S-nitrosoglutathione reductase alleviates morphine analgesic tolerance by restricting PKCα S-nitrosation
Ling-Yan Su,
Lijin Jiao,
Qianjin Liu,
Xinhua Qiao,
Ting Xie,
Zhiyu Ma,
Min Xu,
Mao-Sen Ye,
Lu-Xiu Yang,
Chang Chen,
Yong-Gang Yao
Affiliations
Ling-Yan Su
Key Laboratory of Genetic Evolution and Animal Models of the Chinese Academy of Sciences, Yunnan Key Laboratory of Animal Models and Human Disease Mechanisms, and KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, 650204, China; College of Food Science and Technology, and Yunnan Key Laboratory of Precision Nutrition and Personalized Food Manufacturing, Yunnan Agricultural University, Kunming, Yunnan, 650201, China
Lijin Jiao
Key Laboratory of Genetic Evolution and Animal Models of the Chinese Academy of Sciences, Yunnan Key Laboratory of Animal Models and Human Disease Mechanisms, and KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, 650204, China
Qianjin Liu
Key Laboratory of Genetic Evolution and Animal Models of the Chinese Academy of Sciences, Yunnan Key Laboratory of Animal Models and Human Disease Mechanisms, and KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, 650204, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, 650204, China
Xinhua Qiao
Key Laboratory of Biomacromolecules (CAS), National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
Ting Xie
Key Laboratory of Biomacromolecules (CAS), National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
Zhiyu Ma
Key Laboratory of Genetic Evolution and Animal Models of the Chinese Academy of Sciences, Yunnan Key Laboratory of Animal Models and Human Disease Mechanisms, and KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, 650204, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, 650204, China
Min Xu
Key Laboratory of Genetic Evolution and Animal Models of the Chinese Academy of Sciences, Yunnan Key Laboratory of Animal Models and Human Disease Mechanisms, and KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, 650204, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, 650204, China
Mao-Sen Ye
Key Laboratory of Genetic Evolution and Animal Models of the Chinese Academy of Sciences, Yunnan Key Laboratory of Animal Models and Human Disease Mechanisms, and KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, 650204, China
Lu-Xiu Yang
Key Laboratory of Genetic Evolution and Animal Models of the Chinese Academy of Sciences, Yunnan Key Laboratory of Animal Models and Human Disease Mechanisms, and KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, 650204, China
Chang Chen
Key Laboratory of Biomacromolecules (CAS), National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China; Corresponding author.
Yong-Gang Yao
Key Laboratory of Genetic Evolution and Animal Models of the Chinese Academy of Sciences, Yunnan Key Laboratory of Animal Models and Human Disease Mechanisms, and KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, 650204, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, 650204, China; National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility), National Resource Center for Non-Human Primates, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, 650107, China; Corresponding author. Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, 650204, China.
Morphine, a typical opiate, is widely used for controlling pain but can lead to various side effects with long-term use, including addiction, analgesic tolerance, and hyperalgesia. At present, however, the mechanisms underlying the development of morphine analgesic tolerance are not fully understood. This tolerance is influenced by various opioid receptor and kinase protein modifications, such as phosphorylation and ubiquitination. Here, we established a murine morphine tolerance model to investigate whether and how S-nitrosoglutathione reductase (GSNOR) is involved in morphine tolerance. Repeated administration of morphine resulted in the down-regulation of GSNOR, which increased excessive total protein S-nitrosation in the prefrontal cortex. Knockout or chemical inhibition of GSNOR promoted the development of morphine analgesic tolerance and neuron-specific overexpression of GSNOR alleviated morphine analgesic tolerance. Mechanistically, GSNOR deficiency enhanced S-nitrosation of cellular protein kinase alpha (PKCα) at the Cys78 and Cys132 sites, leading to inhibition of PKCα kinase activity, which ultimately promoted the development of morphine analgesic tolerance. Our study highlighted the significant role of GSNOR as a key regulator of PKCα S-nitrosation and its involvement in morphine analgesic tolerance, thus providing a potential therapeutic target for morphine tolerance.
