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Abstract Background Neuropathic pain is chronic pain and has few effective control strategies. Studies have demonstrated that microRNAs have functions in neuropathic pain. However, no study has been conducted to demonstrate the role and mechanism of microRNA (miR)-31-5p in neuropathic pain. Accordingly, this study sought to determine the pathological role of miR-31-5p in chronic constriction injury (CCI) -induced neuropathic pain mouse models. Methods We used CCI surgery to establish mouse neuropathic pain model. Behavioral tests were performed to evaluate pain sensitivity of mice. Expressions of miR-31-5p and inflammatory cytokines in dorsal root ganglion (DRG) were examined by polymerase chain reaction. Animals or cells were received with/without miR-31-5p mimic or inhibitor to investigate its role in neuropathic pain. The mechanism of miR-31-5p was assayed using western blotting, immunofluorescence staining and dual-luciferase reporter assay. Results We found that CCI led to a significant decrease in miR-31-5p levels. Knockout of miR-31-5p and administration of miPEP31 exacerbated pain in C57BL/6 mice. Meanwhile, miR-31-5p overexpression increased the paw withdrawal threshold and latency. TRAF6 is one of the target gene of miR-31-5p, which can trigger a complex inflammatory response. TRAF6 was associated with pain and that reducing the DRG expression of TRAF6 could alleviate pain. In addition, miR-31-5p overexpression inhibited the TRAF6 expression and reduced the neuroinflammatory response. Conclusions All the results reveal that miR-31-5p could potentially alleviate pain in CCI mouse models by inhibiting the TRAF6 mediated neuroinflammatory response. MiR-31-5p upregulation is highlighted here as new target for CCI treatment.

Abstract Bupivacaine, a local anaesthetic, is widely applied in the epidural or subarachnoid space to clinically manage acute and chronic pain. However, the underlying mechanisms are complex and unclear. Glycine transporter 1 (GlyT1) in the spinal cord plays a critical role in various pathologic pain conditions. Therefore, we sought to determine whether bupivacaine exerts its analgesic effect by regulating GlyT1 expression and to determine the underlying mechanisms of regulation. Primary astrocytes prepared from the spinal cord of rats were treated with bupivacaine. The protein levels of GlyT1, brain-derived neurotrophic factor (BDNF) and phosphorylated adenosine 5′-monophosphate (AMP)-activated protein kinase α (p-AMPKα) were measured by western blotting or immunofluorescence. In addition, 7,8-dihydroxyflavone (7,8-DHF, BDNF receptor agonist) and AMPK shRNA were applied to verify the relationship between the regulation of GlyT1 by bupivacaine and the p-AMPKα/BDNF signalling pathway. After treatment with bupivacaine, GlyT1 expression was diminished in a concentration-dependent manner, while the expression of BDNF and p-AMPK was increased. Moreover, 7,8-DHF decreased GlyT1 expression, and AMPK knockdown suppressed the upregulation of BDNF expression by bupivacaine. Finally, we concluded that bupivacaine reduced GlyT1 expression in spinal astrocytes by activating the p-AMPKα/BDNF signalling pathway. These results provide a new mechanism for the analgesic effect of intrathecal bupivacaine in the treatment of acute and chronic pain.

Neuropathic pain (NP) is a chronic and intractable disease that is widely present in the general population. It causes painful behavior and even mood changes such as anxiety and depression by altering the metabolism of substances. However, there have been limited metabolomics studies conducted in relation to neuropathic pain. Therefore, in this study, the effects of NP on metabolites in serum and the dorsal root ganglion (DRG) were investigated using a non-targeted metabolomics approach detected by gas chromatography–mass spectrometry (GC-MS) and liquid chromatography–mass spectrometry (LC-MS) to uncover differential metabolites and affected metabolic pathways associated with NP. Sixty mice were divided into the following two groups: a chronic constriction injury (CCI) of the sciatic nerve group and a sham group (n = 30, each). After 7 days of CCI modeling, the metabolite profiles of serum and the DRG were analyzed using GC/LC-MS for both the CCI and sham groups of mice. Multivariate analysis revealed differential metabolites and altered metabolic pathways between the CCI and sham groups. In the CCI group, our findings provided insights into the complex phospholipid, amino acid and acylcarnitine metabolic perturbations of DRG metabolism. In addition, phospholipid metabolic disorders and impaired glucose metabolism were observed in the serum. Moreover, the metabolic differences in the DRG and serum were correlated with each other. The results from this untargeted metabolomics study provide a perspective on the metabolic impact of NP on serum and the DRG.

Abstract Background The α2-adrenergic agonist dexmedetomidine (DEX) is a sedative and can be used as an adjunct to hypnotics. The study sought to evaluate the effects of different doses of DEX on the requirements for propofol for loss of consciousness (LOC) in patients monitored via the bispectral index (BIS). Methods In this randomized, double-blind, three arm parallel group design and placebo-controlled trial, 73 patients aged between 18 and ~ 65 years with a BMI range of 18.0–24.5 kg·m− 2 and an American Society of Anesthesiologists (ASA) grade I or II who were scheduled for general anesthesia at the General Hospital of Ningxia Medical University were included in this study. Anesthesiologists and patients were blinded to the syringe contents. All patients were randomly assigned in a 1:1:1 ratio to receive a 0.5 μg·kg− 1 DEX infusion (0.5 μg·kg− 1 DEX group; n = 24), a 1.0 μg·kg− 1 DEX infusion (1.0 μg·kg− 1 DEX group; n = 25) or a saline infusion (control group; n = 24) for 10 min. Propofol at a concentration of 20 mg·kg− 1·h− 1 was then infused at the end of the DEX or saline infusion. The propofol infusion was stopped when the patient being infused lost consciousness. The primary endpoint were propofol requirements for LOC and BIS value at LOC. Results The data from 73 patients were analyzed. The propofol requirements for LOC was reduced in the DEX groups compared with the control group (1.12 ± 0.33 mg·kg− 1 for the 0.5 μg·kg− 1 DEX group vs. 1.79 ± 0.39 mg·kg− 1 for the control group; difference, 0.68 mg·kg− 1 [95% CI, 0.49 to 0.87]; P = 0.0001) (0.77 ± 0.27 mg·kg− 1 for the 1.0 μg·kg− 1 DEX group vs. 1.79 ± 0.39 mg·kg− 1 for the control group; difference, 1.02 mg·kg− 1 [95% CI, 0.84 to 1.21]; P = 0.0001). The propofol requirements for LOC was lower in the 1.0 μg·kg− 1 DEX group than the 0.5 μg·kg− 1 DEX group (0.77 ± 0.27 mg·kg− 1 vs. 1.12 ± 0.33 mg·kg− 1, respectively; difference, 0.34 mg·kg− 1 [95% CI, 0.16 to 0.54]; P = 0.003). At the time of LOC, the BIS value was higher in the DEX groups than in the control group (67.5 ± 3.5 for group 0.5 μg·kg− 1 DEX vs. 60.5 ± 3.8 for the control group; difference, 7.04 [95% CI, 4.85 to 9.23]; P = 0.0001) (68.4 ± 4.1 for group 1.0 μg·kg− 1 DEX vs. 60.5 ± 3.8 for the control group; difference, 7.58 [95% CI, 5.41 to 9.75]; P = 0.0001). Conclusion The study showed that DEX (both 0.5 and 1.0 μg·kg− 1 DEX) reduced the propofol requirements for LOC. DEX pre-administration increased the BIS value for LOC induced by propofol. Clinical trial registration The study was registered at ClinicalTrials.gov (trial ID: NCT02783846 on May 26, 2016).

Protein arginine methyltransferase-6 participates in a range of biological functions, particularly RNA processing, transcription, chromatin remodeling, and endosomal trafficking. However, it remains unclear whether protein arginine methyltransferase-6 modifies neuropathic pain and, if so, what the mechanisms of this effect. In this study, protein arginine methyltransferase-6 expression levels and its effect on neuropathic pain were investigated in the spared nerve injury model, chronic constriction injury model and bone cancer pain model, using immunohistochemistry, western blotting, immunoprecipitation, and label-free proteomic analysis. The results showed that protein arginine methyltransferase-6 mostly co-localized with β-tubulin III in the dorsal root ganglion, and that its expression decreased following spared nerve injury, chronic constriction injury and bone cancer pain. In addition, PRMT6 knockout (Prmt6–/–) mice exhibited pain hypersensitivity. Furthermore, the development of spared nerve injury–induced hypersensitivity to mechanical pain was attenuated by blocking the decrease in protein arginine methyltransferase-6 expression. Moreover, when protein arginine methyltransferase-6 expression was downregulated in the dorsal root ganglion in mice without spared nerve injury, increased levels of phosphorylated extracellular signal-regulated kinases were observed in the ipsilateral dorsal horn, and the response to mechanical stimuli was enhanced. Mechanistically, protein arginine methyltransferase-6 appeared to contribute to spared nerve injury–induced neuropathic pain by regulating the expression of heterogeneous nuclear ribonucleoprotein-F. Additionally, protein arginine methyltransferase-6-mediated modulation of heterogeneous nuclear ribonucleoprotein-F expression required amino acids 319 to 388, but not classical H3R2 methylation. These findings indicated that protein arginine methyltransferase-6 is a potential therapeutic target for the treatment of peripheral neuropathic pain.