Analgesic effect of dexmedetomidine in rats after chronic constriction injury by mediating microRNA-101 expression and the E2F2-TLR4-NF-κB axis.
E2F2
TLR4/NF-κB signalling
chronic constriction injury
dexmedetomidine
microRNA-101
neuropathic pain
Journal
Experimental physiology
ISSN: 1469-445X
Titre abrégé: Exp Physiol
Pays: England
ID NLM: 9002940
Informations de publication
Date de publication:
09 2020
09 2020
Historique:
received:
04
03
2020
accepted:
23
07
2020
pubmed:
25
7
2020
medline:
21
10
2021
entrez:
25
7
2020
Statut:
ppublish
Résumé
What is the central question of this study? Dexmedetomidine has a capacity for sedation, anti-anxiety and analgesia with minimal suppression of respiratory function; what is its role in neuropathic pain and what is the involvement of miRNAs? What is the main finding and its importance? Dexmedetomidine attenuates inflammation and apoptosis and the stimulation of TLR4-NF-κB signalling in rat spinal cord via miR-101 overexpression and E2F2 downregulation. The significant analgesic effect of dexmedetomidine (Dex) has been underscored in neuropathic pain (NPP), but the underlying mechanism remains unclear. This study explored the functional effect of Dex on microRNA (miR)-101-regulated E2 promoter binding factor 2 (E2F2) with the engagement of Toll-like receptor 4 (TLR4)-nuclear factor-κB (NF-κB) signalling. Chronic constriction injury (CCI) was performed to generate an NPP rat model. The expression of miR-101, E2F2 and TLR4-NF-κB signalling-relevant proteins was assessed by RT-quantitative PCR, immunoblotting and immunohistochemistry. Inflammatory factors were detected by enzyme-linked immunosorbent assay. The results showed that Dex increased mechanical withdrawal threshold and thermal latency to withdraw. The expression of interleukin (IL)-6, IL-8 and tumour necrosis factor-α was increased in CCI rats, but these trends were reversed by Dex. In addition, Dex repressed caspase-9 expression and apoptotic cell numbers in spinal cord tissues in CCI rats. Moreover, the expression of E2F2 was significantly increased, while miR-101 was diminished in CCI rats, which was reversed by Dex. Furthermore, miR-101 inhibitor, E2F2 restoration or administration of a TLR4-specific agonist weakened the effect of Dex. Together, these results suggest that Dex has the capacity to ameliorate NPP by regulating the miR-101-E2F2-TLR4-NF-κB axis in rats subjected to CCI.
Substances chimiques
Analgesics
0
E2F2 Transcription Factor
0
MIRN101 microRNA, rat
0
MicroRNAs
0
NF-kappa B
0
Tlr4 protein, rat
0
Toll-Like Receptor 4
0
Dexmedetomidine
67VB76HONO
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1588-1597Informations de copyright
© 2020 The Authors. Experimental Physiology © 2020 The Physiological Society.
Références
Allegri, M., Baron, R., Hans, G., Correa-Illanes, G., Mayoral Rojals, V., Mick, G., & Serpell, M. (2016). A pharmacological treatment algorithm for localized neuropathic pain. Current Medical Research and Opinion, 32, 377-384.
Bennett, G. J., & Xie, Y. K. (1988). A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain, 33, 87-107.
Christianson, C. A., Dumlao, D. S., Stokes, J. A., Dennis, E. A., Svensson, C. I., Corr, M., & Yaksh, T. L. (2011). Spinal TLR4 mediates the transition to a persistent mechanical hypersensitivity after the resolution of inflammation in serum-transferred arthritis. Pain, 152, 2881-2891.
Cowie, A. M., Dittel, B. N., & Stucky, C. L. (2019). A novel sex-dependent target for the treatment of postoperative pain: The NLRP3 inflammasome. Frontiers in Neurology, 10, 622.
Dai, D., Wang, J., Jiang, Y., Yuan, L., Lu, Y., Zhang, A., … Chen, X. (2019). Small RNA sequencing reveals microRNAs related to neuropathic pain in rats. Brazilian Journal of Medical and Biological Research, 52, e8380.
Ebersberger, A. (2018). The analgesic potential of cytokine neutralization with biologicals. European Journal of Pharmacology, 835, 19-30.
Gilron, I., & Dickenson, A. H. (2014). Emerging drugs for neuropathic pain. Expert Opinion on Emerging Drugs, 19, 329-341.
Gu, J., Chen, J., Xia, P., Tao, G., Zhao, H., & Ma, D. (2011). Dexmedetomidine attenuates remote lung injury induced by renal ischemia-reperfusion in mice. Acta Anaesthesiologica Scandinavica, 55, 1272-1278.
Huang, T., Yang, J., Zhang, J., Ke, W., Zou, F., Wan, C., … Zheng, H. (2020). MiR-101-3p down-regulates TLR2 expression, leading to reduction in cytokines production by Treponema pallidum-stimulated macrophages. Journal of Investigative Dermatology, 140, 1566-1575.e1.
Ji, D., Zhou, Y., Li, S., Li, D., Chen, H., Xiong, Y., … Xu, H. (2017). Anti-nociceptive effect of dexmedetomidine in a rat model of monoarthritis via suppression of the TLR4/NF-κB p65 pathway. Experimental and Therapeutic Medicine, 14, 4910-4918.
Kong, Q., Wu, X., Qiu, Z., Huang, Q., Xia, Z., & Song, X. (2020). Protective effect of dexmedetomidine on acute lung injury via the upregulation of tumour necrosis factor-α-induced protein-8-like 2 in septic mice. Inflammation, 43, 833-846.
Kopaladze, R. A. (2000). [Methods for the euthanasia of experimental animals-the ethics, esthetics and personnel safety]. Uspekhi Fiziologicheskikh Nauk, 31, 79-90.
Lei, S., Lu, P., Lu, Y., Zheng, J., Li, W., Wang, N., … Zhang, P. (2020). Dexmedetomidine alleviates neurogenesis damage following neonatal midazolam exposure in rats through JNK and P38 MAPK pathways. ACS Chemical Neuroscience, 11, 579-591.
Li, X., Wang, J., Wang, Z., Dong, C., Dong, X., Jing, Y., … Fan, G. (2008). Tumor necrosis factor-α of red nucleus involved in the development of neuropathic allodynia. Brain Research Bulletin, 77, 233-236.
Liu, X. M., Chen, Q. H., Hu, Q., Liu, Z., Wu, Q., Liang, S. S., … Zhang, X. K. (2020). Dexmedetomidine protects intestinal ischemia-reperfusion injury via inhibiting p38 MAPK cascades. Experimental and Molecular Pathology, 115, 104444.
Mai, L., Zhu, X., Huang, F., He, H., & Fan, W. (2020). p38 mitogen-activated protein kinase and pain. Life Sciences, 256, 117885.
Nagakura, Y., Takahashi, M., Noto, T., Sekizawa, T., Oe, T., Yoshimi, E., … Shimizu, Y. (2012). Different pathophysiology underlying animal models of fibromyalgia and neuropathic pain: Comparison of reserpine-induced myalgia and chronic constriction injury rats. Behavioural Brain Research, 226, 242-249.
Nwachukwu, C., Idehen, H. O., Edomwonyi, N. P., & Umeh, B. (2020). Postoperative analgesic effect of intrathecal dexmedetomidine on bupivacaine subarachnoid block for open reduction and internal fixation of femoral fractures. Nigerian Journal of Clinical Practice, 23, 172-178.
Pei, W., Zou, Y., Wang, W., Wei, L., Zhao, Y., & Li, L. (2018). Tizanidine exerts anti-nociceptive effects in spared nerve injury model of neuropathic pain through inhibition of TLR4/NF-κB pathway. International Journal of Molecular Medicine, 42, 3209-3219.
Percie du Sert, N., & Rice, A. S. (2014). Improving the translation of analgesic drugs to the clinic: Animal models of neuropathic pain. British Journal of Pharmacology, 171, 2951-2963.
Salat, K., Gryzlo, B., & Kulig, K. (2018). Experimental drugs for neuropathic pain. Current Neuropharmacology, 16, 1193-1209.
Schnabel, A., Meyer-Friessem, C. H., Reichl, S. U., Zahn, P. K., & Pogatzki-Zahn, E. M. (2013). Is intraoperative dexmedetomidine a new option for postoperative pain treatment? A meta-analysis of randomized controlled trials. Pain, 154, 1140-1149.
Siniscalco, D., Fuccio, C., Giordano, C., Ferraraccio, F., Palazzo, E., Luongo, L., … de Novellis, V. (2007). Role of reactive oxygen species and spinal cord apoptotic genes in the development of neuropathic pain. Pharmacological Research, 55, 158-166.
Sun, T., Song, W. G., Fu, Z. J., Liu, Z. H., Liu, Y. M., & Yao, S. L. (2006). Alleviation of neuropathic pain by intrathecal injection of antisense oligonucleotides to p65 subunit of NF-κB. British Journal of Anaesthesia, 97, 553-558.
Tang, C., & Xia, Z. (2017). Dexmedetomidine in perioperative acute pain management: A non-opioid adjuvant analgesic. Journal of Pain Research, 10, 1899-1904.
Vilardo, E., Barbato, C., Ciotti, M., Cogoni, C., & Ruberti, F. (2010). MicroRNA-101 regulates amyloid precursor protein expression in hippocampal neurons. Journal of Biological Chemistry, 285, 18344-18351.
Wang, N., & Wang, M. (2019). Dexmedetomidine suppresses sevoflurane anesthesia-induced neuroinflammation through activation of the PI3K/Akt/mTOR pathway. BMC Anesthesiology, 19, 134.
Wang, S., Wang, L., Wu, C., Sun, S., & Pan, J. H. (2018). E2F2 directly regulates the STAT1 and PI3K/AKT/NF-κB pathways to exacerbate the inflammatory phenotype in rheumatoid arthritis synovial fibroblasts and mouse embryonic fibroblasts. Arthritis Research & Therapy, 20, 225.
Weerink, M. A. S., Struys, M., Hannivoort, L. N., Barends, C. R. M., Absalom, A. R., & Colin, P. (2017). Clinical pharmacokinetics and pharmacodynamics of dexmedetomidine. Clinical Pharmacokinetics, 56, 893-913.
Wu, J., Sabirzhanov, B., Stoica, B. A., Lipinski, M. M., Zhao, Z., Zhao, S., … Faden, A. I. (2015). Ablation of the transcription factors E2F1-2 limits neuroinflammation and associated neurological deficits after contusive spinal cord injury. Cell Cycle, 14, 3698-3712.
Xie, T., Zhang, J., Kang, Z., Liu, F., & Lin, Z. (2019). miR-101 down-regulates mTOR expression and attenuates neuropathic pain in chronic constriction injury rat models. Neuroscience Research, 10.1016/j.neures.2019.09.002. Published online ahead of print.
Xu, L., Liu, Y., Sun, Y., Li, H., Mi, W., & Jiang, Y. (2018). Analgesic effects of TLR4/NF-κB signaling pathway inhibition on chronic neuropathic pain in rats following chronic constriction injury of the sciatic nerve. Biomedicine & Pharmacotherapy, 107, 526-533.
Xun, S., & Zheng, R. (2020). Dexmedetomidine alleviates neuropathic pain by regulating JAK/STAT pathway in rats. Journal of Cellular Biochemistry, 121, 2277-2283.
Yang, H., Wu, L., Deng, H., Chen, Y., Zhou, H., Liu, M., … Lv, X. (2020). Anti-inflammatory protein TSG-6 secreted by bone marrow mesenchymal stem cells attenuates neuropathic pain by inhibiting the TLR2/MyD88/NF-κB signaling pathway in spinal microglia. Journal of Neuroinflammation, 17, 154.
Yang, I. V., Alper, S., Lackford, B., Rutledge, H., Warg, L. A., Burch, L. H., & Schwartz, D. A. (2011). Novel regulators of the systemic response to lipopolysaccharide. American Journal of Respiratory Cell and Molecular Biology, 45, 393-402.
Yang, X., Chen, H., Chen, Y., Birnbaum, Y., Liang, R., Ye, Y., & Qian, J. (2018). Circulating miRNA expression profiling and target prediction in patients receiving dexmedetomidine. Cellular Physiology and Biochemistry, 50, 552-568.
Zatroch, K. K., Knight, C. G., Reimer, J. N., & Pang, D. S. (2017). Refinement of intraperitoneal injection of sodium pentobarbital for euthanasia in laboratory rats (Rattus norvegicus). BMC Veterinary Research, 13, 60.
Zhao, L., Zhai, M., Yang, X., Guo, H., Cao, Y., Wang, D., … Liu, C. (2019). Dexmedetomidine attenuates neuronal injury after spinal cord ischaemia-reperfusion injury by targeting the CNPY2-endoplasmic reticulum stress signalling. Journal of Cellular and Molecular Medicine, 23, 8173-8183.
Zhao, Y., & Ai, Y. (2019). Knockdown of lncRNA MALAT1 alleviates bupivacaine-induced neurotoxicity via the miR-101-3p/PDCD4 axis. Life Sciences, 232, 116606.
Zhao, Y. X., Yao, M. J., Liu, Q., Xin, J. J., Gao, J. H., & Yu, X. C. (2020). Electroacupuncture treatment attenuates paclitaxel-induced neuropathic pain in rats via inhibiting spinal glia and the TLR4/NF-κB pathway. Journal of Pain Research, 13, 239-250.