Melatonin alleviates morphine analgesic tolerance in mice by decreasing NLRP3 inflammasome activation
Qianjin Liu,
Ling-Yan Su,
Chunli Sun,
Lijin Jiao,
Ying Miao,
Min Xu,
Rongcan Luo,
Xin Zuo,
Rongbin Zhou,
Ping Zheng,
Wei Xiong,
Tian Xue,
Yong-Gang Yao
Affiliations
Qianjin Liu
Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, 650223, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, 650204, China
Ling-Yan Su
Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, 650223, China; Corresponding author.
Chunli Sun
Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, 650204, China; State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, 650223, China
Lijin Jiao
Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, 650223, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, 650204, China
Ying Miao
Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, 650223, China; Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230026, China
Min Xu
Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, 650223, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, 650204, China
Rongcan Luo
Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, 650223, China
Xin Zuo
Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230026, China
Rongbin Zhou
Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230026, China
Ping Zheng
Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, 650204, China; State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, 650223, China; KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, 650223, China
Wei Xiong
Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230026, China; CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, 200031, China
Tian Xue
Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230026, China; CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, 200031, China
Yong-Gang Yao
Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, 650223, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, 650204, China; KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, 650223, China; CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, 200031, China; Corresponding author.Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, 650223, China.
Morphine is frequently used for pain relief, but long-term morphine therapy in patients with chronic pain results in analgesic tolerance and hyperalgesia. There are no effective therapeutic treatments that limit these detrimental side effects. We found pretreatment with melatonin could decrease morphine-induced analgesic tolerance. There was a significant activation of the NLRP3 inflammasome in the prefrontal cortex and the peripheral blood of morphine-treated mice compared to control animals, which could be blocked by melatonin. The inflammasome activation induced by morphine was mediated by the microglia. SiRNA knockdown or pharmacological inhibition of the NLRP3 abolished the morphine-induced inflammasome activation. Co-administration of melatonin and low-dose morphine had better analgesia effects in the murine models of pain and led to a lower NLRP3 inflammasome activity in brain tissues. Mice deficient for Nlrp3 had a higher nociceptive threshold and were less sensitive to develop morphine-induced analgesic tolerance and acetic acid-induced pain relative to wild-type animals. Concordantly, we observed a significantly elevated level of serum IL-1β, which indicates an increase of NLRP3 inflammasome activity associated with the reduced level of serum melatonin, in heroin-addicted patients relative to healthy individuals. Our results provide a solid basis for conducting a clinical trial with the co-administration of melatonin and morphine for the relief of severe pain.
