Suppression of KCNQ/M (Kv7) potassium channels in the spinal cord contributes to the sensitization of dorsal horn WDR neurons and pain hypersensitivity in a rat model of bone cancer pain

Bone cancer pain (BCP) is a severe type of hyperpathic pain occurring with primary bone tumors or advanced cancers which metastasize to bones. BCP can detrimentally reduce quality of life and presents a challenge to modern medicine. Studies have shown that exogenous H2S may act as a neuroprotectant to protect against some diseases in central nervous system. The preset study aimed to investigate the antinociceptive effect of H2S in BCP. We first measured the changes of serum H2S in patients with BCP and analyzed the relationship between them, then investigated the effect of H2S preconditioning on BCP, and explored the mechanism in rat model. Our results revealed that serum H2S level was negatively correlated with pain scores. In the rat model of BCP, preconditioning with H2S significantly reduced BCP, demonstrated by the decrease of thermal hyperalgesia and mechanical allodynia. The mechanism of H2S preconditioning may involve microglia deactivation and inflammation inhibition in the spinal cord, in which the proliferator-activated receptor gamma/p38/Jun N-terminal kinase pathway is activated. Impact statement Bone cancer pain (BCP) significantly decreases the life quality of patients or their life expectancy and causes a severe health burden to the society. However, as the exact mechanism of BCP is still poorly understood, no effective treatment has been developed yet. There are some pain medicines now, but they have some inevitable side effects. Additional therapeutic strategies are urgently needed. First, we revealed that preconditioning with H2S significantly reduced BCP, demonstrated by the decrease of thermal hyperalgesia and mechanical allodynia. Second, the mechanism of H2S preconditioning was elucidated. It may involve microglia deactivation and inflammation inhibition in the spinal cord, in which the proliferator-activated receptor gamma/p38/Jun N-terminal kinase pathway is activated. This novel finding may significantly help us to understand the difference between the roles of endogenous H2S and exogenous H2S in the development of BCP and present us a new strategy of pain management.

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The bone cancer pain induced expression of NR1 and NOS on the dorsal horn of murine spinal cord

Cell Biology International ◽

10.1016/j.cellbi.2008.01.279 ◽

2008 ◽

Vol 32 (3) ◽

pp. S65-S66

Author(s):

Dong Huang ◽

Shai Hong Zhu ◽

Xiao Ling Huang ◽

Jing Song Zeng ◽

Yong Hong Gu ◽

...

Keyword(s):

Spinal Cord ◽

Cancer Pain ◽

Dorsal Horn ◽

Bone Cancer ◽

Bone Cancer Pain ◽

Induced Expression

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Neuroligins Facilitate The Development of Bone Cancer Pain via Regulating Synaptic Transmission

10.21203/rs.3.rs-991135/v1 ◽

2021 ◽

Author(s):

Xianqiao Xie ◽

Yang Li ◽

Shanchun Su ◽

Xiaohui Li ◽

Xueqin Xu ◽

...

Keyword(s):

Spinal Cord ◽

Chronic Pain ◽

Cancer Pain ◽

Dorsal Horn ◽

Spinal Dorsal Horn ◽

Bone Cancer ◽

Bone Cancer Pain ◽

Rat Spinal Cord ◽

Spinal Dorsal

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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Corrigendum to “DNMT3a contributes to the development and maintenance of bone cancer pain by silencing Kv1.2 expression in spinal cord dorsal horn”

Molecular Pain ◽

10.1177/1744806920963460 ◽

2020 ◽

Vol 16 ◽

pp. 174480692096346

Keyword(s):

Spinal Cord ◽

Cancer Pain ◽

Dorsal Horn ◽

Bone Cancer ◽

Spinal Cord Dorsal Horn ◽

Bone Cancer Pain ◽

Spinal Cord Dorsal

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Electrical peripheral nerve stimulation relieves bone cancer pain by inducing Arc protein expression in the spinal cord dorsal horn

Journal of Pain Research ◽

10.2147/jpr.s149470 ◽

2018 ◽

Vol Volume 11 ◽

pp. 599-609 ◽

Cited By ~ 2

Author(s):

Ke-fu Sun ◽

Wan-wen Feng ◽

Yue-peng Liu ◽

Yan-bin Dong ◽

Li Gao ◽

...

Keyword(s):

Spinal Cord ◽

Peripheral Nerve ◽

Protein Expression ◽

Cancer Pain ◽

Dorsal Horn ◽

Nerve Stimulation ◽

Bone Cancer ◽

Spinal Cord Dorsal Horn ◽

Bone Cancer Pain ◽

Spinal Cord Dorsal

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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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