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

Abstract

Studies demonstrated that spinal autophagy was impaired in spinal nerve ligation (SNL) rats. However, the relationship of endoplasmic reticulum (ER) stress and ERphagy 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 ERphagy 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 SNLinduced 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.

Dexmedetomidine at a dose of 1 µM attenuates H9c2 cardiomyocyte injury under 3 h of hypoxia exposure and 3 h of reoxygenation through the inhibition of endoplasmic reticulum stress

“…These findings indicate that DEX attenuates ERS-associated apoptosis and regulates ERS via an unknown mechanism that is inhibited by 4-PBA, as reflected by the decreased expression of CHOP, GRP78 and caspase-12 at the mRNA and protein levels. Consistent results were observed in a study by Liu et al ( 26 ), in which DEX intervention led to a significant reduction in the expression level of GRP78, a marker of ERS, and to ER-phagy, while treatment with 4-PBA successfully elevated the expression of GRP78. In a study by Liu et al ( 30 ), DEX exerted a similar effect in an animal model of cerebral ischemia-reperfusion injury, decreasing the levels of CHOP and GRP78.…”

“…In previous studies, DEX exhibited a protective role in the hearts of diabetic mice by interfering with ERS or autophagy, thereby suppressing IRI (6,23); however, the results were partially attributed to the diabetes context. Furthermore, researchers have focused on the study of cells other than cardiomyocytes, such as endothelial cells, under IRI or hypoxia/reoxygenation (H/R) conditions (24,25), and have examined several crucial ERS chaperones, proteins and apoptosis indicators that are produced by organs other than the heart under IRI or H/R conditions (6,(26)(27)(28)(29)(30). These studies have shown that DEX effectively regulates the function of non-cardiomyocytes and interferes with the ERS signaling pathway under these conditions.…”

Dexmedetomidine as an adjuvant for patients undergoing breast cancer surgery

“…[ 29 ] It was also reported that the NRS at rest was positively correlated with serum IL-6 at postoperative day 1; the NRS at walking was positively correlated with CRP at postoperative day 1 and IL-6 at postoperative day 1 to day 3. [ 31 ] Furthermore, Liu et al [ 32 ] suggested that DEX may alleviate pain via elevating endoplasmic reticulum autophagy, showing the downregulated expression of Grp78, LC3-I, p62, while upregulated expression of and FAM134B. The study of Lee et al [ 33 ] revealed that DEX may exert non-nociceptive roles by acting as an inhibitor of TRPV1 (transient receptor potential cation channel subfamily V member in the peripheral nervous system and then reducing capsaicin-induced calcium responses to block the transmission of pain signals.…”

Endoplasmic reticulum–mitochondria interplay in chronic pain: The calcium connection

“…Intrathecal treatment of chemical chaperones, 4-PBA and tauroursodeoxycholic acid (TUDCA), was also found to partially reverse nociceptive behaviours after SNL. 147 , 148 In the periphery, Yamaguchi et al. 142 found that BiP, XBP1, and CHOP expression was elevated in the sensory neurons as early as one day post-SNL only to recover within a week.…”