Inhibition of Oligodendrocyte Apoptosis in the Prelimbic Medial Prefrontal Cortex Prevents Fentanyl-induced Hyperalgesia in Rats

  • Xi-Xi Wang
    Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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  • Ling-Ling Cui
    Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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  • Si-Fei Gan
    Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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  • Ze-Ru Zhang
    Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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  • Jing Xiao
    Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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  • Chen-Hong Li
    The Laboratory of Membrane Ion Channels and Medicine, Key Laboratory of Cognitive Science, State Ethnic Affairs Commission, College of Biomedical Engineering, South-Central University for Nationalities, Wuhan, Hubei, China
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  • Fang Luo
    Address reprint requests to Fang Luo., Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang avnue1095#, Wuhan, Hubei, China.
    Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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Published:January 09, 2022DOI:


      • Oligodendrocyte apoptosis decreased myelin proteins in OIH.
      • Oligodendrocyte apoptosis in the PL-mPFC is a key trigger for OIH.
      • Blockage of oligodendrocyte apoptosis in the PL-mPFC prevents OIH.


      Opioid-induced hyperalgesia (OIH) is a problem associated with prolonged use of opioids in chronic pain management, and its effective treatment has been hampered by lack of mechanistic evidence. Oligodendrocytes have recently been linked with several pain-related diseases; however, little is known its role in OIH. The prelimbic medial prefrontal cortex (PL-mPFC) has emerged as a significant center of pain regulation, and is rich in oligodendrocytes. Herein we explored the effect of oligodendrocyte apoptosis of PL-mPFC on OIH. Using a fentanyl-induced rat model of OIH and proteomics analysis of the PL-mPFC, we observed a downregulation in 5 types of myelin-related proteins originating from oligodendrocytes; this was further verified by western blotting. Meanwhile, cleaved-caspase 3 (an apoptosis marker) was increased, whereas the oligodendrocyte precursor cell (OPC) marker NG2 remained unchanged. These results suggest that downregulated myelin-related proteins may be associated with oligodendrocyte apoptosis rather than a reduction in their generating source, and immunohistochemistry confirmed this hypothesis. Behaviorally, prophylactic blockade of oligodendrocyte apoptosis by microinjection of z-DEVD-fmk into the PL-mPFC prevented fentanyl-induced mechanical and thermal hyperalgesia, but downregulated myelin basic protein (mbp) gradually recovered in 12 h. We suggest that OIH may be primed in part via oligodendrocyte apoptosis in the PL-mPFC.


      In this study we showed that oligodendrocyte apoptosis in the PL-mPFC is a key trigger for fentanyl-induced hyperalgesia. Targeting oligodendrocyte apoptosis in the PL-mPFC may prevented hyperalgesia priming induced by fentanyl.

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