Pretreatment of the ROS Inhibitor Phenyl-N-tert-butylnitrone Alleviates Sleep Deprivation-Induced Hyperalgesia by Suppressing Microglia Activation and NLRP3 Inflammasome Activity in the Spinal Dorsal Cord

Abstract

Sleep deprivation, a common perioperative period health problem, causes ocular discomfort and affects postsurgical pain. However, the mechanism of sleep deprivation-induced increased pain sensitivity is elusive. This study aims to explore the role of ROS in sleep deprivation (SD)-induced hyperalgesia and the underlying mechanism. A 48-h continuous SD was performed prior to the hind paw incision pain modeling in mice. We measured ROS levels, microglial activation, DNA damage and protein levels of iNOS, NLRP3, p-P65 and P65 in mouse spinal dorsal cord. The involvement of ROS in SD-induced prolongation of postsurgical pain was further confirmed by intrathecal injection of ROS inhibitor, phenyl-N-tert-butylnitrone (PBN). Pretreatment of 48-h SD in mice significantly prolonged postsurgical pain recovery, manifesting as lowered paw withdrawal mechanical threshold and paw withdrawal thermal latency. It caused ROS increase and upregulation of iNOS on both Day 1 and 7 in mouse spinal dorsal cord. In addition, upregulation of NLRP3 and p-P65, microglial activation and DNA damage were observed in mice pretreated with 48-h SD prior to the incision. Notably, intrathecal injection of PBN significantly reversed the harmful effects of SD on postsurgical pain recovery, hyperalgesia, microglial activation and DNA damage via the NF-κB signaling pathway. Collectively, ROS increase is responsible for SD-induced hyperalgesia through activating microglial, triggering DNA damage and enhancing NLRP3 inflammasome activity in the spinal dorsal cord.

Dehydrocorydaline alleviates sleep deprivation-induced persistent postoperative pain in adolescent mice through inhibiting microglial P2Y12 receptor expression in the spinal cord

“…Using the PWMT as an indicator pain, we found that SD decreased the pain threshold in mice, while spontaneous pain had not yet transpired, as result that persisted for approximately 10 days. This finding slightly deviates from the research results of Huang et al, 22 and may be attributed to differences in the duration of SD induction and the age of mice. More importantly, SD significantly increased and prolonged postoperative incisional pain.…”

“…The mouse SD model was induced in an SD chamber, as previously described. 22 In brief, mice subjected to SD were placed in an SD chamber (Xinruan, China) for 4.5 days and kept awake by a continuously rotating metal bar, which was set to the same speed, force, and direction of rotation to minimize experimental error. Food and water were placed on the walls of the chamber for the mice to take freely.…”

“…The plantar incision model was generated as previously reported. 22 In brief, the mice were anesthetized with sevoflurane, immobilized in the supine position, and the right hind paw was routinely disinfected with sterile iodophor and covered with cavity wipes. Next, an incision was made approximately 0.5cm incision from the heel of the right hind paw towards the toe, after which the muscle was gently and carefully elevated at the incision site.…”

Glucose competition between endothelial cells in the blood-spinal cord barrier and infiltrating regulatory T cells is linked to sleep restriction-induced hyperalgesia

“…Sleep loss may cause the accumulation of proinflammatory cytokines in blood and this may be cause by Enhanced efflux through the BBB [ 40 ]. Our previous study found that SR-induced hyperalgesia is associated with the inflammation of the spinal dorsal cord [ 27 ]. Consistently, our findings of increased levels of pro-inflammatory factors in the spinal cord and activation of glia confirmed the previous conclusion.…”

Farnesol Exerts Protective Effects against Chronic Sleep Deprivation‐Induced Cognitive Impairment via Activation SIRT1/Nrf2 Pathway in the Hippocampi of Adult Mice

“…[9] ROS plays a role in glutamatedependent long-term potentiation (LTP) and that moderate levels of ROS are vital for neuronal growth and development. [10] Studies have demonstrated that SD is accompanied by decreased antioxidant and increased ROS, [11][12][13] meanwhile leading to elevated levels of plasma pro-inflammatory factors such as tumor necrosis factor (TNF)-𝛼 and interleukin (IL)-1𝛼. [14] Silent information regulator factor 2-related enzyme 1 (Sirt1), a nicotinamide adenine dinucleotide-dependent histone deacetylase, regulates cellular responses to injury like antioxidant defense and apoptosis.…”