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

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

Neurochemical Research ◽

10.1007/s11064-015-1815-7 ◽

2015 ◽

Vol 41 (5) ◽

pp. 1200-1208 ◽

Cited By ~ 20

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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Suppression of histone deacetylases by SAHA relieves bone cancer pain in rats via inhibiting activation of glial cells in spinal dorsal horn and dorsal root ganglia

Journal of Neuroinflammation ◽

10.1186/s12974-020-01740-5 ◽

2020 ◽

Vol 17 (1) ◽

Author(s):

Xiao-Tao He ◽

Xiao-Fan Hu ◽

Chao Zhu ◽

Kai-Xiang Zhou ◽

Wen-Jun Zhao ◽

...

Keyword(s):

Cancer Pain ◽

Dorsal Horn ◽

Glial Cells ◽

Dorsal Root Ganglia ◽

Histone Deacetylases ◽

Dorsal Root ◽

Spinal Dorsal Horn ◽

Bone Cancer ◽

Bone Cancer Pain ◽

Spinal Dorsal

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The analgesic effects of pioglitazone in the bone cancer pain rats via regulating the PPARγ/PTEN/mTOR signaling pathway in the spinal dorsal horn

Biomedicine & Pharmacotherapy ◽

10.1016/j.biopha.2020.110692 ◽

2020 ◽

Vol 131 ◽

pp. 110692 ◽

Cited By ~ 1

Author(s):

Wei Gu ◽

Yu’e Sun ◽

Wanjie Gu ◽

Yulin Huang ◽

Jinhua Bo ◽

...

Keyword(s):

Cancer Pain ◽

Signaling Pathway ◽

Dorsal Horn ◽

Spinal Dorsal Horn ◽

Bone Cancer ◽

Mtor Signaling ◽

Bone Cancer Pain ◽

Mtor Signaling Pathway ◽

Analgesic Effects ◽

Spinal Dorsal

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

Integrative Cancer Therapies ◽

10.1177/1534735421995237 ◽

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.

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