Morphine induces dysfunction of PINK1/Parkin-mediated mitophagy in spinal cord neurons implying involvement in antinociceptive tolerance  

作　　者：Hong Kong Chun-Yi Jiang Liang Hu Peng Teng Yan Zhang Xiu-Xiu Pan Xiao-Di Sun Wen-Tao Liu 

机构地区：[1]Neuroprotective Drug Discovery Key Laboratory of Nanjing Medical University,Department of Pharmacology,Nanjing Medical University,Nanjing,China [2]Research Division of Pharmacology,China Pharmaceutical University,Nanjing,China [3]Department of Anesthesiology,The First Affiliated Hospital of Nanjing Medical University,Nanjing,China [4]Department of Pharmacy,Sir Run Run Shaw Hospital Affiliated to Nanjing Medical University,Nanjing,China

出　　处：《Journal of Molecular Cell Biology》2019年第12期1056-1068,共13页分子细胞生物学报（英文版）

基　　金：the National Natural Science Foundation of China(81870870 to C.-Y.J.,81202513,and 81471142);Natural Science Foundation for Young Scientists of Jiangsu Province(BK20161033);the Key Project of Nanjing Medical University Sciente and Technology Innovation Foundation(2017NJMUCX004).

摘　　要：The development of opioid-induced analgesic tolerance is a clinical challenge in long-term use for managing chronic pain. The mechanisms of morphine tolerance are poorly understood. Mitochondria-derived reactive oxygen species (ROS) is a crucial signal inducing analgesic tolerance and pain. Chronic administration of morphine leads to robust ROS production and accumulation of damaged mitochondria, which are immediately removed by mitophagy. Here, we show that morphine inhibits mitochondria damage-induced accumulation of PTEN-induced putative kinase 1 (PINK1) in neurons. It interrupts the recruitment of Parkin to the impaired mitochondria and inhibits the ubiquitination of mitochondrial proteins catalyzed by Parkin. Consequently, morphine suppresses the recognition of autophagosomes to the damaged mitochondria mediated by LC3 and sequestosome-1 (SQSTM1/p62). Thus, morphine inhibits autophagy flux and leads to the accumulation of SQSTM1/p62. Finally, the impaired mitochondria cannot be delivered to lysosomes for degradation and ultimately induces robust ROS production and morphine tolerance. Our findings suggest that the dysfunction of mitophagy is involved in morphine tolerance. The deficiency of PINK1/Parkin-mediated clearance of damaged mitochondria is crucial for the generation of excessive ROS and important to the development of analgesic tolerance. These findings suggest that the compounds capable of stabilizing PINK1 or restoring mitophagy may be utilized to prevent or reduce opioid tolerance during chronic pain management.

关 键 词：MITOPHAGY PINK1 PARKIN ROS SQSTM1/p62 morphine tolerance 

分 类 号：R96[医药卫生—药理学]