Neurophysiological mechanisms of cancer-induced bone pain

Zheng, Xuan-Qi; Wu, Yuhao; Huang, Jinfeng; Wu, Ai-Min

doi:10.1016/j.jare.2021.06.006

Cited by 48 publications

(32 citation statements)

References 107 publications

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“…Bone cancer pain (BCP), one of the most severe types of chronic pain, involves the complex interaction of various molecular events, resulting in a combination of inflammatory and neuropathic pain [1][2][3]. Specifically, peripheral sensitization, which mainly involves persistent afferent stimulation at the site of bone metastasis, inflammatory responses and changes in the plasticity of primary sensory neurons in the dorsal root ganglion (DRG), plays an essential role in the occurrence and development of BCP [4]. Pain information processing starts from activation of peripheral nociceptors in the DRG, and DRG neurons act as a bridge between the internal and external environments.…”

Section: Introductionmentioning

confidence: 99%

Activation of the STING pathway induces peripheral sensitization via neuroinflammation in a rat model of bone cancer pain

et al. 2022

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Background Neuroinflammation in the peripheral nervous system has been linked to cancer metastasis-induced bone pain. The stimulator of interferon genes (STING), an innate immune sensor for cytosolic DNA, plays an important role in inflammation and cancer metastasis and is reported to be a critical regulator of nociception. Here, we examined the role of STING in primary nociceptive neurons and chronic pain to determine if it could be a new target for treating bone cancer pain (BCP). Methods Walker 256 cancer cells were injected intratibially to induce bone cancer pain in rats. STING and its downstream inflammatory factors in dorsal root ganglia (DRG) were detected using western blotting and immunofluorescent staining. Transmission electron microscopy and the BCL2-associated X (Bax) expression were used to detect the mitochondrial stress in DRG neurons. C-176, a specific inhibitor of STING, was used to block STING activation and to test the pain behavior. Results Mechanical hyperalgesia and spontaneous pain were observed in BCP rats, accompanied by the upregulation of the STING expression in the ipsilateral L4-5 DRG neurons which showed significant mitochondrion stress. The STING/TANK-binding kinase 1 (TBK1)/nuclear factor-kappa B (NF-κB) pathway activation was observed in the DRGs of BCP rats as well as increased IL-1β, IL-6, and TNF-α expression. C-176 alleviated bone cancer pain and reduced the STING and its downstream inflammatory pathway. Conclusion We provide evidence that STING pathway activation leads to neuroinflammation and peripheral sensitization. Pharmacological blockade of STING may be a promising novel strategy for preventing BCP.

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Section: Introductionmentioning

confidence: 99%

Activation of the STING pathway induces peripheral sensitization via neuroinflammation in a rat model of bone cancer pain

et al. 2022

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“…Previous studies have reported that CIBP would alter the synapses and circuits in the medial prefrontal cortex (mPFC), increasing pain sensitivity, and further inducing negative emotions, such as anxiety and depression, which may aggravate the pain and create a vicious circle [ 4 , 5 , 6 , 7 , 8 ]. Neuroinflammation in chronic pain is increasingly being demonstrated by researchers [ 9 , 10 , 11 , 12 , 13 ]: Mao et al proved that inhibiting neuroinflammation in the spinal cord can relieve CIBP [ 14 ]; the study of Wei et al showed that neuroinflammation of the central spinal may be important for the persistent nociceptive changes in complex regional pain syndrome model [ 15 ]. Microglia have been regarded as primary mediators of neuroinflammation in the formation of cancer pain [ 16 , 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

STING Contributes to Cancer-Induced Bone Pain by Promoting M1 Polarization of Microglia in the Medial Prefrontal Cortex

Zhang

Wang

et al. 2022

Cancers

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The medial prefrontal cortex (mPFC) is the main cortical area for processing both sensory and affective aspects of pain. Recently, mPFC was reported to participate in cancer-induced bone pain (CIBP) via the mechanism of central inflammation. STING is a key component of neuroinflammation in the central neuron system by activating downstream TBK1 and NF-κB signaling pathways. We aimed to investigate whether STING regulated neuroinflammation in the mPFC in rat models of CIBP. It is worth noting that we found a significant upregulation of STING in the mPFC after CIBP, accompanied by activation of TBK1 and NF-κB signaling pathways. In addition, pain and anxiety-like behaviors were alleviated by intraperitoneal injection of the STING inhibitor C-176. Furthermore, in microglia GMI-R1 cells, C-176 reversed LPS-induced M1 polarization. Collectively, this evidence indicated that STING may contribute to cancer-induced bone pain by activating TBK1 and NF-κB, and by promoting M1 polarization of microglia in the mPFC.

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“…Currently, it is suggested that neuropathic pain is a main component of CIBP. 28 The pathways of neuropathic pain are not well understood. Neuropathic pain is a complex phenomenon caused by interactions between multiple physiological systems, including the immune system.…”

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confidence: 99%

“…27 First, the structure of OF1105 was superimposed on the structure of the human TRPA1 ion channel in complex with the covalent agonist benzyl isothiocyanate (BITC). As described previously, 28 we considered that compound OF1105 also reacts with Cys621, opening the 1,2-dithiolane ring. All possible complexes formed in this reaction were considered in the calculations (Figures 3a andS2).…”

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confidence: 99%

Lipoyl-Based Antagonists of Transient Receptor Potential Cation A (TRPA1) Downregulate Osteosarcoma Cell Migration and Expression of Pro-Inflammatory Cytokines

Francesconi

Corzana

Kontogianni

et al. 2022

ACS Pharmacol. Transl. Sci.

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Osteosarcoma is a heterogeneous tumor intimately linked to its microenvironment, which promotes its growth and spread. It is generally accompanied by cancer-induced bone pain (CIBP), whose main component is neuropathic pain. The TRPA1 ion channel plays a key role in metastasis and is increasingly expressed in bone cancer. Here, a novel TRPA1 inhibitor is described and tested together with two other known TRPA1 antagonists. The novel lipoyl derivative has been successfully assessed for its ability to reduce human osteosarcoma MG-63 cell viability, motility, and gene expression of the CIBP pro-inflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α). A putative three-dimensional (3D) model of the inhibitor covalently bound to TRPA1 is also proposed. The in vitro data suggest that the novel inhibitor described here may be highly interesting and stimulating for new strategies to treat osteosarcomas.

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Neurophysiological mechanisms of cancer-induced bone pain

Cited by 48 publications

References 107 publications

Activation of the STING pathway induces peripheral sensitization via neuroinflammation in a rat model of bone cancer pain

Activation of the STING pathway induces peripheral sensitization via neuroinflammation in a rat model of bone cancer pain

STING Contributes to Cancer-Induced Bone Pain by Promoting M1 Polarization of Microglia in the Medial Prefrontal Cortex

Lipoyl-Based Antagonists of Transient Receptor Potential Cation A (TRPA1) Downregulate Osteosarcoma Cell Migration and Expression of Pro-Inflammatory Cytokines

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