Endoplasmic Reticulum Stress in the Dorsal Root Ganglion Contributes to the Development of Pain Hypersensitivity after Nerve Injury

Yamaguchi, Yosuke; Oh‐hashi, Kentaro; Matsuoka, Yutaka; Takemura, Hitomi; Yamakita, Shunsuke; Matsuda, Megumi; Sawa, Teiji; Amaya, Fumimasa

doi:10.1016/j.neuroscience.2018.08.005

Cited by 27 publications

(21 citation statements)

References 31 publications

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“… 141 It is unlikely that UPR by-products from injured axons are the only source of ER stress markers observed in the DRG considering that ER stress markers are elevated in the DRG as early as one day after injury. 142 Regardless, axonal ER stress is proposed to be beneficial and essential for nerve regeneration and locomotor recovery possibly by addressing the high demand of protein synthesis required for axonal outgrowth. In this respect, the upregulation of ERp57, an ER resident disulfide isomerase, was found to improve axonal regeneration and locomotion following sciatic nerve injury.…”

Section: Pathophysiology Impacting the Er And Mitochondriamentioning

confidence: 99%

Endoplasmic reticulum–mitochondria interplay in chronic pain: The calcium connection

et al. 2020

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Chronic pain is a debilitating condition that affects roughly a third to a half of the world’s population. Despite its substantial effect on society, treatment for chronic pain is modest, at best, notwithstanding its side effects. Hence, novel therapeutics are direly needed. Emerging evidence suggests that calcium plays an integral role in mediating neuronal plasticity that underlies sensitization observed in chronic pain states. The endoplasmic reticulum and the mitochondria are the largest calcium repositories in a cell. Here, we review how stressors, like accumulation of misfolded proteins and oxidative stress, influence endoplasmic reticulum and mitochondria function and contribute to chronic pain. We further examine the shuttling of calcium across the mitochondrial-associated membrane as a mechanism of cross-talk between the endoplasmic reticulum and the mitochondria. In addition, we discuss how endoplasmic reticulum stress, mitochondrial impairment, and calcium dyshomeostasis are implicated in various models of neuropathic pain. We propose a novel framework of endoplasmic reticulum–mitochondria signaling in mediating pain hypersensitivity. These observations require further investigation in order to develop novel therapies for chronic pain.

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Section: Pathophysiology Impacting the Er And Mitochondriamentioning

confidence: 99%

Endoplasmic reticulum–mitochondria interplay in chronic pain: The calcium connection

et al. 2020

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“…15,17 Emerging evidence is now demonstrating that ER stress may also be a significant factor for developing pain hypersensitivity in various animal models across a variety of cell types. [18][19][20][21][22][23][24][25] In this study, we investigated whether ER stress in DRG neurons contributes to the well characterized pain hypersensitivity that occurs in the EAE model and by extension in MS. 7,26 2 | MATERIALS AND METHODS…”

Section: Introductionmentioning

confidence: 99%

Endoplasmic reticulum stress in the dorsal root ganglia regulates large‐conductance potassium channels and contributes to pain in a model of multiple sclerosis

et al. 2020

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Neuropathic pain is a common symptom of multiple sclerosis (MS) and current treatment options are ineffective. In this study, we investigated whether endoplasmic reticulum (ER) stress in dorsal root ganglia (DRG) contributes to pain hypersensitivity in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. Inflammatory cells and increased levels of ER stress markers are evident in post‐mortem DRGs from MS patients. Similarly, we observed ER stress in the DRG of mice with EAE and relieving ER stress with a chemical chaperone, 4‐phenylbutyric acid (4‐PBA), reduced pain hypersensitivity. In vitro, 4‐PBA and the selective PERK inhibitor, AMG44, normalize cytosolic Ca2+ transients in putative DRG nociceptors. We went on to assess disease‐mediated changes in the functional properties of Ca2+‐sensitive BK‐type K+ channels in DRG neurons. We found that the conductance‐voltage (GV) relationship of BK channels was shifted to a more positive voltage, together with a more depolarized resting membrane potential in EAE cells. Our results suggest that ER stress in sensory neurons of MS patients and mice with EAE is a source of pain and that ER stress modulators can effectively counteract this phenotype.

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“…In this study, we constructed a neuropathic pain model by using SNL and injected miR-155 agomir or antagomir into the rats via intrathecal catheter. SNL of the neighbouring (L5) spinal nerve is the most popular periph-eral neuropathy model [45]. In the SNL, L5 spinal nerves are tightly ligated at a location distal to the dorsal root ganglia.…”

Section: Discussionmentioning

confidence: 99%

Suppression of miR-155 attenuates neuropathic pain by inducing an M1 to M2 switch in microglia

Zhang¹,

Chen²,

Nai³

et al. 2020

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Introduction: The polarization state of microglia affects the progress of neuropathic pain. MiR-155 modulates polarization of microglia, while its role in neuropathic pain has not been well studied. Material and methods: We separately used lipopolysaccharide (LPS) and interleukin 4 (IL-4) for constructing an M1/M2 polarization model in BV-2 cells. The levels of CD86, iNOS, CD206, Arg and miR-155 were measured by western blot or qRT-PCR, as needed. Subsequently, BV-2 cells were transfected with miR-155 mimics or inhibitor to explore the effects of miR-155 on polarization states. We also constructed a neuropathic pain model by applying spinal nerve ligation (SNL) in Wistar rats with miR-155 agomir or antagomir injection. The withdrawal threshold was measured by Von Frey fibre needle. The levels of interleukin 1β (IL-1β), tumour necrosis factor α (TNF-α) and the proportion of M1-polarized microglia in primary microglia from rats were measured by ELISA and flow cytometry. Results: LPS induced M1 polarization in BV-2 cells with increasing of CD86, iNOS and miR-155, while IL-4 induced M2 polarization in BV-2 cells with increasing of CD206, Arg and decreasing of miR-155. MiR-155 mimics upregulated CD86 and downregulated CD206, whereas miR-155 inhibitor downregulated CD86 and upregulated CD206. MiR-155 antagomir increased the withdrawal threshold, decreased the production of IL-1β, TNF-α and the proportion of M1-polarized microglia in primary microglia. Conclusions: Results demonstrate that suppression of miR-155 attenuates neuropathic pain by inducing an M1 to M2 switch in microglia. Our findings provide a new perspective to understand the function of miR-155 in microglia.

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Endoplasmic Reticulum Stress in the Dorsal Root Ganglion Contributes to the Development of Pain Hypersensitivity after Nerve Injury

Cited by 27 publications

References 31 publications

Endoplasmic reticulum–mitochondria interplay in chronic pain: The calcium connection

Endoplasmic reticulum–mitochondria interplay in chronic pain: The calcium connection

Endoplasmic reticulum stress in the dorsal root ganglia regulates large‐conductance potassium channels and contributes to pain in a model of multiple sclerosis

Suppression of miR-155 attenuates neuropathic pain by inducing an M1 to M2 switch in microglia

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