PMID- 30776493 OWN - NLM STAT- MEDLINE DCOM- 20200213 LR - 20200213 IS - 1872-7972 (Electronic) IS - 0304-3940 (Linking) VI - 701 DP - 2019 May 14 TI - PI3K/Akt signaling pathway may be involved in MCP-1-induced P2X4R expression in cultured microglia and cancer-induced bone pain rats. PG - 100-105 LID - S0304-3940(19)30116-8 [pii] LID - 10.1016/j.neulet.2019.02.024 [doi] AB - P2X4 receptor (P2X4R), a subtype of P2 purinergic receptors, is an ATP-gated receptor through which activity of spinal microglia instigates pain hypersensitivity in various pain conditions. Accumulating evidence indicates that monocyte chemoattractant protein-1 (MCP-1) plays an important role in chronic pain facilitation, and it could stimulate microglia activation and involve in regulating P2X4R expression. However, the mechanism of MCP-1 in regulating the expression of P2X4R in microglia is poorly understood, and whether MCP-1 can aggravate pain via up-regulating spinal P2X4R expression in Cancer-induced Bone Pain (CIBP) remains unclear. In this study, we observed that Iba-1 and P2X4R expression is increased in microglia treated with MCP-1, and blockade with a selective CCR2 antagonist RS-504393 suppressed microglia activation and reduced P2X4R expression in cultured microglia. In response to MCP-1, the expression level of p-Akt was also increased and RS-504393 inhibited the increase. Besides, PI3K inhibitor LY 294002 could attenuate MCP-1-induced P2X4R expression in cultured microglia. MCP-1 was found to be associated with P2X4R expression and mechanical allodynia induced by CIBP in vivo since the expression of MCP-1 was increased in CIBP and RS-504393 alleviated the P2X4R expression and mechanical allodynia in CIBP. Moreover, RS-504393 also reduced the increase of p-Akt induced by CIBP. Inhibition of PI3K/Akt pathway may partly reduce MCP-1/CCR2-induced expression of P2X4R and mechanical allodynia in CIBP rats. CI - Copyright (c) 2019 Elsevier B.V. All rights reserved. FAU - Yan, Ying AU - Yan Y AD - Department of Anesthesiology, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, Shandong 266005, China. Electronic address: 1281987612@qq.com. FAU - Liang, Yongxin AU - Liang Y AD - Department of Anesthesiology, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, Shandong 266005, China. Electronic address: liangzi66@hotmail.com. FAU - Ding, Tao AU - Ding T AD - Department of Articular Surgery, The Affiliated Hospital of Qingdao University, 1677 Wutaishan Road, Qingdao, Shandong 266000, China. Electronic address: 872649997@qq.com. FAU - Chu, Haichen AU - Chu H AD - Department of Anesthesiology, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, Shandong 266005, China. Electronic address: chiefchu@163.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190215 PL - Ireland TA - Neurosci Lett JT - Neuroscience letters JID - 7600130 RN - 0 (Aif1 protein, rat) RN - 0 (Benzoxazines) RN - 0 (Calcium-Binding Proteins) RN - 0 (Ccl2 protein, rat) RN - 0 (Ccr2 protein, rat) RN - 0 (Chemokine CCL2) RN - 0 (Chromones) RN - 0 (Microfilament Proteins) RN - 0 (Morpholines) RN - 0 (Phosphoinositide-3 Kinase Inhibitors) RN - 0 (RS 504393) RN - 0 (Receptors, CCR2) RN - 0 (Receptors, Purinergic P2X4) RN - 0 (Spiro Compounds) RN - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) SB - IM MH - Animals MH - Benzoxazines/pharmacology MH - Calcium-Binding Proteins/metabolism MH - Cancer Pain/*metabolism MH - Cell Line, Tumor MH - Chemokine CCL2/metabolism/*pharmacology MH - Chromones/pharmacology MH - Female MH - Hyperalgesia/metabolism MH - Mammary Neoplasms, Experimental/metabolism/pathology MH - Microfilament Proteins/metabolism MH - Microglia/*drug effects/metabolism MH - Morpholines/pharmacology MH - Phosphatidylinositol 3-Kinases/*metabolism MH - Phosphoinositide-3 Kinase Inhibitors/pharmacology MH - Primary Cell Culture MH - Proto-Oncogene Proteins c-akt/*metabolism MH - Rats MH - Rats, Sprague-Dawley MH - Receptors, CCR2/antagonists & inhibitors/metabolism MH - Receptors, Purinergic P2X4/*metabolism MH - Signal Transduction MH - Spiro Compounds/pharmacology OTO - NOTNLM OT - Cancer-induced bone pain (CIBP) OT - Microglia OT - Monocyte chemoattractant protein 1 (MCP-1) OT - P2X4R OT - PI3K/Akt signaling pathway EDAT- 2019/02/19 06:00 MHDA- 2020/02/14 06:00 CRDT- 2019/02/19 06:00 PHST- 2018/10/15 00:00 [received] PHST- 2019/02/13 00:00 [revised] PHST- 2019/02/14 00:00 [accepted] PHST- 2019/02/19 06:00 [pubmed] PHST- 2020/02/14 06:00 [medline] PHST- 2019/02/19 06:00 [entrez] AID - S0304-3940(19)30116-8 [pii] AID - 10.1016/j.neulet.2019.02.024 [doi] PST - ppublish SO - Neurosci Lett. 2019 May 14;701:100-105. doi: 10.1016/j.neulet.2019.02.024. Epub 2019 Feb 15.