Involvement of spinal NADPH oxidase 4 and endoplasmic reticulum stress in morphine ‐tolerant rats

Schematic of the mechanism by which NOX4 participates in the development of morphine tolerance. Repeated administration of morphine upregulated the expression of NOX4 in the rat spinal cord by promoting the ER stress response. Then, BIP and the three UPR sensors (PERK, IRE1 and ATF6) were activated, which subsequently led to the upregulation of autophagy in GABAergic neurons and eventually led to the development of morphine tolerance. Blocking the activation of NOX4 in the spinal cord may be a new method for preventing the development of morphine tolerance. AbstractMorphine tolerance (MT) is currently a challenging issue related to intractable pain treatment. Studies have shown that reactive oxygen species (ROSs) derived from NADPH oxidase (NOX) and produced in response to endoplasmic reticulum (ER) stress participate in MT development. However, which NOX subtype initiates ER stress during MT development is unclear. NOX4 is mainly expressed on intracellular membranes, such as the ER and mitochondrial membranes, and its sole function is to produce ROS. Whether NOX4 is activated during MT development and the mechanisms underlying the association between NOX4 and ER stress during this process still need to be confirmed. In our study, we used the classic morphine-tolerant rat model and evaluated the analgesic effect of intrathecally injected morphine through a hot water tail-flick assay. Our research demonstrated for the first time that chronic morphine administration upregulates...

Source: Journal of Neurochemistry - December 9, 2023 Category: Neuroscience Authors: Xuyang Xiao, Jingjie Yang, Qian Bai, Zhitao Wang, Yan Chen, Yue Si, Yaowei Xu, Zhisong Li, Huilian Bu Tags: ORIGINAL ARTICLE Source Type: research