Abstract
The gastrointestinal epithelium is critical for maintaining a symbiotic relationship with commensal microbiota. Chronic morphine exposure can compromise the gut epithelial barrier in mice and lead to dysbiosis. Recently, studies have implicated morphine-induced dysbiosis in the mechanism of antinociceptive tolerance and reward, suggesting the presence of a gut-brain axis in the pharmacological effects of morphine. However, the mechanism(s) underlying morphine-induced changes in the gut microbiome remains unclear. The pro-inflammatory cytokine, Interleukin-18 (IL-18), released by enteric neurons can modulate gut barrier function. Therefore, in the present study we investigated the effect of morphine on IL-18 expression in the mouse ileum. We observed that chronic morphine exposure in vivo induces IL-18 expression in the ileum myenteric plexus that is attenuated by naloxone. Given that mu-opioid receptors (MORs) are mainly expressed in enteric neurons, we also characterized morphine effects on the excitability of cholinergic (excitatory) and vasoactive intestinal peptide (VIP)-expressing (inhibitory) myenteric neurons. We found fundamental differences in the electrical properties of cholinergic and VIP neurons such that VIP neurons are more excitable than cholinergic neurons. Furthermore, MORs were primarily expressed in cholinergic neurons, although a subset of VIP neurons also expressed MORs and responded to morphine in electrophysiology experiments. In conclusion, these data show that morphine increases IL-18 in ileum myenteric plexus neurons via activation of MORs in a subset of cholinergic and VIP neurons. Thus, understanding the neurochemistry and electrophysiology of MOR-expressing enteric neurons can help to delineate mechanisms by which morphine perturbs the gut barrier.
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Acknowledgements
This study was supported by National Institutes of Health grants: P30DA033934, R01DA036975. EK is a visiting grad student from Bursa Uludag University, Faculty of Veterinary Medicine, Department of Physiology. She was supported by YÖK (Council of Higher Education) 100/200 Doctoral Research Fellowship Programme, TÜBİTAK (The Scientific and Technological Research Council of Turkey) 2214-A (International Research Fellowship Programme for PhD Students) and TÜBİTAK 2211-C (National PhD Scholarship Programme in the Priority Fields in Science and Technology). The graphical abstract was created using BioRender.com.
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KHM, EK, and ARG are co-first authors and they contributed equally to the development of this manuscript. KHM, EK, ARG, WLD, and HIA conceived the hypothesis, designed experiments, and contributed to the drafting of the manuscript. KHM, EK, ARG, KW, SM, and MK performed experiments and data analysis. ARM provided transgenic mice, contributed to the conceptualization of the study, and drafting of the manuscript. All authors have read and approved the final version of the manuscript.
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Muchhala, K.H., Koseli, E., Gade, A.R. et al. Chronic Morphine Induces IL-18 in Ileum Myenteric Plexus Neurons Through Mu-opioid Receptor Activation in Cholinergic and VIPergic Neurons. J Neuroimmune Pharmacol 17, 111–130 (2022). https://doi.org/10.1007/s11481-021-10050-3
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DOI: https://doi.org/10.1007/s11481-021-10050-3