NADPH-oxidase 4 promotes autophagy in spinal neurons through activating ER stress during the development of morphine tolerance

Abstract Morphine tolerance is one of the current challenging issues in the treatment of chronic pain. Recent studies have shown that ROS derived by NADPH oxidase (NOX) and endoplasmic reticulum (ER) stress is participated in the development of morphine tolerance. However, which NOX subtype initiates the ER stress during the development of morphine tolerance is not fully clear. NOX4 mainly expressed at intracellular membranes, such as ER and mitochondria, which sole function is to produce ROS as the major product. At present, whether NOX4 is activated and the mechanisms between NOX4 and ER stress during the development of morphine tolerance still need to be confirmed. Here, our research, for the first time, demonstrated that chronic administration of morphine up-regulated the expression of NOX4 at spinal cord through activating the three ER stress sensors (PERK, IRE1, ATF6), and subsequently leading to the activation of LC3B and P62 (a well-known autophagy marker) in GABAergic neurons. Therefore, our results may suggest that regulating NOX4 and the key factor of ER stress or autophagy may be a promising strategy to treat and prevent the development of morphine tolerance.