Dexmedetomidine Alleviated Endoplasmic Reticulum Stress via Inducing ER-phagy in the Spinal Cord of Neuropathic Pain Model

Yongda Liu; Shuang Wang; Zhibin Wang; Mengmeng Ding; Xingyue Li; Jiao Guo; Guang Han; Ping Zhao

doi:10.3389/fnins.2020.00090

Dexmedetomidine Alleviated Endoplasmic Reticulum Stress via Inducing ER-phagy in the Spinal Cord of Neuropathic Pain Model

Front Neurosci. 2020 Feb 28:14:90. doi: 10.3389/fnins.2020.00090. eCollection 2020.

Authors

Yongda Liu^{1

2}, Shuang Wang³, Zhibin Wang^{1

2}, Mengmeng Ding^{1

2}, Xingyue Li^{1

2}, Jiao Guo^{1

2}, Guang Han^{1

2}, Ping Zhao^{1

2}

Affiliations

¹ Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang, China.
² Department of Pain Management, Shengjing Hospital of China Medical University, Shenyang, China.
³ Department of Anesthesiology, First Affiliated Hospital of China Medical University, Shenyang, China.

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.

Keywords: ER stress; ER-phagy; autophagy; dexmedetomidine; neuropathic pain; spinal cord.