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Inhibition of MicroRNA-15a/16 Expression Alleviates Neuropathic Pain Development through Upregulation of G Protein-Coupled Receptor Kinase 2  

Li, Tao (Department of Anesthesiology, China-Japan Union Hospital, Jilin University)
Wan, Yingchun (Department of Endocrinology, China-Japan Union Hospital, Jilin University)
Sun, Lijuan (Department of Endocrinology, China-Japan Union Hospital, Jilin University)
Tao, Shoujun (Department of Anesthesiology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine)
Chen, Peng (Department of Anesthesiology, China-Japan Union Hospital, Jilin University)
Liu, Caihua (Department of Anaesthesiology, The Central Hospital of Wuhan Affiliated with Tongji Medical College of Huazhong University of Science and Technology)
Wang, Ke (Department of Gynaecology and Obstetrics, China-Japan Union Hospital, Jilin University)
Zhou, Changyu (Department of Gastroenterology, China-Japan Union Hospital, Jilin University)
Zhao, Guoqing (Department of Anesthesiology, China-Japan Union Hospital, Jilin University)
Publication Information
Biomolecules & Therapeutics / v.27, no.4, 2019 , pp. 414-422 More about this Journal
There is accumulating evidence that microRNAs are emerging as pivotal regulators in the development and progression of neuropathic pain. MicroRNA-15a/16 (miR-15a/16) have been reported to play an important role in various diseases and inflammation response processes. However, whether miR-15a/16 participates in the regulation of neuroinflammation and neuropathic pain development remains unknown. In this study, we established a mouse model of neuropathic pain by chronic constriction injury (CCI) of the sciatic nerves. Our results showed that both miR-15a and miR-16 expression was significantly upregulated in the spinal cord of CCI rats. Downregulation of the expression of miR-15a and miR-16 by intrathecal injection of a specific inhibitor significantly attenuated the mechanical allodynia and thermal hyperalgesia of CCI rats. Furthermore, inhibition of miR-15a and miR-16 downregulated the expression of interleukin-$1{\beta}$ and tumor-necrosis factor-${\alpha}$ in the spinal cord of CCI rats. Bioinformatic analysis predicted that G protein-coupled receptor kinase 2 (GRK2), an important regulator in neuropathic pain and inflammation, was a potential target gene of miR-15a and miR-16. Inhibition of miR-15a and miR-16 markedly increased the expression of GRK2 while downregulating the activation of p38 mitogen-activated protein kinase and $NF-{\kappa}B$ in CCI rats. Notably, the silencing of GRK2 significantly reversed the inhibitory effects of miR-15a/16 inhibition in neuropathic pain. In conclusion, our results suggest that inhibition of miR-15a/16 expression alleviates neuropathic pain development by targeting GRK2. These findings provide novel insights into the molecular pathogenesis of neuropathic pain and suggest potential therapeutic targets for preventing neuropathic pain development.
GRK2; miR-15a/16; Neuropathic pain; p38 MAPK;
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1 Lombardi, M. S., Kavelaars, A. and Heijnen, C. J. (2002) Role and modulation of G protein-coupled receptor signaling in inflammatory processes. Crit. Rev. Immunol. 22, 141-163.
2 Lombardi, M. S., van den Tweel, E., Kavelaars, A., Groenendaal, F., van Bel, F. and Heijnen, C. J. (2004) Hypoxia/ischemia modulates G protein-coupled receptor kinase 2 and beta-arrestin-1 levels in the neonatal rat brain. Stroke 35, 981-986.   DOI
3 Lucas, E., Cruces-Sande, M., Briones, A. M., Salaices, M., Mayor, F., Jr., Murga, C. and Vila-Bedmar, R. (2015) Molecular physiopathology of obesity-related diseases: multi-organ integration by GRK2. Arch. Physiol. Biochem. 121, 163-177.   DOI
4 Moon, H. G., Yang, J., Zheng, Y. and Jin, Y. (2014) miR-15a/16 regulates macrophage phagocytosis after bacterial infection. J. Immunol. 193, 4558-4567.   DOI
5 Nijboer, C. H., Heijnen, C. J., Willemen, H. L., Groenendaal, F., Dorn, G. W., 2nd, van Bel, F. and Kavelaars, A. (2010) Cell-specific roles of GRK2 in onset and severity of hypoxic-ischemic brain damage in neonatal mice. Brain Behav. Immun. 24, 420-426.   DOI
6 O'Connor, A. B. and Dworkin, R. H. (2009) Treatment of neuropathic pain: an overview of recent guidelines. Am. J. Med. 122, S22-32.   DOI
7 Penela, P., Murga, C., Ribas, C., Salcedo, A., Jurado-Pueyo, M., Rivas, V., Aymerich, I. and Mayor, F., Jr. (2008) G protein-coupled receptor kinase 2 (GRK2) in migration and inflammation. Arch. Physiol. Biochem. 114, 195-200.   DOI
8 Peregrin, S., Jurado-Pueyo, M., Campos, P. M., Sanz-Moreno, V., Ruiz-Gomez, A., Crespo, P., Mayor, F., Jr. and Murga, C. (2006) Phosphorylation of p38 by GRK2 at the docking groove unveils a novel mechanism for inactivating p38MAPK. Curr. Biol. 16, 2042-2047.   DOI
9 Sakai, A. and Suzuki, H. (2014) Emerging roles of microRNAs in chronic pain. Neurochem. Int. 77, 58-67.   DOI
10 Spinetti, G., Fortunato, O., Caporali, A., Shantikumar, S., Marchetti, M., Meloni, M., Descamps, B., Floris, I., Sangalli, E., Vono, R., Faglia, E., Specchia, C., Pintus, G., Madeddu, P. and Emanueli, C. (2013) MicroRNA-15a and microRNA-16 impair human circulating proangiogenic cell functions and are increased in the proangiogenic cells and serum of patients with critical limb ischemia. Circ. Res. 112, 335-346.   DOI
11 Su, S., Shao, J., Zhao, Q., Ren, X., Cai, W., Li, L., Bai, Q., Chen, X., Xu, B., Wang, J., Cao, J. and Zang, W. (2017) MiR-30b attenuates neuropathic pain by regulating voltage-gated sodium channel Nav1.3 in rats. Front. Mol. Neurosci. 10, 126.   DOI
12 Suo, Z., Wu, M., Citron, B. A., Wong, G. T. and Festoff, B. W. (2004) Abnormality of G-protein-coupled receptor kinases at prodromal and early stages of Alzheimer's disease: an association with early beta-amyloid accumulation. J. Neurosci. 24, 3444-3452.   DOI
13 Svensson, C. I., Schafers, M., Jones, T. L., Powell, H. and Sorkin, L. S. (2005) Spinal blockade of TNF blocks spinal nerve ligation-induced increases in spinal P-p38. Neurosci. Lett. 379, 209-213.   DOI
14 Willemen, H. L., Eijkelkamp, N., Wang, H., Dantzer, R., Dorn, G. W., 2nd, Kelley, K. W., Heijnen, C. J. and Kavelaars, A. (2010) Microglial/macrophage GRK2 determines duration of peripheral IL-1betainduced hyperalgesia: contribution of spinal cord CX3CR1 , p38 and IL-1 signaling. Pain 150, 550-560.   DOI
15 Tsuda, M., Mizokoshi, A., Shigemoto-Mogami, Y., Koizumi, S. and Inoue, K. (2004) Activation of p38 mitogen-activated protein kinase in spinal hyperactive microglia contributes to pain hypersensitivity following peripheral nerve injury. Glia 45, 89-95.   DOI
16 van Hecke, O., Austin, S. K., Khan, R. A., Smith, B. H. and Torrance, N. (2014) Neuropathic pain in the general population: a systematic review of epidemiological studies. Pain 155, 654-662.   DOI
17 Vroon, A., Heijnen, C. J. and Kavelaars, A. (2006) GRKs and arrestins: regulators of migration and inflammation. J. Leukoc. Biol. 80, 1214-1221.   DOI
18 Ahmed, M. R., Bychkov, E., Gurevich, V. V., Benovic, J. L. and Gurevich, E. V. (2008) Altered expression and subcellular distribution of GRK subtypes in the dopamine-depleted rat basal ganglia is not normalized by l-DOPA treatment. J. Neurochem. 104, 1622-1636.   DOI
19 Ambros, V. (2004) The functions of animal microRNAs. Nature 431, 350-355.   DOI
20 Wang, H., Heijnen, C. J., Eijkelkamp, N., Garza Carbajal, A., Schedlowski, M., Kelley, K. W., Dantzer, R. and Kavelaars, A. (2011) GRK2 in sensory neurons regulates epinephrine-induced signalling and duration of mechanical hyperalgesia. Pain 152, 1649-1658.   DOI
21 Willemen, H. L., Huo, X. J., Mao-Ying, Q. L., Zijlstra, J., Heijnen, C. J. and Kavelaars, A. (2012) MicroRNA-124 as a novel treatment for persistent hyperalgesia. J. Neuroinflammation 9, 143.   DOI
22 Woodall, M. C., Woodall, B. P., Gao, E., Yuan, A. and Koch, W. J. (2016) Cardiac fibroblast GRK2 deletion enhances contractility and remodeling following ischemia/reperfusion injury. Circ. Res. 119, 1116-1127.   DOI
23 Yue, J. and Tigyi, G. (2010) Conservation of miR-15a/16-1 and miR-15b/16-2 clusters. Mamm. Genome 21, 88-94.   DOI
24 Yang, D., Yang, Q., Wei, X., Liu, Y., Ma, D., Li, J., Wan, Y. and Luo, Y. (2017a) The role of miR-190a-5p contributes to diabetic neuropathic pain via targeting SLC17A6. J. Pain Res. 10, 2395-2403.   DOI
25 Yang, X., Tang, X., Sun, P., Shi, Y., Liu, K., Hassan, S. H., Stetler, R. A., Chen, J. and Yin, K. J. (2017b) MicroRNA-15a/16-1 antagomir ameliorates ischemic brain injury in experimental stroke. Stroke 48, 1941-1947.   DOI
26 Ye, E. A., Liu, L., Jiang, Y., Jan, J., Gaddipati, S., Suvas, S. and Steinle, J. J. (2016) miR-15a/16 reduces retinal leukostasis through decreased pro-inflammatory signaling. J. Neuroinflammation 13, 305.   DOI
27 Calin, G. A., Cimmino, A., Fabbri, M., Ferracin, M., Wojcik, S. E., Shimizu, M., Taccioli, C., Zanesi, N., Garzon, R., Aqeilan, R. I., Alder, H., Volinia, S., Rassenti, L., Liu, X., Liu, C. G., Kipps, T. J., Negrini, M. and Croce, C. M. (2008) MiR-15a and miR-16-1 cluster functions in human leukemia. Proc. Natl. Acad. Sci. U.S.A. 105, 5166-5171.   DOI
28 Andersen, H. H., Duroux, M. and Gazerani, P. (2014) MicroRNAs as modulators and biomarkers of inflammatory and neuropathic pain conditions. Neurobiol. Dis. 71, 159-168.   DOI
29 Bartel, D. P. (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281-297.   DOI
30 Bennett, G. J. and Xie, Y. K. (1988) A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 33, 87-107.   DOI
31 Chaplan, S. R., Bach, F. W., Pogrel, J. W., Chung, J. M. and Yaksh, T. L. (1994) Quantitative assessment of tactile allodynia in the rat paw. J. Neurosci. Methods 53, 55-63.   DOI
32 Chen, W., Guo, S. and Wang, S. (2016) MicroRNA-16 alleviates inflammatory pain by targeting Ras-related protein 23 (RAB23) and inhibiting p38 MAPK activation. Med. Sci. Monit. 22, 3894-3901.   DOI
33 Denk, F. and McMahon, S. B. (2012) Chronic pain: emerging evidence for the involvement of epigenetics. Neuron 73, 435-444.   DOI
34 Eijkelkamp, N., Heijnen, C. J., Willemen, H. L., Deumens, R., Joosten, E. A., Kleibeuker, W., den Hartog, I. J., van Velthoven, C. T., Nijboer, C., Nassar, M. A., Dorn, G. W., 2nd, Wood, J. N. and Kavelaars, A. (2010) GRK2: a novel cell-specific regulator of severity and duration of inflammatory pain. J. Neurosci. 30, 2138-2149.   DOI
35 Kavelaars, A., Eijkelkamp, N., Willemen, H. L., Wang, H., Carbajal, A. G. and Heijnen, C. J. (2011) Microglial GRK2: a novel regulator of transition from acute to chronic pain. Brain Behav. Immun. 25, 1055-1060.   DOI
36 Zhang, F., Xiang, S., Cao, Y., Li, M., Ma, Q., Liang, H., Li, H., Ye, Y., Zhang, Y., Jiang, L., Hu, Y., Zhou, J., Wang, X., Nie, L., Liang, X., Gong, W. and Liu, Y. (2017) EIF3D promotes gallbladder cancer development by stabilizing GRK2 kinase and activating PI3K-AKT signaling pathway. Cell Death Dis. 8, e2868.   DOI
37 Haanpaa, M., Attal, N., Backonja, M., Baron, R., Bennett, M., Bouhassira, D., Cruccu, G., Hansson, P., Haythornthwaite, J. A., Iannetti, G. D., Jensen, T. S., Kauppila, T., Nurmikko, T. J., Rice, A. S., Rowbotham, M., Serra, J., Sommer, C., Smith, B. H. and Treede, R. D. (2011) NeuPSIG guidelines on neuropathic pain assessment. Pain 152, 14-27.   DOI
38 Hargreaves, K., Dubner, R., Brown, F., Flores, C. and Joris, J. (1988) A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 32, 77-88.   DOI
39 Ji, L. J., Shi, J., Lu, J. M. and Huang, Q. M. (2018) MiR-150 alleviates neuropathic pain via inhibiting toll-like receptor 5. J. Cell. Biochem. 119, 1017-1026.   DOI
40 Jiangpan, P., Qingsheng, M., Zhiwen, Y. and Tao, Z. (2016) Emerging role of microRNA in neuropathic pain. Curr. Drug Metab. 17, 336-344.   DOI
41 Kleibeuker, W., Ledeboer, A., Eijkelkamp, N., Watkins, L. R., Maier, S. F., Zijlstra, J., Heijnen, C. J. and Kavelaars, A. (2007) A role for G protein-coupled receptor kinase 2 in mechanical allodynia. Eur. J. Neurosci. 25, 1696-1704.   DOI
42 Krol, J., Loedige, I. and Filipowicz, W. (2010) The widespread regulation of microRNA biogenesis, function and decay. Nat. Rev. Genet. 11, 597-610.   DOI