Journal Article

Morphine promotes microglial activation by upregulating the EGFR/ERK signaling pathway

Yang, Yaqiong, Sun, Yu, Wang, Ziheng, Jiang, Hong, Hu, Rong, Yan, Jia, Li, Wenlong

2021

Overview

Although they represent the cornerstone of analgesic therapy, opioids, such as morphine, are limited in efficacy by drug tolerance, hyperalgesia and other side effects. Activation of microglia and the consequent production of proinflammatory cytokines play a key pathogenic role in morphine tolerance, but the exact mechanisms are not well understood. This study aimed to investigate the regulatory mechanism of epidermal growth factor receptor (EGFR) on microglial activation induced by morphine in mouse microglial BV-2 cells. In this research, BV-2 cells were stimulated with morphine or pretreated with AG1478 (an inhibitor of EGFR). Expression levels of cluster of differentiation molecule 11b (CD11b), EGFR, and phospho-EGFR were detected by immunofluorescence staining. Cell signaling was assayed by Western blot. The migration ability of BV-2 cells was tested by Transwell assay. The production of interleukin-1beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) in the cell supernatant was determined by ELISA. We observed that the expression of CD11b induced by morphine was increased in a dose- and time- dependent manner in BV-2 cells. Phosphorylation levels of EGFR and ERK1/2, migration of BV-2 cells, and production of IL-1β and TNFα were markedly enhanced by morphine treatment. The activation, migration, and production of proinflammatory cytokines in BV-2 cells were inhibited by blocking the EGFR signaling pathway with AG1478. The present study demonstrated that the EGFR/ERK signaling pathway may represent a novel pharmacological strategy to suppress morphine tolerance through attenuation of microglial activation.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Analgesics / Anesthesiology / Attenuation / Biology and Life Sciences / CD11b antigen / Cell migration / Cell signaling / Cytokines / Drug tolerance / Enzyme-linked immunosorbent assay / Epidermal growth factor / Epidermal growth factor receptors / Experiments / Extracellular signal-regulated kinase / Genetic aspects / Growth factors / Health aspects / Hyperalgesia / IL-1β / Immunofluorescence / Inflammation / Interleukins / Kinases / Medicine / Medicine and Health Sciences / Membranes / Microglia / Morphine / Narcotics / Opioids / Pain / Pain perception / Pharmaceuticals / Phosphorylation / Physical Sciences / Regulatory mechanisms (biology) / Research and Analysis Methods / Side effects / Signal transduction / Signaling / Tumor necrosis factor-TNF / Tumor necrosis factor-α / Variance analysis