scholarly journals Metformin Attenuates Bone Cancer Pain by Reducing TRPV1 and ASIC3 Expression

2021 ◽  
Vol 12 ◽  
Author(s):  
He-Ya Qian ◽  
Fang Zhou ◽  
Rui Wu ◽  
Xiao-Jun Cao ◽  
Tao Zhu ◽  
...  
Keyword(s):  
Cancer Pain ◽  
Mechanical Allodynia ◽  
Intrathecal Injection ◽  
Treatment Strategies ◽  
Bone Cancer ◽  
Current Treatment ◽  
Bone Cancer Pain ◽  
Spinal Dorsal ◽  
Walker 256 ◽  
Von Frey Filaments

Bone cancer pain (BCP) is a common pathologic pain associated with destruction of bone and pathological reconstruction of nervous system. Current treatment strategies in clinical is inadequate and have unacceptable side effects due to the unclear pathology mechanism. In the present study, we showed that transplantation of Walker 256 cells aggravated mechanical allodynia of BCP rats (**p < 0.01 vs. Sham), and the expression of ASIC3 (Acid-sensitive ion channel 3) and TRPV1 was obviously enhanced in L4-6 dorsal root ganglions (DRGs) of BCP rats (**p < 0.01 vs. Sham). ASIC3 and TRPV1 was mainly expressed in CGRP and IB4 positive neurons of L4-6 DRGs. While, TRPV1 but not ASIC3 was markedly upregulated in L4-6 spinal dorsal horn (SDH) of BCP rats (**p < 0.01 vs. Sham). Importantly, intrathecal injection of CPZ (a TRPV1 inhibitor) or Amiloride (an ASICs antagonist) markedly increased the paw withdraw threshold (PWT) of BCP rats response to Von Frey filaments (**p < 0.01 vs. BCP + NS). What’s more, intraperitoneally injection of Metformin or Vinorelbine markedly elevated the PWT of BCP rats, but reduced the expression of TRPV1 and ASIC3 in L4-6 DRGs and decreased the TRPV1 expression in SDH (*p < 0.05, **p < 0.01 vs. BCP + NS). Collectively, these results suggest an effective analgesic effect of Metformin on mechanical allodynia of BCP rats, which may be mediated by the downregulation of ASIC3 and TRPV1.

scholarly journals Inducible Lentivirus-Mediated siRNA against TLR4 Reduces Nociception in a Rat Model of Bone Cancer Pain

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Ruirui Pan ◽  
Huiting Di ◽  
Jinming Zhang ◽  
Zhangxiang Huang ◽  
Yuming Sun ◽  
...  
Keyword(s):  
Cancer Pain ◽  
Pain Treatment ◽  
Intrathecal Injection ◽  
Bone Cancer ◽  
Bone Cancer Pain ◽  
Prolonged Treatment ◽  
Small Interference Rna ◽  
Long Term Treatment ◽  
Walker 256

Although bone cancer pain is still not fully understood by scientists and clinicians alike, studies suggest that toll like receptor 4 (TLR4) plays an important role in the initiation and/or maintenance of pathological pain state in bone cancer pain. A promising treatment for bone cancer pain is the downregulation of TLR4 by RNA interference; however, naked siRNA (small interference RNA) is not effective in long-term treatments. In order to concoct a viable prolonged treatment for bone cancer pain, an inducible lentivirus LvOn-siTLR4 (tetracycline inducible lentivirus carrying siRNA targeting TLR4) was prepared and the antinociception effects were observed in bone cancer pain rats induced by Walker 256 cells injection in left leg. Results showed that LvOn-siTLR4 intrathecal injection with doxycycline (Dox) oral administration effectively reduced the nociception induced by Walker 256 cells while inhibiting the mRNA and protein expression of TLR4. Proinflammatory cytokines as TNF-αand IL-1βin spinal cord were also decreased. These findings suggest that TLR4 could be a target for bone cancer pain treatment and tetracycline inducible lentivirus LvOn-siTLR4 represents a new potential option for long-term treatment of bone cancer pain.

scholarly journals Electroacupuncture Attenuates Morphine Tolerance in Rats with Bone Cancer Pain by Inhibiting PI3K/Akt/JNK1/2 Signaling Pathway in the Spinal Dorsal Horn

2021 ◽  
Vol 20 ◽  
pp. 153473542199523
Author(s):  
Bin Jiang ◽  
Xuemei Zhong ◽  
Junfan Fang ◽  
Aijun Zhang ◽  
Wen WangD ◽  
...  
Keyword(s):  
Protein Expression ◽  
Cancer Pain ◽  
Signaling Pathway ◽  
Dorsal Horn ◽  
Spinal Dorsal Horn ◽  
Intrathecal Injection ◽  
Bone Cancer ◽  
Morphine Tolerance ◽  
Bone Cancer Pain ◽  
Spinal Dorsal

Purpose: Morphine is often used for the treatment of moderate and severe cancer pain, but long-term use can lead to morphine tolerance. Methods for effectively inhibiting morphine tolerance and the related mechanism of action are of great significance for the treatment of cancer pain. Previous studies have shown that electroacupuncture (EA) can inhibit the occurrence of morphine tolerance, but the mechanism is not yet clear. The aim of the present study was to explore the signaling pathway by which EA attenuates the development of bone cancer pain (BCP)-morphine tolerance (MT). Materials and methods: Changes in the paw withdrawal threshold (PWT) of rats with bone cancer pain-morphine tolerance were observed in a study of EA combined with intrathecal injection of a PI3K inhibitor (LY294002) or agonist (insulin-like growth factor-1 [IGF-1]). We also tested the protein expression of phosphorylated phosphatidylinositol 3-kinase (p-PI3K), phosphorylated protein kinase B (p-Akt), phosphorylated c-Jun NH2-terminal kinase 1/2 (p-JNK1/2), and β-arrestin2 in the L4-6 spinal dorsal horn of rats. Results: The protein expression of p-PI3K, p-Akt, p-JNK1/2, and β-arrestin2 was upregulated in the L4-6 spinal dorsal horn of rats with bone cancer pain and bone cancer pain-morphine tolerance. EA delayed the occurrence of morphine tolerance in rats with bone cancer pain and downregulated the protein expression of p-PI3K, p-Akt, p-JNK1/2, and β-arrestin2 in the L4-6 spinal dorsal horn of rats with bone cancer pain-morphine tolerance. Intrathecal injection of LY294002 attenuated the development of morphine tolerance and downregulated the protein expression of p-Akt, p-JNK1/2, and β-arrestin2 in the spinal dorsal horn of rats with bone cancer pain-morphine tolerance. In addition, the inhibitory effect of EA on morphine tolerance was reversed by IGF-1. Conclusion: The mechanism underlying the ability of EA to attenuate morphine tolerance may be associated with inhibition of the PI3K/Akt/JNK1/2 signaling pathway.

scholarly journals Sigma-1 Receptor Antagonist BD1047 Reduces Mechanical Allodynia in a Rat Model of Bone Cancer Pain through the Inhibition of Spinal NR1 Phosphorylation and Microglia Activation

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Shanshan Zhu ◽  
Chenchen Wang ◽  
Yuan Han ◽  
Chao Song ◽  
Xueming Hu ◽  
...  
Keyword(s):  
Cancer Pain ◽  
Receptor Antagonist ◽  
Mechanical Allodynia ◽  
Intrathecal Injection ◽  
Bone Cancer ◽  
Bone Cancer Pain ◽  
Induction Phase ◽  
Sprague Dawley ◽  
Sigma 1 Receptor ◽  
Sigma 1

Previous studies have demonstrated that sigma-1 receptor plays important roles in the induction phase of rodent neuropathic pain; however, whether it is involved in bone cancer pain (BCP) and the underlying mechanisms remain elusive. The aim of this study was to examine the potential role of the spinal sigma-1 receptor in the development of bone cancer pain. Walker 256 mammary gland carcinoma cells were implanted into the intramedullary space of the right tibia of Sprague-Dawley rats to induce ongoing bone cancer-related pain behaviors; our findings indicated that, on days 7, 10, 14, and 21 after operation, the expression of sigma-1 receptor in the spinal cord was higher in BCP rats compared to the sham rats. Furthermore, intrathecal injection of 120 nmol of sigma-1 receptor antagonist BD1047 on days 5, 6, and 7 after operation attenuated mechanical allodynia as well as the associated induction of c-Fos and activation of microglial cells, NR1, and the subsequent Ca2+-dependent signals of BCP rats. These results suggest that sigma-1 receptor is involved in the development of bone cancer pain and that targeting sigma-1 receptor may be a new strategy for the treatment of bone cancer pain.

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.

Connexin 43 Mediates CXCL12 Production from Spinal Dorsal Horn to Maintain Bone Cancer Pain in Rats

2015 ◽  
Vol 41 (5) ◽  
pp. 1200-1208 ◽  
Author(s):  
Li-Hua Hang ◽  
Shu-Na Li ◽  
Hong Luo ◽  
Wei-Wei Shu ◽  
Zu-Min Mao ◽  
...  
Keyword(s):  
Cancer Pain ◽  
Dorsal Horn ◽  
Connexin 43 ◽  
Spinal Dorsal Horn ◽  
Bone Cancer ◽  
Bone Cancer Pain ◽  
Spinal Dorsal
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