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MicroRNA-146a-5p attenuates visceral hypersensitivity through targeting chemokine CCL8 in the spinal cord in a mouse model of colitis.
Brain Res Bull. 2018 05; 139:235-242.BR

Abstract

Visceral pain, observed in inflammatory bowel disease (IBD) patients, is a challenging medical problem and remains poorly understood because the mechanisms underlying it are unclear. Emerging evidence indicates that microRNAs (miRNAs) play a crucial role in the pathogenesis of acute and chronic pain. In this study, we aimed to explore the potential role of miR-146a-5p (the mature form of miR-146a) in a mouse model of colitis induced by intracolonic injection of trinitrobenzene sulfonic acid (TNBS). We found that induction of colitis resulted in visceral hyperalgesia manifested by a decreased pain threshold to colorectal distension and upregulation of miR-146a-5p expression in the lumbosacral spinal cord. In situ hybridization and immunohistochemistry results showed that miR-146a-5p was colocalized with neuronal marker NeuN, but not with astrocytic marker GFAP or microglial marker IBA-1. Dual-luciferase reporter assay showed that miR-146a-5p directly targeted the 3'-untranslated region (UTR) of CCL8, which was previously identified as an important regulator of visceral pain. In cultured Neuro-2a cells, TNF-α-induced CCL8 upregulation was decreased by transfection of miR-146a-5p mimic dose-dependently. In vivo, exogenous supplementation of miR-146a-5p by intrathecal miR-146a-5p agomir significantly alleviated visceral pain and decreased CCL8 expression in colitis mice. Furthermore, inhibition of CCL8 expression by CCL8 siRNA relieved colitis-induced visceral nociception. Finally, in naïve mice intrathecal miR-146a-5p antagomir upregulated CCL8 expression and induced visceral pain hypersensitivity, which could be partially rescued by neutralization of CCL8. Taken together, the present findings indicate that miR-146a-5p may be an endogenous suppressor of visceral pain and exogenous supplementation of miR-146a-5p could exert an analgesic effect at least partly by targeting spinal CCL8 expression. Thus, miR-146a-5p may serve as a novel therapeutic target for visceral pain intervention in the context of colitis.

Authors+Show Affiliations

Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, China; Department of Nutrition and Food Hygiene, School of Public Health, Nantong University, Nantong, Jiangsu 226019, China.Pain Research Laboratory, Institute of Nautical Medicine, Nantong University, Nantong, Jiangsu 226019, China.Pain Research Laboratory, Institute of Nautical Medicine, Nantong University, Nantong, Jiangsu 226019, China.Department of Occupational Medicine and Environmental Hygiene, School of Public Health, Nantong University, Nantong, Jiangsu 226019, China.Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, China. Electronic address: zhangyouli1957@163.com.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29550454

Citation

Lu, Ying, et al. "MicroRNA-146a-5p Attenuates Visceral Hypersensitivity Through Targeting Chemokine CCL8 in the Spinal Cord in a Mouse Model of Colitis." Brain Research Bulletin, vol. 139, 2018, pp. 235-242.
Lu Y, Cao DL, Zhao LX, et al. MicroRNA-146a-5p attenuates visceral hypersensitivity through targeting chemokine CCL8 in the spinal cord in a mouse model of colitis. Brain Res Bull. 2018;139:235-242.
Lu, Y., Cao, D. L., Zhao, L. X., Han, Y., & Zhang, Y. L. (2018). MicroRNA-146a-5p attenuates visceral hypersensitivity through targeting chemokine CCL8 in the spinal cord in a mouse model of colitis. Brain Research Bulletin, 139, 235-242. https://doi.org/10.1016/j.brainresbull.2018.03.007
Lu Y, et al. MicroRNA-146a-5p Attenuates Visceral Hypersensitivity Through Targeting Chemokine CCL8 in the Spinal Cord in a Mouse Model of Colitis. Brain Res Bull. 2018;139:235-242. PubMed PMID: 29550454.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - MicroRNA-146a-5p attenuates visceral hypersensitivity through targeting chemokine CCL8 in the spinal cord in a mouse model of colitis. AU - Lu,Ying, AU - Cao,De-Li, AU - Zhao,Lin-Xia, AU - Han,Yu, AU - Zhang,You-Li, Y1 - 2018/03/14/ PY - 2018/01/13/received PY - 2018/03/04/revised PY - 2018/03/07/accepted PY - 2018/3/20/pubmed PY - 2019/3/13/medline PY - 2018/3/19/entrez KW - CCL8 KW - Colitis KW - MiR-146a-5p KW - TNBS KW - Visceral pain SP - 235 EP - 242 JF - Brain research bulletin JO - Brain Res. Bull. VL - 139 N2 - Visceral pain, observed in inflammatory bowel disease (IBD) patients, is a challenging medical problem and remains poorly understood because the mechanisms underlying it are unclear. Emerging evidence indicates that microRNAs (miRNAs) play a crucial role in the pathogenesis of acute and chronic pain. In this study, we aimed to explore the potential role of miR-146a-5p (the mature form of miR-146a) in a mouse model of colitis induced by intracolonic injection of trinitrobenzene sulfonic acid (TNBS). We found that induction of colitis resulted in visceral hyperalgesia manifested by a decreased pain threshold to colorectal distension and upregulation of miR-146a-5p expression in the lumbosacral spinal cord. In situ hybridization and immunohistochemistry results showed that miR-146a-5p was colocalized with neuronal marker NeuN, but not with astrocytic marker GFAP or microglial marker IBA-1. Dual-luciferase reporter assay showed that miR-146a-5p directly targeted the 3'-untranslated region (UTR) of CCL8, which was previously identified as an important regulator of visceral pain. In cultured Neuro-2a cells, TNF-α-induced CCL8 upregulation was decreased by transfection of miR-146a-5p mimic dose-dependently. In vivo, exogenous supplementation of miR-146a-5p by intrathecal miR-146a-5p agomir significantly alleviated visceral pain and decreased CCL8 expression in colitis mice. Furthermore, inhibition of CCL8 expression by CCL8 siRNA relieved colitis-induced visceral nociception. Finally, in naïve mice intrathecal miR-146a-5p antagomir upregulated CCL8 expression and induced visceral pain hypersensitivity, which could be partially rescued by neutralization of CCL8. Taken together, the present findings indicate that miR-146a-5p may be an endogenous suppressor of visceral pain and exogenous supplementation of miR-146a-5p could exert an analgesic effect at least partly by targeting spinal CCL8 expression. Thus, miR-146a-5p may serve as a novel therapeutic target for visceral pain intervention in the context of colitis. SN - 1873-2747 UR - https://www.unboundmedicine.com/medline/citation/29550454/MicroRNA_146a_5p_attenuates_visceral_hypersensitivity_through_targeting_chemokine_CCL8_in_the_spinal_cord_in_a_mouse_model_of_colitis_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0361-9230(18)30023-6 DB - PRIME DP - Unbound Medicine ER -