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. 2024 Mar 5:966:176333.
doi: 10.1016/j.ejphar.2024.176333. Epub 2024 Jan 24.

The μ-opioid receptor-mediated Gi/o protein and β-arrestin2 signaling pathways both contribute to morphine-induced side effects

Jing Xia  1 , Xiaoyan Li  1 , Hongyu Zhu  1 , Xiaohui Zhou  1 , Ji Chen  2 , Qihong Li  3 , Shupeng Li  4 , Haichen Chu  5 , Mingxin Dong  6
Affiliations

The μ-opioid receptor-mediated Gi/o protein and β-arrestin2 signaling pathways both contribute to morphine-induced side effects

Jing Xia et al. Eur J Pharmacol. .

Abstract

The μ-opioid receptor-biased agonist theory holds that Gio protein signaling mediates the analgesic effect of opioids and the related side effects via the β-arrestin2 signaling pathway. A series of μ-opioid-biased agonists have been developed in accordance with this theory, and the FDA has approved TRV130 (as a representative of biased agonists) for marketing. However, several reports have raised the issue of opioid side effects associated with the use of agonists. In this study, five permeable peptides were designed to emulate 11 S/T phosphorylation sites at the μ-opioid receptor (MOR) carboxyl-terminal. In vitro experiments were performed to detect the activation level of G proteins from the cAMP inhibition assay and the β-arrestin2 recruitment by the BRET assay. Designed peptides might effectively interfere with the activation of the Gio and β-arrestin2 pathways when combined with morphine. The resulting morphine-induced tolerance, respiratory inhibition, and constipation in mice showed that the β-arrestin2 pathway was responsible for morphine tolerance while the Gio signaling pathway was involved with respiratory depression and constipation and that these side effects were significantly related to phosphorylation sites S363 and T370. This study may provide new directions for the development of safer and more effective opioid analgesics, and the designed peptides may be an effective tool for exploring the mechanism by which μ-opioid receptors function, with the potential of reducing the side effects that are associated with clinical opioid treatment.

Keywords: Constipation; G(io) pathway; Respiratory depression; Tolerance; β-arrestin2; μ-Opioid receptor.

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Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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