title: Morphine enhances IL-1β release through toll-like receptor 4-mediated endocytic pathway in microglia.
abstract: Morphine creates a neuroinflammatory response and enhances release of the proinflammatory cytokines like interleukin-1β (IL-1β), which compromises morphine analgesia as well as induces morphine tolerance. In this study, we attempted to investigate the mechanisms of morphine induced IL-1β synthesis and release. Microglial cells were treated with morphine (100 μM) once daily for 3 days. Control groups underwent the same procedure but received sterile saline injection instead of morphine. Toll-like receptor 4 (TLR4) and P2X4 receptor (P2X4R) signaling were analyzed using Western blot; immunofluorescence was used to detect the signaling of CD68; real-time RT-PCR and ELISA kit was used to measure the messenger RNA and protein synthesis and release level of IL-1β. Morphine enhanced IL-1β synthesis and P2X4R protein expression. TLR4 were responsible for morphine-induced IL-1β synthesis, while morphine-induced IL-1β release was via P2X4R. Morphine-induced IL-1β release is mediated by endocytosis of TLR4. These results indicated that TLR4 and P2X4R pathways mediated IL-1β synthesis and release in microglia followed chronic morphine. TLR4 internalization is the main mechanism of morphine-induced microglia activation and IL-1β release.
authors: Department of Anesthesiology, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, 266071, China. liangzi66@hotmail.com.
authors: Yongxin
authors: Y
authors: Liang
authors: Department of Anesthesiology, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, 266071, China.
authors: Haichen
authors: H
authors: Chu
authors: Department of Anesthesiology, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, 266071, China.
authors: Yanan
authors: Y
authors: Jiang
authors: Department of Anesthesiology, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, 266071, China.
authors: Li
authors: L
authors: Yuan
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004705:Endocytosis / Q000187:drug effects; D053583:Interleukin-1beta / Q000378:metabolism*; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D009020:Morphine / Q000494:pharmacology*; D009294:Narcotics / Q000494:pharmacology*; D051381:Rats; D058848:Receptors, Purinergic P2X4 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D053583:Interleukin-1beta; D009294:Narcotics; D058848:Receptors, Purinergic P2X4; D051197:Toll-Like Receptor 4; D009020:Morphine
keywords: Interleukin-1β; Microglia; Morphine; P2X4 receptors; Toll-like receptor 4