吗啡
TLR3型
药理学
痛觉过敏
信号转导
医学
化学
细胞生物学
生物
伤害
内科学
受体
Toll样受体
先天免疫系统
作者
Bing Wang,Dongsheng Le,Jie Liu,Xuexue Zhang,Fan Yang,Guo-Rong Lai,Chao Zhang,Mai-Lin Zhao,Yijun Shen,Ping-Sheng Liao,Tong Liu,Yuexin Liang
标识
DOI:10.1016/j.xcrm.2024.101782
摘要
Long-term morphine use leads to tolerance and hyperalgesia in patients with chronic pain, with neuroinflammation playing a key role, but its underlying mechanisms remain elusive. This study determines that repeated intrathecal morphine injections increase double-stranded RNA (dsRNA) production in spinal neurons, due to downregulated adenosine deaminase RNA specific 1 (ADAR1) expression. Lentivirus-induced ADAR1 elevation decreases the high levels of intracellular dsRNA and attenuates morphine tolerance and hyperalgesia. dsRNA is released into cerebrospinal fluid via exosomes (Exos) after repeated morphine injections and is taken up by microglia for TLR3-TRIF-IL-6 signaling activation. Blocking Exos release with GW4869 or inhibition of TLR3 signaling mitigates neuroinflammation, preventing the development of morphine tolerance and hyperalgesia. Intrathecal injection of TLR3 inhibitor alone shows analgesic effects in neuropathic pain, and co-administration with morphine amplifies the analgesic efficacy of morphine. These findings demonstrate that targeting dsRNA-TLR3 signaling to mitigate neuroinflammation could be a promising treatment for morphine tolerance.
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