible mechanisms. Eight-week male C57BL/6 mice were randomized into four groups: the control group, the morphine group, the gliotoxin fluorocitrate (FC) group, and the FC plus morphine group. OIC was induced by injection of morphine subcutaneously. Colonic motility was evaluated by in vivo motility assays and colonic migrating motor complex (CMMC) in vitro. Both the Ca2+ responses and the release of inflammatory cytokine by EGCs were detected in vitro. Proteins were detected by immunofluorescence staining and Western blot. The morphine group showed prolonged gastrointestinal motility compared with the control group. Once EGCs were disrupted by FC, such inhibitory effect was abolished. There was a remarkable enhancement of the GFAP expression on colonic EGCs. Immunofluorescence exhibited that μ-opioid receptor (MOR) collocated with GFAP, indicating the existence of MOR in EGCs. Moreover, morphine activated the EGCs significantly through enhancing GFAP expression and Ca2+ amplitude. Both effects can be reversed by MOR-siRNA. Morphine treatment elevated the enteric glial release of proinflammatory cytokines notably and this effect was abolished when EGCs were silenced by MOR-siRNA. The activation of EGCs via MOR and the increased proinflammatory cytokine from EGCs may be involved in morphine-induced constipation. These results provided a potential therapeutic target for OIC.

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Data Availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgments

We want to express our gratitude to Professor Shengxi Wu and his colleagues (Department of Neurobiology, Air Force Medical University, Xi’an, Shaanxi Province, China) who shared equipment and reagents generously in getting the preliminary data.

Funding

The National Natural Science Foundation of China (Grants 81774113, 81974540) and the Overseas, Hong Kong & Macao Scholars Collaborative Researching Fund (Grant 81228022).

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  1. Hui Gao and Yuxin Zhang contributed equally to this work.

Authors and Affiliations

  1. Department of Anesthesiology & Center for Brain Science, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061, Shaanxi Province, China

    Hui Gao, Yuxin Zhang, Yansong Li, Haiqing Chang, Bo Cheng, Na Li, Wei Yuan, Shuang Li & Qiang Wang

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Contributions

QW and HG conceived of the study, designed, and coordinated it. HG and YXZ contributed equally to this work (HG is the first author, and YXZ is the co-first author). HG, YXZ, and YSL performed the experiments and drafted the manuscript. BC, HQC, and NL carried out data analysis and contributed to the drafting of the manuscript. SL and WY were involved in data analysis and revised the manuscript. All authors read and approved the final manuscript.

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Correspondence to Qiang Wang.

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All procedures performed in studies involving animals were approved by the ethical standards of Institutional Animal Care and Use Committees of Xi’an Jiaotong University, Xi’an, China. Mice received humane care following the Guidelines for the Care and Use of Laboratory Animals of the National Institutes of Health.

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Gao, H., Zhang, Y., Li, Y. et al. μ-Opioid Receptor–Mediated Enteric Glial Activation Is Involved in Morphine-Induced Constipation. Mol Neurobiol 58, 3061–3070 (2021). https://doi.org/10.1007/s12035-021-02286-0

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