EphrinB-EphB receptor signaling contributes to bone cancer pain via Toll-like receptor and proinflammatory cytokines in rat spinal cord

Abstract Background The underlying mechanism of chronic pain involves the plasticity in synaptic receptors and neurotransmitters. This study aimed to investigate potential roles of neuroligins (NLs) within the spinal dorsal horn of rats in a newly established bone cancer pain (BCP) model. Methods Using our rat BCP model, we assessed pain hypersensitivity over time. Quantitative real-time polymerase chain reaction and Western blot analysis were performed to investigate NL expression, and NLs were overexpressed in the rat spinal cord using lentiviral vectors. Immunofluorescence staining and whole-cell patch-clamp recordings were deployed to investigate the role of NLs in the development of BCP. Results We observed reduced expression levels of NL1 and NL2, but not NL3, within the rat spinal cord, which were found to be associated with and essential for the development of BCP in our model. Accordingly, NL1 or NL2 overexpression in the spinal cord alleviated mechanical hypersensitivity of rats. Electrophysiological experiments indicated that NL1 and NL2 are involved in BCP via regulating γ-aminobutyric acid-ergic interneuronal synapses and the activity of glutamatergic interneuronal synapses, respectively. Conclusions Our observations unravel the role of NLs in cancer-related chronic pain and further suggest that inhibitory mechanisms are central features of BCP in the spinal dorsal horn. These results provide a new perspective and basis for subsequent studies elucidating the onset and progression of BCP.

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Spinal cannabinoid receptor 2 activation reduces hypersensitivity associated with bone cancer pain and improves the integrity of the blood–spinal cord barrier

Regional Anesthesia and Pain Medicine ◽

10.1136/rapm-2019-101262 ◽

2020 ◽

Vol 45 (10) ◽

pp. 783-791

Author(s):

Chenchen Wang ◽

Ke Xu ◽

Yu Wang ◽

Yanting Mao ◽

Yulin Huang ◽

...

Keyword(s):

Spinal Cord ◽

Mouse Model ◽

Cancer Pain ◽

Proinflammatory Cytokines ◽

Cannabinoid Receptor ◽

Bone Cancer ◽

Bone Cancer Pain ◽

Pain Hypersensitivity ◽

Cannabinoid Receptor 2 ◽

Blood Spinal Cord Barrier

BackgroundDisruption of the blood–spinal cord barrier (BSCB) can facilitate inflammation that results in pain hypersensitivity. Proinflammatory cytokines produced by activated microglia and astrocytes damage the BSCB. This study aims to explore whether the BSCB is damaged in the bone cancer pain (BCP) model and to investigate a potential role and mechanism of JWH015 ((2-methyl-1-propyl-1H-indol-3-yl)−1-naphthalenylmethanone), a selective cannabinoid receptor 2 (CB2R) agonist, in preserving the BSCB integrity in the BCP model.MethodsWe used a male mouse model of BCP. Pain hypersensitivity was measured over time. Evans blue dye extravasation, transmission electron microscopy and Western blotting were performed to investigate the permeability and structural integrity of the BSCB. Immunofluorescence staining and western blotting were used to investigate the effect of JWH015 on the activation of glial cells and the levels of proinflammatory cytokines.ResultsA single intrathecal injection of JWH015 ameliorated pain hypersensitivity, the BSCB disruption and microglia and astrocyte activation. Decreases in the expression of ZO-1 and claudin-5 were partially restored by JWH015. The levels of the proinflammatory cytokines interleukin-1β and tumor necrosis factor-α and the enzyme MMP9 were reduced by JWH015. However, all effects were prevented by pretreatment with a CB2R-selective antagonist, AM630 ((6-iodo-2-methyl-1-(2-morpholinoethyl)−1H-indol-3-yl)(4-methoxyphenyl)methanone).ConclusionsJWH015 alleviates neuroinflammation and maintains the BSCB integrity and permeability in a mouse model of BCP, which is probably mediated by inhibiting glial cells activation. This study reveals the new analgesic mechanism of JWH015 on BCP and provides a perspective to explore novel drugs that target the BSCB to control BCP.

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Effects of p38 MAPK inhibitor on the rat pain behavior and proinflammatory cytokines in a metastatic bone cancer pain model

The Chinese-German Journal of Clinical Oncology ◽

10.1007/s10330-007-0191-4 ◽

2008 ◽

Vol 7 (3) ◽

pp. 154-158 ◽

Cited By ~ 1

Author(s):

Cuiju Tang ◽

Shiying Yu ◽

Min Zhang ◽

Rui Jiang ◽

Na Li ◽

...

Keyword(s):

Cancer Pain ◽

P38 Mapk ◽

Proinflammatory Cytokines ◽

Bone Cancer ◽

Pain Behavior ◽

Bone Cancer Pain ◽

Pain Model ◽

P38 Mapk Inhibitor ◽

Mapk Inhibitor

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MiR-135-5p Alleviates Bone Cancer Pain by Regulating Astrocyte-Mediated Neuroinflammation in Spinal Cord through JAK2/STAT3 Signaling Pathway

Molecular Neurobiology ◽

10.1007/s12035-021-02458-y ◽

2021 ◽

Author(s):

Ming Liu ◽

Xuefeng Cheng ◽

Hong Yan ◽

Jingli Chen ◽

Caihua Liu ◽

...

Keyword(s):

Spinal Cord ◽

Cancer Pain ◽

Signaling Pathway ◽

Bone Cancer ◽

Bone Cancer Pain ◽

Stat3 Signaling ◽

Stat3 Signaling Pathway

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Effects of Parecoxib on Pain Threshold and Inflammatory Factors IL-1β, IL-6 and TNF-𝜶 in Spinal Cord of Rats with Bone Cancer Pain

Journal of College of Physicians And Surgeons Pakistan ◽

10.29271/jcpsp.2019.06.528 ◽

2019 ◽

Vol 29 (6) ◽

pp. 528-531

Author(s):

Jun Chen ◽

Xiufeng Cong ◽

Xiuzhu Zhan ◽

Zheng Zhou ◽

Wei Zheng

Keyword(s):

Spinal Cord ◽

Cancer Pain ◽

Pain Threshold ◽

Bone Cancer ◽

Inflammatory Factors ◽

Bone Cancer Pain

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Levo-Tetrahydropalmatine Attenuates Bone Cancer Pain by Inhibiting Microglial Cells Activation

Mediators of Inflammation ◽

10.1155/2015/752512 ◽

2015 ◽

Vol 2015 ◽

pp. 1-9 ◽

Cited By ~ 9

Author(s):

Mao-yin Zhang ◽

Yue-peng Liu ◽

Lian-yi Zhang ◽

Dong-mei Yue ◽

Dun-yi Qi ◽

...

Keyword(s):

Spinal Cord ◽

Cancer Pain ◽

Mechanical Allodynia ◽

Thermal Hyperalgesia ◽

Bone Cancer ◽

Microglial Cells ◽

Bone Cancer Pain ◽

Enzyme Linked Immunosorbent Assay ◽

Analgesic Effects ◽

Before And After

Objective. The present study is to investigate the analgesic roles of L-THP in rats with bone cancer pain caused by tumor cell implantation (TCI).Methods. Thermal hyperalgesia and mechanical allodynia were measured at different time points before and after operation. L-THP (20, 40, and 60 mg/kg) were administrated intragastrically at early phase of postoperation (before pain appearance) and later phase of postoperation (after pain appearance), respectively. The concentrations of TNF-α, IL-1β, and IL-18 in spinal cord were measured by enzyme-linked immunosorbent assay. Western blot was used to test the activation of astrocytes and microglial cells in spinal cord after TCI treatment.Results. TCI treatment induced significant thermal hyperalgesia and mechanical allodynia. Administration of L-THP at high doses significantly prevented and/or reversed bone cancer-related pain behaviors. Besides, TCI-induced activation of microglial cells and the increased levels of TNF-αand IL-18 were inhibited by L-THP administration. However, L-THP failed to affect TCI-induced astrocytes activation and IL-1βincrease.Conclusion. This study suggests the possible clinical utility of L-THP in the treatment of bone cancer pain. The analgesic effects of L-THP on bone cancer pain maybe underlying the inhibition of microglial cells activation and proinflammatory cytokines increase.

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