The Ameliorative Effects of Isorhynchophylline on Morphine Dependence Are Mediated Through the Microbiota-Gut-Brain Axis.

Zhu Chen,Luo Chaohua,Ou Jinying,Mo Zhixian,Xiao Shilin,Zhou Qichun,Li Chan,Chen Zhijie,Zhou Yuting,Li Jing

doi:10.3389/fphar.2021.526923

Abstract

Morphine abuse is a global public health problem. Increasing evidence has shown that gut microbiota dysbiosis plays an important role in several central nervous system diseases. However, whether there is an association between gut microbiota and morphine dependence remains unclear. In this study, the effects of isorhynchophylline on morphine dependence were evaluated based on the microbiota-gut-brain axis (MGBA). The results showed that isorhynchophylline could reverse the changes in alpha and beta diversity, composition, and richness of the intestinal flora occurring in morphine-dependent zebrafish, as well as the morphine-induced changes in the expression of MGBA-related genes in BV2 cells and the brain and intestine of zebrafish. Based on the results, we then used antibiotics to evaluate whether disrupting the gut microbiota would affect morphine addiction in zebrafish. The results showed that the antibiotic-induced intestinal floral imbalance changed the behavior of morphine-dependent zebrafish, the characteristics of the zebrafish intestinal flora, and the expression of MGBA-related genes in the zebrafish brain and intestine. Importantly, we also show that, following antibiotic administration, the ameliorative effects of isorhynchophylline on morphine addiction were lost. Together, our results indicate that the gut microbiota interacts with the brain, and dysbiosis of the intestinal flora may affect the efficacy of isorhynchophylline in the body. Our findings provide a novel framework for understanding the mechanisms of morphine addiction through the MGBA and may provide new therapeutic strategies for the use of Chinese medicines in the prevention of drug addiction.

Highlights

Morphine is a potent opioid analgesic that is highly addictive, and its abuse is a serious social and public health concern worldwide
The results showed that morphine treatment led to the activation of BV2 cells, whereas exposure to isorhynchophylline attenuated the morphine-induced activation of AIF1 in BV2 cells (Figure 2)
Compared with the control group, the mRNA expression levels of dopamine receptor D2 (Drd2), 5-hydroxytryptamine receptor 2A (Htr2a), glutamate decarboxylase 1 (Gad1), and Gad2 were significantly higher in the M group than in the control group, whereas the mRNA expression levels of Drd2, Htr1aa, Gad1, and Gad2 in the M + I and M + MH groups were significantly reduced when compared with those in the M group

Summary

Introduction

Morphine is a potent opioid analgesic that is highly addictive, and its abuse is a serious social and public health concern worldwide. Long-term morphine use results in serious damage to the central nervous system (CNS), and commonly leads to opioid-induced bowel dysfunction (OBD) such as nausea, vomiting, gastroesophageal reflux, and constipation (Brock et al, 2012). Traditional Chinese medicine (TCM) is commonly used to treat addiction, presenting multitarget curative potential and nonaddictive properties. Isorhynchophylline is one of the main active ingredients of Uncaria rhynchophylla, a herb used in TCM that has been shown to protect against cerebral ischemia and nerve cell damage, and exhibits anti-inflammatory properties (Kang et al, 2002; Yuan et al, 2009; Lu et al, 2012). Recent studies have shown that isorhynchophylline exerts important pharmacological effects on the nervous system in mice, such as improving cognitive and memory impairment, antagonizing Aβ-induced neurotoxicity, and eliciting antidepressive effects (Xian et al, 2013; Xian et al, 2014a; Xian et al, 2014b; Xian et al, 2017)

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Conclusion