Document Type
Article
Publication Date
5-12-2011
Description
Opioids have been widely applied in clinics as one of the most potent pain relievers for centuries, but their abuse has deleterious physiological effects beyond addiction. However, the underlying mechanism by which microglia in response to opioids remains largely unknown. Here we show that morphine induces the expression of Toll-like receptor 9 (TLR9), a key mediator of innate immunity and inflammation. Interestingly, TLR9 deficiency significantly inhibited morphine-induced apoptosis in microglia. Similar results were obtained when endogenous TLR9 expression was suppressed by the TLR9 inhibitor CpGODN. Inhibition of p38 MAPK by its specific inhibitor SB203580 attenuated morphine-induced microglia apoptosis in wild type microglia. Morphine caused a dramatic decrease in Bcl-2 level but increase in Bax level in wild type microglia, but not in TLR9 deficient microglia. In addition, morphine treatment failed to induce an increased levels of phosphorylated p38 MAPK and MAP kinase kinase 3/6 (MKK3/6), the upstream MAPK kinase of p38 MAPK, in either TLR9 deficient or μ-opioid receptor (μOR) deficient primary microglia, suggesting an involvement of MAPK and μOR in morphine-mediated TLR9 signaling. Moreover, morphine-induced TLR9 expression and microglia apoptosis appears to require μOR. Collectively, these results reveal that opioids prime microglia to undergo apoptosis through TLR9 and μOR as well. Taken together, our data suggest that inhibition of TLR9 and/or blockage of μOR is capable of preventing opioid-induced brain damage.
Creative Commons License
This work is licensed under a Creative Commons Attribution 3.0 License.
Citation Information
He, Lei; Li, Hui; Chen, Lin; Miao, Junying; Jiang, Yulin; Zhang, Yi; Xiao, Zuoxiang; Hanley, Gregory; Li, Yi; Zhang, Xiumei; LeSage, Gene; Peng, Ying; and Yin, Deling. 2011. Toll-Like Receptor 9 Is Required for Opioid-Induced Microglia Apoptosis. PLoS ONE. Vol.6(4). https://doi.org/10.1371/journal.pone.0018190 PMID: 21559519
Copyright Statement
© 2011 He et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.