μ-Opioid Receptor–Mediated Enteric Glial Activation Is Involved in Morphine-Induced Constipation
- 23 February 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Molecular Neurobiology
- Vol. 58 (7), 3061-3070
- https://doi.org/10.1007/s12035-021-02286-0
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.Keywords
Funding Information
- the National Science Foundation of China (81774113, 81974540)
- Joint Research Fund for Overseas Chinese Scholars and Scholars in Hong Kong and Macao (81228022)
This publication has 37 references indexed in Scilit:
- Opioid-Induced Constipation (OIC) GuidelineGastroenterology, 2019
- Opioids in Gastroenterology: Treating Adverse Effects and Creating Therapeutic BenefitsClinical Gastroenterology and Hepatology, 2017
- Enhanced Sensitivity of 3 4 Nicotinic Receptors in Enteric Neurons after Long-Term Morphine: Implication for Opioid-Induced ConstipationThe Journal of pharmacology and experimental therapeutics, 2016
- Differences in the morphine-induced inhibition of small and large intestinal transit: Involvement of central and peripheral μ-opioid receptors in miceEuropean Journal of Pharmacology, 2016
- A systematic review and meta-analysis of the prevalence of chronic widespread pain in the general populationPain, 2016
- Mechanisms That Underlie μ-Opioid Receptor Agonist–Induced Constipation: Differential Involvement of μ-Opioid Receptor Sites and Responsible RegionsThe Journal of pharmacology and experimental therapeutics, 2013
- Opioid-induced constipation negatively impacts pain management, productivity, and health-related quality of life: Findings from the National Health and Wellness SurveyJournal of Opioid Management, 2009
- The Prevalence, Severity, and Impact of Opioid-Induced Bowel Dysfunction: Results of a US and European Patient Survey (PROBE 1)Pain Medicine, 2009
- Involvement of μ-opioid receptors in antinociception and inhibition of gastrointestinal transit induced by 7-hydroxymitragynine, isolated from Thai herbal medicine Mitragyna speciosaEuropean Journal of Pharmacology, 2006
- Size of neurons and glial cells in the enteric ganglia of mice, guinea-pigs, rabbits and sheepJournal of Neurocytology, 1984