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.

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

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

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.

scholarly journals Upregulation of Spinal ASIC1 and NKCC1 Expression Contributes to Chronic Visceral Pain in Rats

2021 ◽  
Vol 13 ◽  
Author(s):  
Yong-Chang Li ◽  
Yuan-Qing Tian ◽  
Yan-Yan Wu ◽  
Yu-Cheng Xu ◽  
Ping-An Zhang ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Signaling Pathway ◽  
Dorsal Horn ◽  
Spinal Dorsal Horn ◽  
Visceral Pain ◽  
Intrathecal Injection ◽  
Adult Rats ◽  
Sodium Potassium ◽  
Spinal Dorsal ◽  
Whole Cell Patch Clamp

Aims: To determine whether acid-sensing ion channel 1 (ASIC1)–sodium-potassium-chloride cotransporter 1 (NKCC1) signaling pathway participates in chronic visceral pain of adult rats with neonatal maternal deprivation (NMD).Methods: Chronic visceral pain was detected by colorectal distension (CRD). Western blotting and Immunofluorescence were performed to detect the expression and location of ASIC1 and NKCC1. Whole-cell patch-clamp recordings were performed to record spinal synaptic transmission.Results: The excitatory synaptic transmission was enhanced and the inhibitory synaptic transmission was weakened in the spinal dorsal horn of NMD rats. ASIC1 and NKCC1 protein expression in the spinal dorsal horn was significantly up-regulated in NMD rats. Incubation of Amiloride reduced the amplitude of mEPSCs. Incubation of Bumetanide (BMT) increased the amplitude of mIPSCs. Intrathecal injection of ASIC1 or NKCC1 inhibitors reversed the threshold of CRD in NMD rats. Also, Amiloride treatment significantly reversed the expression of NKCC1 in the spinal dorsal horn of NMD rats.Conclusion: Our data suggest that the ASIC1-NKCC1 signaling pathway is involved in chronic visceral pain in NMD rats.

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.

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