Morphine Protects Spinal Cord Astrocytes from Glutamate-Induced Apoptosis via Reducing Endoplasmic Reticulum Stress

Zhang, Chao; Wang, Chendan; Ren, Jianbo; Guo, Xiangjie; Yun, Keming

doi:10.3390/ijms17101523

Cited by 18 publications

(12 citation statements)

References 42 publications

(49 reference statements)

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“…So far, only a few studies have reported the effect of opioid on ER stress. In vitro study suggested that morphine could protect primary cultured astrocytes from glutamate-induced apoptosis via reducing Ca 2+ overload and ER stress pathways ( Zhang et al, 2016 ). Naloxone, an opioid receptor antagonist, could upregulate gene expression of ER chaperones in PC12 cells, including BiP, calnexin, ER protein 29 and protein disulfide isomerase, and ER stress sensors, including ATF6, IRE1, and PERK.…”

Section: Discussionmentioning

confidence: 99%

Endoplasmic Reticulum Stress in Spinal Cord Contributes to the Development of Morphine Tolerance

Liu

Zhou

Peng

et al. 2018

Front. Mol. Neurosci.

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Morphine tolerance remains an intractable problem, which hinders its prolonged use in clinical practice. Endoplasmic reticulum (ER) stress has been proved to play a fundamental role in the pathogenesis of Alzheimer’s disease, diabetes, atherosclerosis, cancer, etc. In this study, we provide the first direct evidence that ER stress may be a significant driver of morphine tolerance. Binding immunoglobulin protein (BiP), the ER stress marker, was significantly upregulated in neurons in spinal dorsal horn in rats being treated with morphine for 7 days. Additionally, chronic morphine treatment resulted in the activation of three arms of unfolded protein response (UPR): inositol-requiring enzyme 1/X-box binding protein 1 (IRE1/XBP1), protein kinase RNA-like ER kinase/eukaryotic initiation factor 2 subunit alpha (PERK/eIF2α), and activating transcription factor 6 (ATF6). More importantly, inhibiting either one of the three cascades could attenuate the development of morphine tolerance. Taken together, our results suggest that ER stress in spinal cord might contribute to the development of morphine tolerance. These findings implicate a potential clinical strategy for preventing morphine tolerance and may contribute to expanding the morphine usage in clinic.

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Section: Discussionmentioning

confidence: 99%

Endoplasmic Reticulum Stress in Spinal Cord Contributes to the Development of Morphine Tolerance

Liu

Zhou

Peng

et al. 2018

Front. Mol. Neurosci.

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“…This result suggests that Nrf2 is activated after DAI and may also play a role in cytoprotection after DAI. Because ER stress is also triggered by excitotoxicity and oxidative stress in neurotrauma conditions 61 – 63 , Nrf2 may be involved in the ER stress process following DAI. Upon ER stress, in addition to transautophosphorylating and phosphorylating, the translation initiation factor eIF2α PERK also phosphorylates Nrf2 and promotes its nuclear translocation 64 , 65 .…”

Section: Discussionmentioning

confidence: 99%

Curcumin mitigates axonal injury and neuronal cell apoptosis through the PERK/Nrf2 signaling pathway following diffuse axonal injury

Huang

Zhao²,

Guo³

et al. 2018

NeuroReport

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Diffuse axonal injury (DAI) accounts for more than 50% of all traumatic brain injury. In response to the mechanical damage associated with DAI, the abnormal proteins produced in the neurons and axons, namely, β-APP and p-tau, induce endoplasmic reticulum (ER) stress. Curcumin, a major component extracted from the rhizome of Curcuma longa, has shown potent anti-inflammatory, antioxidant, anti-infection, and antitumor activity in previous studies. Moreover, curcumin is an activator of nuclear factor-erythroid 2-related factor 2 (Nrf2) and promotes its nuclear translocation. In this study, we evaluated the therapeutic potential of curcumin for the treatment of DAI and investigated the mechanisms underlying the protective effects of curcumin against neural cell death and axonal injury after DAI. Rats subjected to a model of DAI by head rotational acceleration were treated with vehicle or curcumin to evaluate the effect of curcumin on neuronal and axonal injury. We observed that curcumin (20 mg/kg intraperitoneal) administered 1 h after DAI induction alleviated the aggregation of p-tau and β-APP in neurons, reduced ER-stress-related cell apoptosis, and ameliorated neurological deficits. Further investigation showed that the protective effect of curcumin in DAI was mediated by the PERK/Nrf2 pathway. Curcumin promoted PERK phosphorylation, and then Nrf2 dissociated from Keap1 and was translocated to the nucleus, which activated ATF4, an important bZIP transcription factor that maintains intracellular homeostasis, but inhibited the CHOP, a hallmark of ER stress and ER-associated programmed cell death. In summary, we demonstrate for the first time that curcumin confers protection against abnormal proteins and neuronal apoptosis after DAI, that the process is mediated by strengthening of the unfolded protein response to overcome ER stress, and that the protective effect of curcumin against DAI is dependent on the activation of Nrf2.

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“…The implications of MSG consumption could go further than hyperalgesia, since glutamate induces astrocyte mitochondrial apoptosis. Glutamate increased the expression of representative apoptotic markers, including cleaved caspase-8, cleaved caspase-9, and cleaved caspase-3, as well as level key markers in endoplasmic reticulum stress, in primary cultured spinal cord astrocytes [ 35 ]. This opens the way for further investigations: Does administration of MSG impacts spinal cord astrocytes?…”

Section: Discussionmentioning

confidence: 99%

Chronic Monosodium Glutamate Administration Induced Hyperalgesia in Mice

et al. 2017

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Monosodium glutamate (MSG) is a widely used food additive. Although it is generally considered safe, some questions regarding the impact of its use on general health have arisen. Several reports correlate MSG consumption with a series of unwanted reactions, including headaches and mechanical sensitivity in pericranial muscles. Endogenous glutamate plays a significant role in nociceptive processing, this neurotransmitter being associated with hyperalgesia and central sensitization. One of the mechanisms underlying these phenomena is the stimulation of Ca2+/calmodulin sensitive nitric oxide synthase, and a subsequent increase in nitric oxide production. This molecule is a key player in nociceptive processing, with implications in acute and chronic pain states. Our purpose was to investigate the effect of this food additive on the nociceptive threshold when given orally to mice. Hot-plate and formalin tests were used to assess nociceptive behaviour. We also tried to determine if a correlation between chronic administration of MSG and variations in central nitric oxide (NO) concentration could be established. We found that a dose of 300 mg/kg MSG given for 21 days reduces the pain threshold and is associated with a significant increase in brain NO level. The implications of these findings on food additive-drug interaction, and on pain perception in healthy humans, as well as in those suffering from affections involving chronic pain, are still to be investigated.

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Morphine Protects Spinal Cord Astrocytes from Glutamate-Induced Apoptosis via Reducing Endoplasmic Reticulum Stress

Cited by 18 publications

References 42 publications

Endoplasmic Reticulum Stress in Spinal Cord Contributes to the Development of Morphine Tolerance

Endoplasmic Reticulum Stress in Spinal Cord Contributes to the Development of Morphine Tolerance

Curcumin mitigates axonal injury and neuronal cell apoptosis through the PERK/Nrf2 signaling pathway following diffuse axonal injury

Chronic Monosodium Glutamate Administration Induced Hyperalgesia in Mice

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