The Pathology of Morphine-Inhibited Nerve Repair and Morphine-Induced Nerve Damage Is Mediated via Endoplasmic Reticulum Stress.

Jie Liu,Guozhong Zhang,Bin Cong,Shanyong Yi,Weibo Shi,Qian Qi,Songjun Wang,Yingmin Li

doi:10.3389/fnins.2021.618190

Abstract

ObjectiveThe aim of the present study was to observe the pathological damage in the cerebral cortex of rats under acute morphine exposure (AME) and different durations of morphine dependence (MD), explore whether endoplasmic reticulum stress (ERS) is involved in the damage process, and assess the effect of morphine exposure on the proliferation and differentiation of newborn neurons.MethodsRat models of AME and different durations of MD were established. Pathological changes in cortical neurons were assessed by hematoxylin and eosin (H&E) and thionine staining. The expression of nuclear receptor-related factor 1 (NURR1) and that of the ERS-related proteins glucose-regulated protein 78 (GRP78), p-eIF2α, activating transcription factor 6 (ATF6), and CHOP in cortical neurons was assessed by immunohistochemistry. Double immunofluorescence labeling was used to observe the expression of Ki-67.ResultsH&E and thionine staining revealed that AME resulted in pyknotic changes in cortical neurons. With prolonged morphine exposure, the number of pyknotic neurons was significantly increased, the protein expression of Ki-67 and NURR1 was significantly decreased, and the protein levels of GRP78, p-eIF2α, ATF6, and CHOP showed marked dynamic changes.ConclusionAME and different durations of MD caused varying degrees of pathological changes in the cortex. Furthermore, the dynamic changes observed in ERS-related protein expression suggested that ERS may be associated with cortical injury. Different durations of MD inhibited the proliferation, differentiation, and migration of newborn neurons, which may affect the nerve repair process after injury.

Highlights

A report by the World Health Organization on the abuse of morphine indicated that the misuse of this drug had increased in recent years (Volkow and Skolnick, 2012)
When the body is stimulated by ischemia, hypoxia, injury, or other insults, the microenvironment of the ER changes, which can result in the accumulation of unfolded or misfolded proteins in the ER lumen and the subsequent induction of endoplasmic reticulum stress (ERS) (Xiang et al, 2017; Muneer and Shamsher Khan, 2019)
Recent studies have shown that the activation of the activating transcription factor 6 (ATF6) signaling pathway mainly exerts a cell-protective role (Hillary and FitzGerald, 2018), whereas the activation of the PERK/p-eIF2α signaling pathway can lead to the upregulation of CCAAT/-enhancer-binding protein homologous protein (CHOP) expression, and continuous CHOP expression can induce cell injury, or even cell death (Hu et al, 2019)

Summary

Introduction

A report by the World Health Organization on the abuse of morphine indicated that the misuse of this drug had increased in recent years (Volkow and Skolnick, 2012). Several studies have shown that MD can inflict varying degrees of injury on different systems of the body, including damage to the heart and lungs, direct effects on the central nervous system, and inhibitory effects on the respiratory center. These effects may lead to acute or chronic cerebral ischemia and hypoxia, which, in turn, may cause nerve damage (Brailoiu et al, 2004; Luo et al, 2013; Rohbani et al, 2019). Nuclear receptor-related factor 1 (NURR1), a member of the orphan nuclear receptor superfamily, is indispensable for neuronal differentiation, migration, maturation, and survival (Dong et al, 2016)

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