Spinal Nrf2 translocation may inhibit neuronal NF‐κB activation and alleviate allodynia in a rat model of bone cancer pain

Fu, Jie; Ni, Chaobo; Ni, Huadong; Xu, Longsheng; He, Qing; Pan, Huaizhong; Huang, Dongdong; Sun, Yanbao; Luo, Ge; Liu, Mingjuan; Yao, Ming

doi:10.1111/jnc.15468

Cited by 17 publications

(12 citation statements)

References 81 publications

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“…We used the rat model of BCP established by Mao Ying et al 23 which was prepared by injecting Walker 256 breast cancer cells into the left tibia of SD rats. Consistent with our previous study, 21 mechanical allodynia occurred in the ipsilateral hind limb within 6 days after tumor inoculation and lasted for 18 days ( Figure 2(a) ). To verify BCP model, we performed 3D CT imaging of the rat tibia 18 days after the inoculation of Walker 256 cells to assess the bone destruction ( Figure 2(b) ).…”

Section: Resultssupporting

confidence: 92%

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CXCR1 participates in bone cancer pain induced by Walker 256 breast cancer cells in female rats

Zhao

et al. 2022

Mol Pain

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Bone cancer pain (BCP) is a clinically intractable mixed pain, involving inflammation and neuropathic pain, and its mechanisms remain unclear. CXC chemokine receptor 1 (CXCR1, IL-8RA) and 2 (CXCR2, IL-8RB) are high-affinity receptors for interleukin 8 (IL8). According to previous studies, CXCR2 plays a crucial role in BCP between astrocytes and neurons, while the role of CXCR1 remains unclear. The objective of this study was to investigate the role of CXCR1 in BCP. We found that CXCR1 expression increased in the spinal dorsal horn. Intrathecal injection of CXCR1 siRNA effectively attenuated mechanical allodynia and pain-related behaviors in rats. It was found that CXCR1 was predominantly co-localized with neurons. Intrathecal injection of CXCR1-siRNA reduced phosphorylated JAK2/STAT3 protein levels and the NLRP3 inflammasome (NLRP3, caspase1, and IL-1β) levels. Furthermore, in vitro cytological experiments confirmed this conclusion. The study results suggest that the spinal chemokine receptor CXCR1 activation mediates BCP through JAK2/STAT3 signaling pathway and NLRP3 inflammasome (NLRP3, caspase1, and IL-1β).

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Section: Resultssupporting

confidence: 92%

“…Besides, HE staining showed a large variety of larger cell nuclei with heterogeneity and eroded bone trabeculae. Consistent with previous studies, 19 , 21 these findings indicate that the BCP model has been effectively developed.…”

Section: Discussionsupporting

confidence: 91%

CXCR1 participates in bone cancer pain induced by Walker 256 breast cancer cells in female rats

Zhao

et al. 2022

Mol Pain

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“…As indicated before, mechanical allodynia was evaluated with a sequence of von Frey monofilaments (BME-404, Institute of Biomedical Sciences, Chinese Academy of Medical Sciences) that were calibrated ( Fu et al, 2021a ). Prior to conducting the experiment, rats were acclimatized for minimum 30 min in a singular, transparent Plexiglas box (grid: 0.5 cm × 0.5 cm; box: 10 cm × 10 cm × 15 cm) on a metal mesh bottom.…”

Section: Methodsmentioning

confidence: 99%

Catalpol ameliorates CFA-induced inflammatory pain by targeting spinal cord and peripheral inflammation

Zhao

Fu²,

Ni³

et al. 2022

Front. Pharmacol.

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Chronic, inflammatory pain is an international health concern that severely diminishes individuals’ quality of life. Catalpol is an iridoid glycoside derived from the roots of Rehmannia glutinosa that possesses anti-inflammatory, antioxidant, and neuroprotective properties for the treating multiple kinds of disorders. Nevertheless, catalpol’s impacts on inflammatory pain and its potential methods of action are still unclear. The purpose of this investigation is to determine the mechanism of catalpol to reduce the inflammatory pain behaviors in a rat model with complete Freund’s adjuvant (CFA). Catwalk, Von-Frey, and open field testing were performed for behavioral assessment. Western blot analysis and real-time quantitative PCR (RT-PCR) were employed to identify variations in molecular expression, while immunofluorescence was utilized to identify cellular localization. Catalpol effectively reduced CFA-induced mechanical allodynia and thermal hyperalgesia when injected intrathecally. Moreover, catalpol can regulate the HDAC4/PPAR-γ-signaling pathway in CFA rat spinal cord neurons. Meanwhile catalpol significantly decreased the expression of the NF-κB/NLRP3 inflammatory axis in the spinal cord of CFA rats. In addition, both in vivo and in vitro research revealed that catalpol treatment inhibited astrocyte activation and increase inflammatory factor expression. Interestingly, we also found that catalpol could alleviate peripheral pain by inhibiting tissue inflammation. Taken together, the findings declared that catalpol may inhibit inflammatory pain in CFA rats by targeting spinal cord and peripheral inflammation.

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“…As reported earlier, Walker 256 tumor cells were injected into the intramedullary space of the left leg using the BCP model. 26 , 27 A small slit was done to the left tibia’s lower one-third while they were sedated using pentobarbital sodium (60 mg/kg, i.p.). Next, Walker 256 cells (10 6 cells/mL) or heat-killed cells (10 6 cells/mL for Sham group) were administered to the tibia intramedullary space.…”

Section: Methodsmentioning

confidence: 99%

“…The bone destruction was observed using 3D CT bone reconstruction technology. The following CT scan parameter settings were based on a previous report 27 : helical scanning, 120 vvkVp; 1 mm layer thickness; care dose 4D technique; 1 mm layer interval; kemel: U30u medium smooth, with SD rats tibia’s CT high-resolution imaging (100 mm view field). At last, for reconstructing the images, the Siemens Syngo MMWP post-processing workstation was utilized.…”

Section: Methodsmentioning

confidence: 99%

miR-155-5p in the spinal cord regulates hypersensitivity in a rat model of bone cancer pain

Liu

Wang

et al. 2022

Mol Pain

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Background: Noncoding microRNAs have emerged as critical players of gene expression in the nervous system, where they contribute to regulating nervous disease. As stated in previous research, the miR-155-5p upregulation happens in the spinal cord at the nociceptive state. It was unclear if miR-155-5p is linked to bone cancer pain (BCP). Herein, we aimed at investigating the miR-155-5p functional regulatory function in BCP process and delineating the underlying mechanism. Methods: The miRNA-155-5p levels and cellular distribution were determined by RNA sequencing, fluorescent in situ hybridization (FISH), and quantitative real-time PCR (qPCR). Immunoblotting, qPCR, dual-luciferase reporter gene assays, immunofluorescence, recombinant overexpression adeno-associated virus, small interfering RNA, intraspinal administration, and behavioral tests were utilized for exploring the downstream signaling pathway. Results: The miR-155-5p high expression in spinal neurons contributes to BCP maintenance. The miR-155-5p blockage via the intrathecal injection of miR-155-5p antagomir alleviated the pain behavior; in contrast, upregulating miR-155-5p by agomir induced pain hypersensitivity. The miR-155-5p bounds directly to TCF4 mRNA’s 3′ UTR. BCP significantly reduced protein expression of TCF4 versus the Sham group. The miR-155-5p inhibition relieved the spinal TCF4 protein’s down-expression level, while miR-155-5p upregulation by miR-155-5p agomir intrathecal injection decreased TCF4 protein expression in naïve rats. Additionally, TCF4 overexpression in BCP rats could increase Kv1.1. Moreover, TCF4 knockdown inhibited Kv1.1 expression in BCP rats. Indeed, TCF4 and Kv1.1 were co-expressed in BCP spinal cord neurons. Conclusion: The study findings stated the miR-155-5p pivotal role in regulating BCP by directly targeting TCF4 in spinal neurons and suggested that miR-155 could be a promising target in treating BCP.

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Spinal Nrf2 translocation may inhibit neuronal NF‐κB activation and alleviate allodynia in a rat model of bone cancer pain

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmerc ial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 17 publications

References 81 publications

CXCR1 participates in bone cancer pain induced by Walker 256 breast cancer cells in female rats

CXCR1 participates in bone cancer pain induced by Walker 256 breast cancer cells in female rats

Catalpol ameliorates CFA-induced inflammatory pain by targeting spinal cord and peripheral inflammation

miR-155-5p in the spinal cord regulates hypersensitivity in a rat model of bone cancer pain

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