scholarly journals Transcriptional regulation of voltage-gated sodium channels contributes to GM-CSF induced pain

2018 ◽  
Author(s):  
Fan Zhang ◽  
Yiying Wang ◽  
Dandan Zhang ◽  
Xizhenzi Fan ◽  
Hao Han ◽  
...  
Keyword(s):  
Cancer Pain ◽  
Thermal Hyperalgesia ◽  
Bone Cancer ◽  
Bone Cancer Pain ◽  
Drg Neurons ◽  
Voltage Gated ◽  
Gm Csf ◽  
Damage Sensing ◽  
Voltage Gated Sodium Channels ◽  
Macrophage Populations

AbstractGranolocyte-macrophage colony stimulating factor (GM-CSF) induces production of granulocyte and macrophage populations from the hematopoietic progenitor cells; it is one of the most common growth factors in the blood. GM-CSF is also involved in bone cancer pain development by regulating tumor-nerve interactions, remodeling of peripheral nerves and sensitization of damage-sensing (nociceptive) nerves. However, the precise mechanism for GM-CSF-dependent pain is unclear. In this study, we found that GM-CSF is highly expressed in human malignant osteosarcoma. Rats implanted with bone cancer cells develop mechanical and thermal hyperalgesia but antagonizing GM-CSF in these animals significantly reduced such hypersensitivity. Nociceptor-specific voltage gated Na+channels Nav1.7, Nav1.8 and Nav1.9 were found to be selectively up-regulated in rat DRG neurons treated with GM-CSF, which resulted in enhanced excitability. GM-CSF activated the Jak2 and Stat3 signaling pathway which promoted the transcription of Nav1.7-1.9 in DRG neurons. Accordingly targeted knocking down either Nav1.7-1.9 or Jak2/Stat3 in DRG neurons alleviated the hyperalgesia in rats. Our findings describe a new bone cancer pain mechanism and provide a new insight into the physiological and pathological functions of GM-CSF.

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

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
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.

scholarly journals Preconditioning with hydrogen sulfide prevents bone cancer pain in rats through a proliferator-activated receptor gamma/p38/Jun N-terminal kinase pathway

2017 ◽  
Vol 243 (1) ◽  
pp. 57-65 ◽  
Author(s):  
Li Zhuang ◽  
Ke Li ◽  
Gaowei Wang ◽  
Tao Shou ◽  
Chunlin Gao ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Cancer Pain ◽  
Rat Model ◽  
Mechanical Allodynia ◽  
Antinociceptive Effect ◽  
Thermal Hyperalgesia ◽  
Bone Cancer ◽  
Bone Cancer Pain ◽  
Kinase Pathway

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.

scholarly journals Up-regulation of PKCγ subunits of rACC neurons contributes to the development of pain sensitivity in bone cancer rats

2019 ◽  
Author(s):  
Meng She ◽  
Hao Feng ◽  
Zequn Feng ◽  
Gongming Wang ◽  
Guanghui Cheng ◽  
...  
Keyword(s):  
Cancer Pain ◽  
Western Blotting ◽  
Mechanical Allodynia ◽  
Sham Group ◽  
Lentiviral Vector ◽  
Thermal Hyperalgesia ◽  
Bone Cancer ◽  
Bone Cancer Pain ◽  
Vehicle Group ◽  
Vector Group

Abstract To explore the role of PKCγ subunits of rostral anterior cingulate cortex (rACC) neurons in the development of bone cancer pain in rats. Healthy female Sprague-Dawley rats were randomly divided into five groups: blank control group (naive group), sham operation group (sham group), bone cancer pain group (BCP group), BCP plus empty lentiviral vector group (vehicle group) and BCP plus PKCγ/shRNA recombinant lentiviral vector group (PKCγ group). The BCP group, vehicle group and PKCγ group received a 10 µl intra-tibial injection of MADB-106 rat mammary carcinoma cell suspension (4.6×10 8 cell/ml). In comparison, the sham group received a 10 µl intra-tibial injection of saline. The mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were assessed on pre-operation day 0 (baseline) and days 3, 7, 14 and 21 after intra-tibial injection, respectively. To downregulate the PKCγ subunits of rACC neurons, the PKCγ group received a 10 µl bilateral rACC injection of shRNA/PKCγ recombinant lentivirus (1.25×10 9 TU/ml) on the day 7 after intra-tibial injection, whereas the vehicle group received an injection of the same dose of empty lentiviral vector. Western blotting, immunohistochemical and immunofluorescence analysis were performed to detect the different expression of PKCγ subunits in rACC neurons among these groups on postoperative days 7 or 21. No significant difference in the baseline of MWT and TWL was found among these five groups ( P > 0.05). However, compared with the naive group and sham group, the rats with bone cancer (BCP group, vehicle group and PKCγ group) demonstrated marked mechanical allodynia and thermal hyperalgesia that was evoked starting on postoperative day 7 following intra-tibial injection of carcinoma cells ( P < 0.05). Meanwhile, the western blotting analysis also confirmed that the expression of PKCγ in rACC neurons was significantly increased in the BCP model groups ( P < 0.05). However, from postoperative days 14-21, the injection of shRNA/PKCγ recombinant lentivirus in the PKCγ group alleviated mechanical allodynia and thermal hyperalgesia ( P < 0.05).The present study indicates that up-regulation of PKCγ subunits of rACC neurons in bone cancer pain rats contributes to the development of bone cancer pain.

scholarly journals Radiotherapy Suppresses Bone Cancer Pain through Inhibiting Activation of cAMP Signaling in Rat Dorsal Root Ganglion and Spinal Cord

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Guiqin Zhu ◽  
Yanbin Dong ◽  
Xueming He ◽  
Ping Zhao ◽  
Aixing Yang ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Dorsal Root Ganglion ◽  
Cancer Pain ◽  
Signaling Pathway ◽  
Dorsal Root ◽  
Mechanical Allodynia ◽  
Thermal Hyperalgesia ◽  
Bone Cancer ◽  
Bone Cancer Pain ◽  
Sprague Dawley

Radiotherapy is one of the major clinical approaches for treatment of bone cancer pain. Activation of cAMP-PKA signaling pathway plays important roles in bone cancer pain. Here, we examined the effects of radiotherapy on bone cancer pain and accompanying abnormal activation of cAMP-PKA signaling. Female Sprague-Dawley rats were used and received tumor cell implantation (TCI) in rat tibia (TCI cancer pain model). Some of the rats that previously received TCI treatment were treated with X-ray radiation (radiotherapy). Thermal hyperalgesia and mechanical allodynia were measured and used for evaluating level of pain caused by TCI treatment. PKA mRNA expression in dorsal root ganglion (DRG) was detected by RT-PCR. Concentrations of cAMP, IL-1β, and TNF-αas well as PKA activity in DRG and the spinal cord were measured by ELISA. The results showed that radiotherapy significantly suppressed TCI-induced thermal hyperalgesia and mechanical allodynia. The level of PKA mRNA in DRG, cAMP concentration and PKA activity in DRG and in the spinal cord, and concentrations of IL-1βand TNF-αin the spinal cord were significantly reduced by radiotherapy. In addition, radiotherapy also reduced TCI-induced bone loss. These findings suggest that radiotherapy may suppress bone cancer pain through inhibition of activation of cAMP-PKA signaling pathway in DRG and the spinal cord.

scholarly journals Curcumin Exerts Antinociceptive Effects in Cancer-Induced Bone Pain via an Endogenous Opioid Mechanism

2021 ◽  
Vol 15 ◽  
Author(s):  
Guanghai Zhao ◽  
Yongqiang Shi ◽  
Chaoyang Gong ◽  
Taicong Liu ◽  
Wei Nan ◽  
...  
Keyword(s):  
Cancer Pain ◽  
Bone Pain ◽  
Antinociceptive Effect ◽  
Bone Cancer ◽  
Bone Cancer Pain ◽  
Drg Neurons ◽  
Advanced Cancer Patients ◽  
Endogenous Opioid ◽  
Analgesic Effects ◽  
Antinociceptive Effects

Cancer pain is one of the main complications in advanced cancer patients, and its management is still challenging. Therefore, there is an urgent need to develop novel pharmacotherapy for cancer pain. Several natural products have attracted the interest of researchers. In previous studies, curcumin has proved to exhibit antitumor, antiviral, antioxidant, anti-inflammatory, and analgesic effects. However, the analgesic mechanism of curcumin has not been elucidated. Thus, in this study, we aimed to elucidate the antinociceptive potency and analgesic mechanism of curcumin in cancer-induced bone pain. Our results showed that consecutive curcumin treatment (30, 60, 120 mg/kg, i.p., twice daily for 11 days) produced significant analgesic activity, but had no effect on the progress of the bone cancer pain. Notably, pretreatment with naloxone, a non-selective opioid receptor antagonist, markedly reversed the antinociceptive effect induced by curcumin. Moreover, in primary cultured rat dorsal root ganglion (DRG) neurons, curcumin significantly up-regulated the expression of proopiomelanocortin (Pomc) and promoted the release of β-endorphin and enkephalin. Furthermore, pretreatment with the antiserum of β-endorphin or enkephalin markedly attenuated curcumin-induced analgesia in cancer-induced bone pain. Our present study, for the first time, showed that curcumin attenuates cancer-induced bone pain. The results also suggested that stimulation of expression of DRG neurons β-endorphin and enkephalin mediates the antinociceptive effect of curcumin in pain hypersensitivity conditions.

scholarly journals Intrathecal Injection of Metabotropic Glutamate Receptor Subtype 3 and 5 Agonist/Antagonist Attenuates Bone Cancer Pain by Inhibition of Spinal Astrocyte Activation in a Mouse Model

2012 ◽  
Vol 116 (1) ◽  
pp. 122-132 ◽  
Author(s):  
Bing-xu Ren ◽  
Xiao-ping Gu ◽  
Ya-guo Zheng ◽  
Cheng-long Liu ◽  
Dan Wang ◽  
...  
Keyword(s):  
Glial Fibrillary Acidic Protein ◽  
Protein Expression ◽  
Cancer Pain ◽  
Thermal Hyperalgesia ◽  
Bone Cancer ◽  
Acidic Protein ◽  
Bone Cancer Pain ◽  
Spontaneous Pain ◽  
Astrocyte Activation ◽  
Metabotropic Glutamate

Background Astrocytes and metabotropic glutamate receptors play important roles in nociceptive processing. However, their roles in bone cancer pain were not well understood. This study sought to investigate whether selective mGluR3 and mGluR5 agonist or antagonist develop antinociceptive effects on bone cancer pain by inhibition of spinal astrocyte activation. Methods C3H/HeNCrlVr mice were inoculated into the intramedullary space of the femur with sarcoma NCTC 2472 cells to induce bone cancer pain. Quantitative real-time reverse transcription-polymerase chain reaction and Western blot experiments examined messenger RNA and protein expression of spinal glial fibrillary acidic protein, mGluR3, and mGluR5. The authors further investigated effects of intrathecal treatment with the mGluR3 agonist (APDC), the mGluR3 antagonist (LY341495), the mGluR5 agonist (CHPG), or the mGluR5 antagonist (MTEP) on nociceptive behaviors and spinal astrocyte activation associated with bone cancer pain. Results Inoculation of sarcoma cells, but not α-MEM solution, induced progressive bone cancer pain and resulted in up-regulation of glial fibrillary acidic protein, mGluR3, and mGluR5 expression on days 10, 14, and 21 postinoculation. Intrathecal administration of APDC and MTEP attenuated bone cancer-evoked spontaneous pain, mechanical allodynia, thermal hyperalgesia, and reduced spinal glial fibrillary acidic protein expression. However, treatment with LY341495 and CHPG induced thermal hyperalgesia and spinal glial fibrillary acidic protein expression in control mice. Conclusions Spinal mGluR3 activation or mGluR5 inhibition reduced bone cancer pain. Inhibition of spinal astrocyte activation may contribute to the analgesic effects. These findings may lead to novel strategies for the treatment of bone cancer pain.

scholarly journals Up-regulation of PKCγ subunits of rACC neurons contributes to the development of pain sensitivity in bone cancer rats

2019 ◽  
Author(s):  
Meng She ◽  
Hao Feng ◽  
Zequn Feng ◽  
Gongming Wang ◽  
Guanghui Cheng ◽  
...  
Keyword(s):  
Cancer Pain ◽  
Western Blotting ◽  
Mechanical Allodynia ◽  
Sham Group ◽  
Lentiviral Vector ◽  
Thermal Hyperalgesia ◽  
Bone Cancer ◽  
Bone Cancer Pain ◽  
Vehicle Group ◽  
Vector Group

Abstract To explore the role of PKCγ subunits of rostral anterior cingulate cortex (rACC) neurons in the development of bone cancer pain in rats. Healthy female Sprague-Dawley rats were randomly divided into five groups: blank control group (naive group), sham operation group (sham group), bone cancer pain group (BCP group), BCP plus empty lentiviral vector group (vehicle group) and BCP plus PKCγ/shRNA recombinant lentiviral vector group (PKCγ group). The BCP group, vehicle group and PKCγ group received a 10 µl intra-tibial injection of MADB-106 rat mammary carcinoma cell suspension (4.6×10 8 cell/ml). In comparison, the sham group received a 10 µl intra-tibial injection of saline. The mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were assessed on pre-operation day 0 (baseline) and days 3, 7, 14 and 21 after intra-tibial injection, respectively. To downregulate the PKCγ subunits of rACC neurons, the PKCγ group received a 10 µl bilateral rACC injection of shRNA/PKCγ recombinant lentivirus (1.25×10 9 TU/ml) on the day 7 after intra-tibial injection, whereas the vehicle group received an injection of the same dose of empty lentiviral vector. Western blotting, immunohistochemical and immunofluorescence analysis were performed to detect the different expression of PKCγ subunits in rACC neurons among these groups on postoperative days 7 or 21. No significant difference in the baseline of MWT and TWL was found among these five groups ( P > 0.05). However, compared with the naive group and sham group, the rats with bone cancer (BCP group, vehicle group and PKCγ group) demonstrated marked mechanical allodynia and thermal hyperalgesia that was evoked starting on postoperative day 7 following intra-tibial injection of carcinoma cells ( P < 0.05). Meanwhile, the western blotting analysis also confirmed that the expression of PKCγ in rACC neurons was significantly increased in the BCP model groups ( P < 0.05). However, from postoperative days 14-21, the injection of shRNA/PKCγ recombinant lentivirus in the PKCγ group alleviated mechanical allodynia and thermal hyperalgesia ( P < 0.05).The present study indicates that up-regulation of PKCγ subunits of rACC neurons in bone cancer pain rats contributes to the development of bone cancer pain.

scholarly journals The TRPA1 Channel Mediates Mechanical Allodynia and Thermal Hyperalgesia in a Rat Bone Cancer Pain Model

2021 ◽  
Vol 2 ◽  
Author(s):  
Qiangwei Liu ◽  
Long Feng ◽  
Xiujing Han ◽  
Weidong Zhang ◽  
Hong Zhang ◽  
...  
Keyword(s):  
Protein Expression ◽  
Cancer Pain ◽  
Mechanical Allodynia ◽  
Sham Group ◽  
Thermal Hyperalgesia ◽  
Bone Cancer ◽  
Bone Cancer Pain ◽  
Left Tibia ◽  
Withdrawal Threshold ◽  
Mrna And Protein Expression

Background: Bone cancer pain (BCP) significantly affects patient quality of life, results in great bodily and emotional pain, and creates difficulties in follow-up treatment and normal life. Transient receptor potential ankyrin 1 (TRPA1) is an essential transduction ion channel related to neuropathic and inflammatory pain. However, the role of TRPA1 in BCP remains poorly understood. This study aimed to explore the relationship between TRPA1 and BCP.Methods: A BCP model was induced by Walker256 cells to the left tibia. The sham group was induced by normal saline to the left tibia. Thereafter, pain behaviors and TRPA1 expression between the BCP group and the sham group were observed on the 14th day of modeling. The TRPA1 antagonist A967079 (10 mg/kg) was injected via tail vein. TRPA1 antisense oligodeoxynucleotide (AS-ODN, 5 nmol/10 μl) and missense oligodeoxynucleotide (MS-ODN, 5 nmol/10 μl) were intrathecally delivered via a mini-osmotic pump for 5 consecutive days to assess the effect of TRPA1 on BCP. Behavioral tests were assessed preoperatively and postoperatively. Real-time quantitative PCR and western blot analyses were used to measure TRPA1 levels among the different groups.Results: The BCP model was successfully established via X-ray and pathological sections at 14 days. Compared to the sham group, the BCP group was more sensitive to mechanical stimuli, cool stimuli and hot stimuli. Intravenously injected A967079 can relieve paw mechanical withdrawal threshold and paw withdrawal thermal latency in rats with BCP. Moreover, AS-ODN can relieve paw mechanical withdrawal threshold and paw withdrawal thermal latency in rats with BCP. Additionally, relative mRNA and protein expression of TRPA1 in the BCP group were much higher than those in the sham group (14.55 ± 1.97 vs. 1 ± 0.04, P &lt; 0.01). Compared to the BCP group, the relative mRNA and protein expression of TRPA1 in the BCP+AS-ODN group was reduced (14.55 ± 1.97 vs. 2.59 ± 0.34, P &lt; 0.01).Conclusions: The TRPA1 channel mediates mechanical allodynia and thermal hyperalgesia in a rat BCP model.

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