Sinomenine attenuates cancer-induced bone pain via suppressing microglial JAK2/STAT3 and neuronal CAMKII/CREB cascades in rat models

Chen, Shuping; Sun, Jia; Zhou, Ya‐Qun; Cao, Fei; Braun, Cody; Luo, Fang; Ye, Dawei; Tian, Yuan

doi:10.1177/1744806918793232

Cited by 47 publications

(33 citation statements)

References 74 publications

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“…10D). Our pervious study has already demonstrated that JAK2/STAT3 was mainly colocalized to microglia in the nociceptive pathway [38]. Furthermore, we assessed the effects of STING on activation of JAK2/STAT3 using BV-2 cells, demonstrating that STING activation could increase the phosphorylation level of JAK2/STAT3 signal in microglia.…”

Section: Early C-176 Administration Attenuated Pain Hypersensitivitymentioning

confidence: 84%

STING/NF-κB/IL-6-mediated inflammation in microglia contributes to spared nerve injury (SNI)-induced neuropathic pain

Sun

Zhou

et al. 2021

Preprint

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Background Innate immune response acts as a first line of host defense against damage and are initiated following the recognition of pathogen-associated molecular patterns (PAMPs). For double-stranded DNA (dsDNA) sensing, interferon gene stimulator (STING) was discovered to be an integral sensor, and could mediate the immune and inflammatory response. However, it is unclear the underlying mechanisms of STING in the development of neuropathic pain. Methods Neuropathic pain model was established by spared nerve injury (SNI). STING agonist DMXAA was introduced into BV-2 cells to assess the inflammatory response in microglia cells. Selective STING antagonist C-176 were administered in the early and late stage following SNI and the mechanical sensitivity and thermal responsiveness were assessed using Von Frey filaments and hot plate tests separately. To investigate the underlying mechanisms, recombinant IL-6 was injected intrathecally and its downstream effectors were examined. The level of dsDNA in the peripheral blood following SNI was assessed using Elisa analysis. STING signaling pathway and its downstream effectors were assessed by qPCR, western blots, Elisa and immunofluorescence staining. Meanwhile, microglia activation and proinflammatory cytokines expression were also assessed in the spinal cord. Results We found dsDNA was significantly increased and STING signaling pathway was activated in dorsal horn microglia following SNI, and our study using BV-2 cells showed that DMXAA significantly activated STING/TANK-binding kinase 1 (TBK1)/nuclear factor-kappa B (NF-κB) pathway, and increased the production of proinflammatory cytokines, as well as phosphorylated the Janus-activated kinase 2/signal transducer activator of transcription 3 (JAK2/STAT3) signal in microglia. Early but not late intrathecal injection of C-176 attenuated SNI-induced pain hypersensitivity, microglia activation, proinflammatory factors and phosphorylated JAK2/STAT3 in the spinal cord dorsal horn. Last, the analgesic effect of C-176 were greatly abolished by recombinant IL-6 following SNI. Conclusions We provided evidence clarifying dsDNA mediated activation of microglial STING signaling pathway, after which promoting expression of proinflammatory cytokines that are required for central sensitization in the spinal cord dorsal horn of SNI model. Further analysis showed that microglial STING/TBK1/NF-κB may contribute to hyperalgesia initiation via IL-6/JAK2/STAT3 signaling. Pharmacological blockade of STING may be a promising target during the initiation of neuropathic pain.

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Section: Early C-176 Administration Attenuated Pain Hypersensitivitymentioning

confidence: 84%

STING/NF-κB/IL-6-mediated inflammation in microglia contributes to spared nerve injury (SNI)-induced neuropathic pain

Sun

Zhou

et al. 2021

Preprint

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“…The NMDA receptor-gated channel regulates calcium influx in the postsynaptic membrane (10,42). Intracellular calcium influx leads to the activation of calmodulin, further activating a variety of signaling pathways, which serve important roles in pain transmission (12,13), including the p38-mitogen-activated protein kinase signaling pathway (46). Therefore, synaptic structure and functional adaptation is an important step in the development of central hyperalgesia (43,44,46).…”

Section: Discussionmentioning

confidence: 99%

“…The phosphorylation of certain molecules in the central and peripheral nerves can cause hyperalgesia in rats with ciBP (10,11). For example, the phosphorylation of calmodulin can activate a variety of signaling pathways to promote inflammatory factors (12,13). oXY, a G protein-coupled receptor agonist, inhibits adenylate cyclase activity, thereby inhibiting caMP production which affects the phosphorylation of membrane proteins (14).…”

Section: Introductionmentioning

confidence: 99%

Phosphoproteomic profiling of oxycodone‑treated spinal cord of rats with cancer‑induced bone pain

Deng

et al. 2019

Mol Med Report

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Treatment of cancer-induced bone pain (ciBP) is challenging in clinical settings. oxycodone (oXY) is used to treat ciBP; however, a lack of understanding of the mechanisms underlying ciBP limits the application of oXY. in the present study, all rats were randomly divided into three groups: The sham group, the ciBP group, and the oXY group. Then, a rat model of ciBP was established by inoculation of Walker 256 tumor cells from rat tibia. Phosphoproteomic profiling of the OXY-treated spinal dorsal cords of rats with ciBP was performed, and 1,679 phosphorylated proteins were identified, of which 160 proteins were significantly different between the ciBP and sham groups, and 113 proteins were significantly different between the CIBP and OXY groups. Gene ontology analysis revealed that these proteins mainly clustered as synaptic-associated cellular components; among these, disks large homolog 3 expression was markedly increased in rats with ciBP and was reversed by oXY treatment. Subsequent domain analysis of the differential proteins revealed several significant synaptic-associated domains. In conclusion, synaptic-associated cellular components may be critical in oXY-induced analgesia in rats with ciBP.

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“…The CIBP model was carried out by inoculating Walker 256 mammary gland carcinoma cells into the right tibia based on previous studies (Chen et al, 2018;Zhou et al, 2018). After anesthesia with pentobarbital sodium (50 mg/kg), a minimal incision in the right leg was made to expose the tibia.…”

Section: Cancer-induced Bone Pain Modelmentioning

confidence: 99%

The therapeutic potential of GABA in neuron-glia interactions of cancer-induced bone pain

Chen

Zhou

et al. 2019

European Journal of Pharmacology

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The development of effective therapeutics for cancer-induced bone pain (CIBP) remains a tremendous challenge owing to its unclear mechanisms. Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system (CNS). Emerging studies have shown that disinhibition in the spinal cord dorsal horn may account for the development of chronic pain. However, the role of GABA in the development of CIBP remains elusive. In addition, accumulating evidence has shown that neuroglial cells in the peripheral nervous system, especially astrocytes and microglial cells, played an important role in the maintenance of CIBP. In this study, we investigated the expression of GABA and Gamma-aminobutyric acid transporter-1 (GAT-1), a transporter of GABA. Our results demonstrate that GABA was decreased in CIBP rats as expected. However, the expression of glutamic acid decarboxylase (GAD) 65 was up-regulated on day 21 after surgery, while the expression of GAD 67 remained unchanged after surgery. We also found that the expression of GAT-1 was up-regulated mainly in the astrocytes of the spinal cord. Moreover, we evaluated the analgesic effect of exogenous GABA and the GAT-1 inhibitor. Intrathecal administration of exogenous GABA and NO-711 (a GAT-1 selective inhibitor) significantly reversed CIBP-induced mechanical allodynia in a dose-dependent manner. These results firstly show that neuron-glia interactions, especially on the GABAergic pathway, contribute to the development of CIBP. In conclusion, exogenous GABA and GAT-1 inhibitor might be alternative therapeutic strategies for the treatment of CIBP.

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Sinomenine attenuates cancer-induced bone pain via suppressing microglial JAK2/STAT3 and neuronal CAMKII/CREB cascades in rat models

Cited by 47 publications

References 74 publications

STING/NF-κB/IL-6-mediated inflammation in microglia contributes to spared nerve injury (SNI)-induced neuropathic pain

STING/NF-κB/IL-6-mediated inflammation in microglia contributes to spared nerve injury (SNI)-induced neuropathic pain

Phosphoproteomic profiling of oxycodone‑treated spinal cord of rats with cancer‑induced bone pain

The therapeutic potential of GABA in neuron-glia interactions of cancer-induced bone pain

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