Regulation of morphine-induced synaptic alterations: Role of oxidative stress, ER stress, and autophagy

Cai, Yu; Lü, Yang; Hu, Guoku; Chen, Xufeng; Niu, Fang; Li, Yuan; Liu, Han; Xiong, Huangui; Arikkath, Jyothi; Buch, Shilpa

doi:10.1083/jcb.201605065

Cited by 85 publications

(84 citation statements)

References 55 publications

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“…Intriguingly, pretreatment of A172 astrocytes with the ER stress inhibitor, 4-PBA or transfection of human astrocytes with PERK siRNA resulted in inhibition of morphine-induced ER stress, autophagy, astrocyte activation as well as expression of proinflammatory cytokines, thereby confirming that ER stress markers lie upstream of autophagy. The present findings are in agreement with our previous report demonstrating that morphine-induced ER stress/autophagy axis was critical for synaptic impairment in hippocampal neurons [43]. Taken together, our in vitro data showed that morphine induces ER stress-mediated defective autophagy which, in turn, leads to astrocyte activation and secretion of proinflammatory cytokines.…”

Section: Discussionsupporting

confidence: 93%

“…Our previous studies have also shown that morphine exposure resulted in synaptic injury in the hippocampal neurons and that this was mediated via the ER stress-autophagy axis [43]. The present study demonstrates that in astrocytes morphine exposure results in initiation of autophagy as well as autophagosome formation.…”

Section: Discussionsupporting

confidence: 75%

“…Chronic use of morphine, however, leads to various ill effects including drug tolerance, addiction, and cognitive impairment [9]. Several studies have implicated the role of morphine in inducing neuronal injury and apoptosis [43,16], impairing microglial chemotaxis [15], and inducing microglial activation [61]. The effects of morphine on astrocytes, especially in the context of ER-stress-mediated defective autophagy, however, have not been reported.…”

Section: Discussionmentioning

confidence: 99%

“…The mechanism(s) by which morphine activates astrocytes both in vitro and in vivo , however, remains poorly understood. A recent study from our group has demonstrated that in the hippocampus, morphine-mediated synaptic impairment involved the oxidative stress-endoplasmic reticulum (ER) stress-autophagy axis [43]. Notably, exposure of rat hippocampal neurons to morphine resulted in activation of autophagy leading in turn, to reduced expression of excitatory synapses, and a concomitant increase in the expression of inhibitory synapses [43].…”

Section: Introductionmentioning

confidence: 99%

“…Drugs of abuse such as cocaine under various experimental conditions have been shown to mediate ER stress, which in turn, regulates the expression of different genes involved in microglial and astrocyte autophagy [50,37]. Morphine-mediated autophagy has also been reported in various cell types, such as bone marrow-derived macrophages [51], neuroblastoma cell line [52], primary hippocampal neurons [43], and microglia [53]. The specific role of morphine in the activation of astrocytes, possibly through ER stress-mediated autophagy, however, has not been studied.…”

Section: Introductionmentioning

confidence: 99%

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Morphine-Mediated Brain Region-Specific Astrocytosis Involves the ER Stress-Autophagy Axis

et al. 2018

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A recent study from our lab has revealed a link between morphine-mediated autophagy and synaptic impairment. The current study was aimed at investigating whether morphine-mediated activation of astrocytes involved the ER stress/autophagy axis. Our in vitro findings demonstrated upregulation of GFAP indicating astrocyte activation with a concomitant increase in the production of proinflammatory cytokines in morphine-exposed human astrocytes. Using both pharmacological and gene-silencing approaches, it was demonstrated that morphine-mediated defective autophagy involved upstream activation of ER stress with subsequent downstream astrocyte activation via the μ-opioid receptor (MOR). In vivo validation demonstrated preferential activation of ER stress/autophagy axis in the areas of the brain not associated with pain such as the basal ganglia, frontal cortex, occipital cortex, and the cerebellum of morphine-dependent rhesus macaques, and this correlated with increased astrocyte activation and neuroinflammation. Interventions aimed at blocking either the MOR or ER stress could thus likely be developed as promising therapeutic targets for abrogating morphine-mediated astrocytosis.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Morphine-Mediated Brain Region-Specific Astrocytosis Involves the ER Stress-Autophagy Axis

et al. 2018

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PDGF‐BB‐Dependent Neurogenesis Buffers Depressive‐Like Behaviors by Inhibition of GABAergic Projection from Medial Septum to Dentate Gyrus

Liu

Chen

et al. 2023

Advanced Science

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Hippocampal circuitry stimulation is sufficient to regulate adult hippocampal neurogenesis and ameliorate depressive-like behavior, but its underlying mechanism remains unclear. Here, it is shown that inhibition of medial septum (MS)-dentate gyrus (DG) circuit reverses the chronic social defeat stress (CSDS)-induced depression-like behavior. Further analysis exhibits that inhibition of gamma-aminobutyric acidergic neurons in MS projecting to the DG (MS GABA+ -DG) increases the expression of platelet-derived growth factor-BB (PDGF-BB) in somatostatin (SOM) positive interneurons of DG, which contributes to the antidepressant-like effects. Overexpression of the PDGF-BB or exogenous administration of PDGF-BB in DG rescues the effect of chronic stress on the inhibition of neural stem cells (NSCs) proliferation and dendritic growth of adult-born hippocampal neurons, as well as on depressive-like behaviors. Conversely, knockdown of PDGF-BB facilitates CSDS-induced deficit of hippocampal neurogenesis and promotes the susceptibility to chronic stress in mice. Finally, conditional knockdown platelet-derived growth factor receptor beta (PDGFR𝜷) in NSCs blocks an increase in NSCs proliferation and the antidepressant effects of PDGF-BB. These results delineate a previously unidentified PDGF-BB/PDGFR𝜷 signaling in regulating depressive-like behaviors and identify a novel mechanism by which the MS GABA+ -DG pathway regulates the expression of PDGF-BB in SOM-positive interneurons.

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Morphine consumption during pregnancy exacerbates neonatal hypoxia‐ischemia injury in rats

Bornavard

Fanaei

Mirshekar

et al. 2020

Intl J of Devlp Neuroscience

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Objective Hypoxia‐Ischemia (HI) is the most common cause of death and disability in human infants. The use of opiate in pregnant women affects their children. The aim of this study was to evaluate the effect of morphine consumption during pregnancy and lactation on vulnerability to neonatal HI in rats. Materials and methods Female Wistar rats were randomly assigned into two groups: Group 1‐Rats that did not receive any treatment during pregnancy and lactation and Group 2‐Rats that received morphine during pregnancy and lactation. After delivery, male offspring were divided into four groups including: (a) SHAM, (b) SHAM/Morphine (SHAM/MO), (c) HI, (d) HI/Morphine (HI/MO). Seven days after HI induction, neurobehavioral tests were performed, and then, brain tissue was taken from the skull to measure cerebral edema, infarct volume, inflammatory factors, oxidative stress, and brain‐derived neurotrophic factor (BDNF). Results Total antioxidant capacity (TAC) and BDNF levels in the HI/MO group were significantly lower than HI and SHAM groups. TNF‐α, C‐reactive protein and total oxidant capacity levels in the HI/MO group were significantly higher than HI and SHAM groups. Cerebral edema and infarct volume in the HI/MO group were significantly higher than the HI group. Conclusion Based on the results, morphine consumption during pregnancy and lactation enhanced the deleterious effects of HI injury in pups.

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Regulation of morphine-induced synaptic alterations: Role of oxidative stress, ER stress, and autophagy

Abstract: Cai et al. demonstrate that morphine exposure dysregulates synaptic balance in the hippocampus. This effect involves a novel pathway involving ROS, ER stress, and autophagy and can be rescued by PDGF.

Cited by 85 publications

References 55 publications

Morphine-Mediated Brain Region-Specific Astrocytosis Involves the ER Stress-Autophagy Axis

Morphine-Mediated Brain Region-Specific Astrocytosis Involves the ER Stress-Autophagy Axis

PDGF‐BB‐Dependent Neurogenesis Buffers Depressive‐Like Behaviors by Inhibition of GABAergic Projection from Medial Septum to Dentate Gyrus

Morphine consumption during pregnancy exacerbates neonatal hypoxia‐ischemia injury in rats

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