Abstract
Studies demonstrated that spinal autophagy was impaired in spinal nerve ligation (SNL) rats. However, the relationship of endoplasmic reticulum (ER) stress and ER-phagy and whether dexmedetomidine (DEX) modulates ER-phagy remain unclear. In this study, male Sprague–Dawley (SD) rats and the SNL animal model were used. 4-Phenylbutyric acid (4-PBA), tunicamycin (TM), rapamycin (RAP), and 3-methyladenine (3-MA) were intrathecally administered, respectively to demonstrate the relationship of ER stress and ER-phagy. Dexmedetomidine (30 μg/kg) was administered as treatment. Mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) tests were performed to evaluate nociceptive hypersensitivity. Protein expressions were examined by Western blot, and the location of glucose-regulated protein 78 (Grp78) was examined by immunofluorescence staining. SNL induced ER stress and ER-phagy impairment. ER stress was altered in rostral ventromedial medulla (RVM); 4-phenylbutyric acid induced analgesic effect via inhibiting ER stress and unfolded protein response (UPR) pathways to induce ER-phagy; tunicamycin led to worsening pain through enhancing ER stress and UPR pathways to further impair ER-phagy. Rapamycin provided analgesic effect through enhancing ER-phagy to relieve SNL-induced ER stress and UPR pathway activation; 3-methyladenine deteriorated pain via further impairing ER-phagy to aggravate ER stress. Dexmedetomidine provided analgesic effect through elevating ER-phagy. In conclusion, ER stress led to ER-phagy impairment in the spinal cord of SNL rats and participated in the nociceptive descending system. ER-phagy impairment was both a trigger and an effector of ER stress via UPR pathways in SNL rats. Dexmedetomidine targeted ER-phagy to provide analgesic effect.
Highlights
Cellular stress, free radical exposure, calcium depletion, and unfolded or misfolded protein accumulation in endoplasmic reticulum (ER) lumen lead to ER stress (Sisinni et al, 2019)
Spinal nerve ligation induced glucose-regulated protein 78 (Grp78) high expression in L3–L5 spinal cord (Figures 2B,D), suggesting that ER stress participates in nociceptive ascending modulation system
Expression of FAM134B was significantly upregulated in spinal cord (Figures 2B,D), suggesting that the level of ER sheets that bind to autophagosomes was increased
Summary
Free radical exposure, calcium depletion, and unfolded or misfolded protein accumulation in endoplasmic reticulum (ER) lumen lead to ER stress (Sisinni et al, 2019). The unfolded protein response (UPR) is a response process that plays a critical role in restoring homeostasis following ER stress (Geronimo-Olvera and Massieu, 2019). We examined PERK/activating transcription factor (ATF) 4, IRE-1/c-Jun N-terminal kinase (JNK), and ATF6 pathways to reveal the possible mechanism underlying UPR and autophagy (Sisinni et al, 2019). Autophagy (macroautophagy) controls homeostasis in various biological and pathological conditions, which could be a nonselective mechanism that degrades general cytosol, proteins, and organelles by lysosomes. Studies suggested that autophagy might provide a protective mechanism in neuropathic pain animal models and clinical trials (Liu X. et al, 2019). The expression of autophagic markers microtubule-associated protein II light chain 3 (LC3) and p62 was examined to evaluate the autophagy level in spinal cord. LC3 is the most widely investigated marker in understanding autophagy, which is capable of evaluating the level of autophagysomes (Forrester et al, 2019). p62/Sequestosome 1 (SQSTM1) can bind to LC3, incorporate into autophagosomes directly, and be degraded by autophagy process (Lim et al, 2014)
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