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Prenatal sevoflurane exposure may pose neurotoxicity to embryonic brain development and lead to cognitive dysfunction in offspring, but the underlying mechanism is still unclear. We aimed to investigate whether sevoflurane could cause neurogenesis abnormality and ferroptosis in embryonic prefrontal cortex (PFC) and to identify the role of nuclear factor-erythroid 2-related factor 2 (Nrf2) in the sevoflurane-related neurotoxicity.We used the rodents and primary neural stem cells to examine whether sevoflurane impacted proliferation, differentiation, ferroptosis and apoptosis in the neural stem cells of embryonic PFC. In addition, the expression of Nrf2 and the intensity of reactive oxygen species (ROS) were also assessed to explore the underlying molecular mechanism.Our results showed that sevoflurane exposure in third trimester could lead to neurogenesis inhibition and ferroptosis in-vivo embryonic PFC, with little influence on apoptosis. Moreover, a significant decrease in the expression of Nrf2 as well as an increase in ROS accumulation were also found in neural stem cells after sevoflurane anesthesia.We conclude that Nrf2-related neurogenesis inhibition and ferroptosis are a central mechanism contributing to sevoflurane-induced neurotoxicity in embryonic brain. The results of the present study are the first to demonstrate that ferroptosis and the expression of Nrf2 are involved in sevoflurane-related neurotoxicity in embryonic brain, which provides new vision for consideration in anesthesia-associated neurological abnormalities.

Morphine tolerance poses a great challenge for clinicians, whose pathogenesis has a close connection with microglial activation and neuroinflammation. Dihydroartemisinin (DHA) that derives from artemisinin, may serve as a potential anti-inflammatory drug. In this study, the effects as well as the underlying mechanism of DHA on suppressing microglial activation and neuroinflammation were explored. The microglial cell line BV-2 cells were induced by morphine and treated with DHA or minocycline. With the application of CCK-8, the cell viability was detected. Western blot was employed to assess the expressions of Ki67, IBa-1, and TLR4 and quantitative real-time PCR (qRT-PCR) was adopted to evaluate miRNA-16 (miR-16) expression. With the adoption of ELISA kits and qRT-PCR, the release of inflammatory cytokines was evaluated. Besides, luciferase reporter assay was applied to testify the binding relationship between miR-16 and TLR4. NF-κB expression was measured by immunofluorescence. DHA reduced cell viability and decreased protein expression of Ki67 and IBa-1 in morphine-induced BV-2 cells. Additionally, DHA contributed to the declined release of pro-inflammatory cytokines. miR-16 was down-regulated by morphine but was up-regulated by DHA concentration-dependently in BV-2 cells. The inhibition of miR-16 partly abolished the inhibitory effects of DHA on morphine-induced microglial activation and neuroinflammation. Moreover, TLR4 was found to be bound to miR-16, and the inhibitory effect of DHA on TLR4/NF-κB was partly reversed by miR-16 inhibition. In conclusion, DHA remarkably suppressed microglial activation and neuroinflammation through regulating miR-16-mediated TLR4/NF-κB signaling. This study may provide a new solution to improve clinical analgesic efficacy of morphine.

Background: There is obvious difference in individual response to opioids. Many studies have examined the correlation between the μ-opioid receptor 1 (OPRM1) 118A>G genetic variation and opioid requirement in pain treatment, but the conclusion remains elusive. Objectives: To investigate whether the OPRM1 118A>G genetic variation is associated with the opioid requirement. Study Design: Systematic review and meta-analysis. Methods: PubMed, Cochrane library, and EMBASE databases were systematically searched up to May 5, 2018, using the keywords “OPRM1,” “genetic variant,” “opioid,” and “pain” to identify reviews or meta-analyses on this topic. Two independent reviewers performed the data extraction and assessed study quality. The authors investigated the standardized mean difference (SMD) of opioid requirement between AA homozygotes and G allele carriers. The authors also examined the association between the OPRM1 118A>G genetic variation and adverse effects such as nausea and vomiting. Potential bias was assessed using the Egger’s test and the Begg’s test. Results: A total of 530 articles were retrieved from the databases searched, and 36 studies involving 8,609 patients were included in the final analysis. G allele carriers required a higher mean opioid dose (SMD: 0.17; 95% confidence interval [CI]: [0.12, 0.22]; P < 0.001) and displayed less nausea risk difference (RD): –0.04; 95% CI: [–0.06, –0.01]), but the incident rate of vomiting has no relationship with the genetic variant than AA homozygotes in a random-effects meta-analysis. Although there was no evidence of publication bias (Begg’s test: P = 0.333; Egger’s: P = 0.561), heterogeneity was present among studies (I2 = 54.3%). In the subgroup meta-analyses, there was also significance observed in the postoperative pain setting. Limitations: In all of the articles reviewed, postoperative pain and cancer pain were mostly discussed except for one in other pain setting. Conclusions: In this meta-analysis, the results indicate the OPRM1 A118G polymorphism was associated with the opioid requirement and the adverse effects in pain treatment especially in postoperative pain. This may provide valuable information for clinicians to adopt personalized pain management by properly using the opioids in individual patients. Key words: OPRM1, genetic variation, opioid, pain, side effect, review, meta-analysis

BackgroundPrevious study has illustrated that the factors can affect the duration of neuromuscular blockade. Vegetarian habits may affect osteoporosis and respiratory muscle tone.Case PresentationThe purpose of this report is to record the first unusual prolonged neuromuscular block by concomitant clindamycin in a vegetarian. ConclusionClinical doses of clindamycin may significantly prolong the neuromuscular blockade of “short-acting” no depolarizing muscle relaxants when the patient is so weak and vegetarian. This requires vigilance and routine monitoring of the neuromuscular junction by the anesthesiologist.

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Background We compared the effects of thoracic epidural analgesia (TEA) to conventional patient‐controlled analgesia (PCA) on several postoperative parameters of recovery after elective video‐assisted thoracoscopic (VATS) lobectomy. Methods Ninety‐eight patients undergoing elective VATS lobectomy were enrolled. The primary endpoint was pain score. Recovery of bowel function, length of stay in the postanesthesia care unit (PACU), duration of postoperative hospital stay, and complications were assessed. Continuous variables were expressed and compared between groups using either a two‐tailed Student's t or Mann‐Whitney U test. Recovery of bowel function was compared using the log‐rank test. Results Baseline characteristics between the groups were similar. Dynamic pain scores on postoperative days (PODs) 0–2 were significantly lower in the TEA group, as were resting pain scores on PODs 1 and 2 (P < 0.05). The mean duration to first flatus (16 ± 0.7 vs. 26 ± 0.7 hours; P < 0.001) and the mean length of stay in the PACU (34 vs. 67 minutes; P = 0.027) were shorter in the TEA compared to the PCA group, respectively. The only difference in postoperative complications was regarding confusion (5 TEA vs. 18 PCA patients; P = 0.002). No difference in overall length of stay was noted. Conclusions Compared to PCA, TEA provided better postoperative pain control after VATS lobectomy and facilitated postoperative recovery of bowel function without increasing the length of hospital stay. This beneficial effect of TEA might be attributed to the attenuation of sympathetic hyperactivation, improved analgesia, and reduced opioid use.

Pain is accompanied by high morbidity and imposes a substantial economic burden on individuals and society. Unfortunately, few effective therapeutic methods are available for pain relief. Berberine is a natural product that has attracted widespread attention in recent years. Studies have shown that berberine has various pharmacological effects, such as analgesic, anti-inflammatory, anti-bacterial, anti-oxidative stress, anti-thrombotic, anti-tumor, and hypoglycemic activity. According to the literature, berberine exerts its pain-relieving activity by downregulation of transient receptor potential vanilloid (TRPV)-1; suppression of toll-like receptor 4 (TLR4), mitogen-activated protein kinase (MAPK), and nuclear factor kappa-B (NF-κB); and modulation of μ opioid receptors. Moreover, berberine could regulate the dopamine and N-methyl-D-aspartic acid (NMDA) systems and induce the expression of Nrf2 to promote analgesia. The present literature review discusses the analgesic effects of berberine in inflammatory pain, neuropathic pain, cancer pain, chemotherapy pain, and morphine tolerance, and discusses the possible mechanism of berberine in pain regulation.

To assess the safety and efficacy of tranexamic acid (TA) on off-pump coronary artery bypass (OPCAB) surgery.Meta-analysis.Operating room, OPCAB surgery, all surgeries were elective measurements. Searching the following data sources respectively: PubMed/MEDLINE, the Cochrane Library, EMBASE and reference lists of identified articles, we performed a meta-analysis of postoperative 24h blood loss, postoperative allogeneic transfusion, re-operation for massive bleeding, postoperative mortality, and postoperative thrombotic complications.Using electronic databases, we selected 15 randomized control trials (RCTs), carried out between 2003 and 2016, with a total of 1250 patients for our review. TA significantly reduced the postoperative 24h blood loss (mean difference -213.32ml, 95% confidence intervals, -247.20ml to -179.43ml; P0.0001). And, TA also significantly reduced the risk of packed red blood cell (PRBCs) transfusion (risk ratio 0.62; 95% confidence intervals 0.51 to 0.76; P0.0001) and fresh frozen plasma (FFP) transfusion (0.65; 0.52 to 0.81; P0.001). There were no statistical significance on platelet transfusion (risk difference -0.00, 95% confidence interval -0.02 to 0.02; P=0.73) and re-operation (0.00, -0.02 to 0.02; P=1.00). No association was found between TA and morbility (risk difference -0.00, 95% confidence interval -0.02 to 0.02; P=0.99) and thrombotic complications (-0.01, -0.01 to 0.02; P=0.70).TA reduced the probability of receiving a PRBCs and FFP transfusion during OPCAB surgery. And no association with postoperative death and thrombotic events was found. However, further trials with an appropriate sample size are required to confirm TA safety in OPCAB surgery.

Morphine, a highly potent analgesic, is one of the most effective drugs for the treatment of severe pain associated with cancer. It directly acts on the central nervous system to relieve pain, but also cause secondary complications, such as addiction, respiratory depression and constipation due to its activities on peripheral tissues. Besides pain relief, morphine is of great importance on cancer management with its effect on tumor development being the subject of debate for many years with some contradictory findings. Morphine has shown both tumor growth-promoting and growth-inhibiting effects in many published research studies. And various signaling pathways have been suggested to be involved in these effects of morphine. Based on a thorough literature review, we summarized the double-faced effects of morphine in tumor development, including tumor cell growth and apoptosis, metastasis, angiogenesis, immunomodulation and inflammation. And we attempted to optimize morphine administration in cancer patients to attenuate its tumor growth-promoting effects.

Background Local anesthesia can reduce the response to surgical stress and decrease the consumption of opioids, which may reduce immunosuppression and potentially delay postoperative tumor recurrence. We compared paravertebral block (PVB) combined with general anesthesia (GA) and general anesthesia regarding their effects on postoperative pain and matrix metalloproteinase-9 (MMP-9) after video-assisted thoracoscopic surgery (VATS) lobectomy. Methods 54 patients undergoing elective VATS lobectomy at a single tertiary care, teaching hospital located in Qingdao between May 2, 2018 and Sep 28, 2018 were randomised by computer to either paravertebral block combined with general anesthesia or general anesthesia. The primary outcomes were pain scores at rest and on cough at 1, 4, 24, and 48 h after surgery. The secondary outcome were plasma concentrations of MMP-9, complications, and length of postoperative hospital stay. Results 75 were enrolled to the study, of whom 21 were excluded before surgery. We analyzed lobectomy patients undergoing paravertebral block combined with general anesthesia (n = 25) or general anesthesia (n = 24). Both groups were similar regarding baseline characteristics. Pain scores at rest at 4 h and 24 h, on cough at 4 h were lower in PVB/GA group, compared with GA group (P P Conclusions The paravertebral block/general anesthesia can provide statistically better pain relief and attenuate MMP-9 response to surgery and after VATS lobectomy. This technique may be beneficial for patients to recover rapidly after lung surgery and reduce postoperative tumor recurrence. Trial registration Chinese Clinical Trial registration number ChiCTR1800016379. Registered 28 May 2018.

Objective: To systematically evaluate the efficacy index and adverse reactions of dezocine in postoperative pain relief, provide statistical theoretical support for guiding clinical application. Methods: We extracted and analyzed multiple data of patients from the PubMed, Embase, The Cochrane Library and China National Knowledge Infrastructure (CNKI) for use in randomized controlled trials of various surgical postoperative pain relief. We used meta-analysis to study several measures of efficacy and safety of dezocine, including visual analogue score (VAS), Ramsay sedation score, mean arterial pressure (MAP), heart rate (HR), Pulse Oxygen Saturation (SpO2) and the incidence of adverse events(AEs). The material data were calculated and analyzed using Review Manager 5.3. Results: After exclusion of literature that did not meet the inclusion criteria, our analysis included 14 randomized controlled trials. The Mean Difference (MD) of VAS at 1 h/6 h/24h between the dezocine group and the placebo group was -1.37 (95% CI -2.07,-0.67, P=0.0001)，-0.52 (95% CI -1.04,0.01, P=0.05)，-0.10 (95% CI -0.39,0.20, P=0.52), respectively. The MD of Ramsay sedation score at 2h/8h was 1.21 (95% CI 0.67,1.75, P＜0.0001) and -0.17 (95% CI -0.59,0.26, P=0.44). The MD of MAP at T0/T1/T2 was -0.28 (95% CI -2.46,1.89, P=0.80)，-2.66 (95% CI -5.07,-0.25, P=0.03)，-4.53 (95% CI -6.17,-2.89, P＜0.00001). The MD of HR at T0/T1/T2 was -2.26(95% CI -4.32,-0.21, P=0.03)，-3.58(95% CI -5.21,-1.96, P＜0.0001),-3.75 (95% CI -11.55,4.04, P=0.35). The MD of SpO2 at T0/T1 was -0.90(95% CI -1.77,-0.03, P=0.04) and 0.36(95% CI 0.02,0.71, P=0.04).The odds ratio (OR) of AEs was 0.53(95% CI 0.39,0.71, P＜0.0001). Conclusion: Dezocine shows appropriate anesthetic efficacy and fewer adverse effects, which can reduce postoperative pain effectively.

Background: This study aimed to evaluate the impact of Infiltration between the Popliteal Artery and Capsule of the posterior Knee (IPACK) combined with an adductor canal block under the guidance of ultrasound on early motor function after Total Knee Arthroplasty (TKA). Methods: A sample of 60 cases who were scheduled for elective unilateral TKA were divided into two groups using random number table method: a group with IPACK combined with an adductor canal block (I group, n = 30), and a group with femoral nerve block combined with superior popliteal sciatic nerve block (FS group, n = 30). Before anesthesia induction was completed, the patients in I group received an ultrasound-guided adductor canal block with 15 mL of 0.375% ropivacaine and an IPACK block with 25 mL of ropivacaine, and the patients in FS group received a femoral nerve block and a superior popliteal sciatic nerve block with 20 mL of 0.375% ropivacaine under ultrasound guidance. Post-operation, all the patients received patient-controlled intravenous analgesia combined with an oral celecoxib capsule to relieve pain and maintain a visual analogue scale score of ≤ 3. Results: The quadriceps femoris muscle strength score was significantly higher in I group than in FS group (p = 0.001), while the modified Bromage score were significantly lower and walking distance results were significantly higher in I group than in FS group (both p = 0.000). Conclusion: Compared with femoral nerve block combined with superior popliteal sciatic nerve block, IPACK combined with adductor canal block had a mild impact on early motor functions after TKA.

There is obvious difference in individual response to opioids. Many studies have examined the correlation between the mu-opioid receptor 1 (OPRM1) 118AG genetic variation and opioid requirement in pain treatment, but the conclusion remains elusive.To investigate whether the OPRM1 118AG genetic variation is associated with the opioid requirement.Systematic review and meta-analysis.PubMed, Cochrane library, and EMBASE databases were systematically searched up to May 5, 2018, using the keywords "OPRM1," "genetic variant," "opioid," and "pain" to identify reviews or meta-analyses on this topic. Two independent reviewers performed the data extraction and assessed study quality. The authors investigated the standardized mean difference (SMD) of opioid requirement between AA homozygotes and G allele carriers. The authors also examined the association between the OPRM1 118AG genetic variation and adverse effects such as nausea and vomiting. Potential bias was assessed using the Egger's test and the Begg's test.A total of 530 articles were retrieved from the databases searched, and 36 studies involving 8,609 patients were included in the final analysis. G allele carriers required a higher mean opioid dose (SMD: 0.17; 95% confidence interval [CI]: [0.12, 0.22]; P0.001) and displayed less nausea risk difference (RD): -0.04; 95% CI: [-0.06, -0.01]), but the incident rate of vomiting has no relationship with the genetic variant than AA homozygotes in a random-effects meta-analysis. Although there was no evidence of publication bias (Begg's test: P = 0.333; Egger's: P = 0.561), heterogeneity was present among studies (I-squared = 54.3%). In the subgroup meta-analyses, there was also significance observed in the postoperative pain setting.In all of the articles reviewed, postoperative pain and cancer pain were mostly discussed except for one in other pain setting.In this meta-analysis, the results indicate the OPRM1 A118G polymorphism was associated with the opioid requirement and the adverse effects in pain treatment especially in postoperative pain. This may provide valuable information for clinicians to adopt personalized pain management by properly using the opioids in individual patients.OPRM1, genetic variation, opioid, pain, side effect, review, meta-analysis.

Background: We intended to investigate the effects of lung protective ventilation on the cognitive function level of patients with esophageal cancer. Methods: Overall, 132 patients with esophageal cancer admitted to Taian Central Hospital, Taian China from January 2013 to January 2017 were enrolled in the study. According to the random number table method, they were divided into observation group and control group, 66 cases each. All patients underwent general anesthesia for thoracoscopic esophageal cancer radical operation, and lung protective ventilation and conventional positive pressure ventilation were used respectively. The levels of SOD, NSE and MDA, MMSE score and WMS memory quotient in the blood of the elbow vein were compared between the two groups at different times. Results: The levels of SOD and MMSE in the observation group at T2 and T3 were higher than those in the control group, and the NSE and MDA levels were lower than those in the control group (P=0.013, 0.033, 0.015, 0.044, 0.034, 0.029, 0.014, 0.017). The incidence of postoperative cognitive impairment was lower in the observation group than in the control group (P=0.007). The WMS memory quotient scores of the patients in the T2, T3, and T4 observation groups were higher than those in the control group (p=0.009, 0.032, 0.040). Conclusion: Lung protective ventilation can reduce the oxidative stress injury for patients and improve their postoperative cognitive function and memory ability.

Background Neuropathic pain can develop after nerve injury, when deleterious changes occur in injured neurons and glia cells. Melanocortin 4 receptor (MC4R) is involved in the regulation of pain due to its high expressions in brain. Moreover, MC4R could mediate the c-Jun N-terminal kinase (JNK) signaling pathway, but whether the MC4R-regulated JNK signaling pathway participated in neuropathic pain after chronic constriction injury (CCI) is still unclear. Methods A total of 128 Sprague-Dawley rats were allocated into four experiment groups: the SHAM group, CCI + NaCl group, CCI + HS group, and CCI + SP + HS group. For the CCI + NaCl group, the sciatic nerves were ligated. For the SHAM group, an identical manner to the CCI without ligation was performed. For CCI + HS and CCI + SP + HS groups, rats were injected with MC4R inhibitor (HS014) and HS014 plus JNK inhibitor (SP600125), respectively, from days 3 to 14 after CCI. Paw withdrawal latency (PWL) and paw withdrawal threshold (PWT) were used to assess the nociceptive behavior. ELISA was used to detect the levels of inflammatory cytokines. qRT-PCR and Western blots (WB) were utilized to examine the mRNA and protein expressions of JNK signaling pathway-related genes. Meanwhile, the expression levels of MC4R and p-JNK were further evaluated by immunohistochemistry (IHC) and immunofluorescence (IF) experiments. Finally, in order to confirm the in vivo results, astrocytes were isolated and transfected with MC4R-overexpression plasmid. Furthermore, the protein expressions of JNK signaling pathway-related genes were tested by WB. Results It was showed that the values of PWL and PWT were significantly increased in CCI + HS group and CCI + SP + HS group compared with CCI + NaCl group. The increased interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-α (TNF-α) secretion in CCI + NaCl group was lowered by HS and SP + HS. MC4R, p-JNK, ATF3, and c-Jun levels were up-regulated with CCI surgery, but down-regulated with HS and SP + HS treatments. Moreover, the IHC and IF results further revealed that MC4R and p-JNK expressions in CCI + NaCl group were remarkably higher than those in HS group and HS + SP group. In vitro data also indicated that HS, SP, and SP + HS could down-regulate the expressions of MC4R, p-JNK, ATF3, and c-Jun in M1830 astrocytes. Conclusion Our findings indicated that MC4R is involved in neuropathic pain by regulating JNK signaling pathway after CCI.

Analgesia with opioids such as morphine is an effective clinical strategy for the treatment of cancer pain and chronic inflammatory pain. However, long-term use of morphine can cause morphine tolerance (MT), which limits the clinical application of opioids. Polysaccharopeptide from Trametes versicolor (TPSP) is a biologically active macromolecule that exerts anti-tumor, immune-enhancing and pain-relieving effects. In order to address the clinical problem of MT, herein, we investigated the inhibitory effect and mechanism of TPSP in rats with inflammatory pain-morphine tolerance. A chronic inflammatory osteoarthritis pain-morphine tolerance model was simulated by injection of complete Freund's adjuvant (CFA) through the ankle joint cavity and continuous intrathecal administration of morphine. Different doses of TPSP (50 μg/kg, 100 μg/kg and 200 μg/kg) were intrathecally administered for consecutive 3 weeks. Our results indicate that TPSP can significantly inhibit the development of morphine dependence and acute withdrawal in rats, alleviate the decrease of paw withdrawal mechanical threshold and heat stimulation retraction latency. In addition, mechanistically at the molecular level, these effects are elicited via up-regulation of the cannabinoid type 2 receptor, up-regulating the level of β-endorphin, and reducing the levels of IL-1, NO and PGE2. In summary, we report for the first time the application of TPSP as an adjunctive therapy strategy for the relief of MT in clinic.

P2X4 receptor (P2X4R), a subtype of P2 purinergic receptors, is an ATP-gated receptor through which activity of spinal microglia instigates pain hypersensitivity in various pain conditions. Accumulating evidence indicates that monocyte chemoattractant protein-1 (MCP-1) plays an important role in chronic pain facilitation, and it could stimulate microglia activation and involve in regulating P2X4R expression. However, the mechanism of MCP-1 in regulating the expression of P2X4R in microglia is poorly understood, and whether MCP-1 can aggravate pain via up-regulating spinal P2X4R expression in Cancer-induced Bone Pain (CIBP) remains unclear. In this study, we observed that Iba-1 and P2X4R expression is increased in microglia treated with MCP-1, and blockade with a selective CCR2 antagonist RS-504393 suppressed microglia activation and reduced P2X4R expression in cultured microglia. In response to MCP-1, the expression level of p-Akt was also increased and RS-504393 inhibited the increase. Besides, PI3K inhibitor LY 294002 could attenuate MCP-1-induced P2X4R expression in cultured microglia. MCP-1 was found to be associated with P2X4R expression and mechanical allodynia induced by CIBP in vivo since the expression of MCP-1 was increased in CIBP and RS-504393 alleviated the P2X4R expression and mechanical allodynia in CIBP. Moreover, RS-504393 also reduced the increase of p-Akt induced by CIBP. Inhibition of PI3K/Akt pathway may partly reduce MCP-1/CCR2-induced expression of P2X4R and mechanical allodynia in CIBP rats.

Chronic pain, including cancer-related pain, is a pain condition often caused by inflammation or dysfunctional nerves. Chronic pain treatment poses a significant health care challenge, where opioids especially morphine are widely used and patients often develop tolerance over time with aggravated pain. microRNA (miRNA) is known to play important roles in regulating gene expressions in the nervous system to affect neuronal network plasticity related to algogenesis and the developing of morphine tolerance. In this article, we reviewed studies conducted in rodent animal models investigating the mechanisms of miRNAs regulation in chronic pain with different phenotypes and morphine tolerance. In addition, the potential of targeting miRNAs for chronic pain and morphine tolerance treatment is also reviewed. Finally, we point out the directions of the future research in chronic pain and morphine tolerance.

Parkinson's disease (PD) is a progressive and degenerative disorder of the central nervous system, characterized by the loss of dopaminergic neurons and muscular rigidity. Treatment with propofol (2,6‑diisopropylphenol) has been observed to attenuate oxidative stress injury via inhibition of programmed cell death. Results from the present study indicate that propofol treatment attenuates 1‑methyl‑4‑phenylpyridinium (MPP+)‑induced oxidative stress, which was demonstrated by increased levels of reactive oxygen species, 4‑hydroxy‑2‑nonenal and protein carbonyls. Furthermore, it was demonstrated that propofol may ameliorate MPP+‑induced mitochondrial dysfunction by increasing the level of ATP and the mitochondrial membrane potential. MTT and lactate dehydrogenase assays indicated that propofol treatment reduces cell vulnerability to MPP+‑induced insult. Propofol was also observed to prevent apoptotic signals by reducing the ratio of Bcl‑2‑associated X protein to B‑cell lymphoma 2, reducing the expression level of cleaved caspase‑3 and attenuating cytochrome c release. Thus, propofol may present as a novel therapeutic strategy for the treatment of PD.

Previous studies have demonstrated that the Wnt/β‑catenin signaling pathway is critical to the induction and maintenance of chronic neuropathic pain caused by peripheral inflammation and nerve damage. Emerging evidence from recent studies suggests that epigenetic mechanisms may also be critical to the pathogenesis of chronic pain. The present study aimed to elucidate the epigenetic mechanisms underlying altered Wnt signaling and their involvement in CCI‑induced neuropathic pain in rat sciatic nerves. The results of the present study demonstrated a significant increase in the expression levels of Wnt3a in the dorsal horn of the rats with CCI. In addition, a significant increase in histone H3 acetylation, and a significant decrease in cytosine methylation in the promoter region of Wnt3a was observed in the dorsal horn of the rats with CCI. Intrathecal application of XAV939, which acts as an inhibitor of Wnt signaling, significantly decreased the expression levels of active β‑catenin, and attenuated the rat behavioral responses to thermal and mechanical pain stimuli. These results suggest that the epigenetic upregulation of Wnt3a in the dorsal horn contributes to the maintenance of pain‑induced behavior in rats with CCI.

Tibial component of total knee arthroplasty (TKA) is designed according to morphology of proximal tibia to a large extent. Owing to racial difference, current design of tibial component based on Caucasian may not be suitable for Chinese patients. Meanwhile, data of proximal tibial morphology in Chinese population is lacking. The objective of this research was to investigate proximal tibial morphology of northeast Chinese population. Computer tomography (CT) image of 164 northeast Chinese participants was collected. After three-dimensional (3D) reconstruction, size of tibia plateau and TKA resected surface were gauged to guide the design of TKA tibia prothesis in northeast Chinese population. Measurement of tibial size mainly includes tibial mediolateral length (tML), tibial medial/lateral anteroposterior length (tMAP and tLAP). Afterwards, tML/tAP ratio of tibia plateau and TKA resected surface were calculated as feature point of tibia prothesis. tMAP/tLAP ratio of TKA resected surface was calculated to represent tibial asymmetry degree. Medial and lateral posterior tibial slope (MPTS and LPTS) were also measured to give reference to posterior angle of tibia prothesis and angle of tibia osteotomy in TKA. Independent sample t test was performed to conduct statistical analysis, P

Morphine creates a neuroinflammatory response and enhances release of the proinflammatory cytokines like interleukin-1β (IL-1β), which compromises morphine analgesia as well as induces morphine tolerance. In this study, we attempted to investigate the mechanisms of morphine induced IL-1β synthesis and release. Microglial cells were treated with morphine (100 μM) once daily for 3 days. Control groups underwent the same procedure but received sterile saline injection instead of morphine. Toll-like receptor 4 (TLR4) and P2X4 receptor (P2X4R) signaling were analyzed using Western blot; immunofluorescence was used to detect the signaling of CD68; real-time RT-PCR and ELISA kit was used to measure the messenger RNA and protein synthesis and release level of IL-1β. Morphine enhanced IL-1β synthesis and P2X4R protein expression. TLR4 were responsible for morphine-induced IL-1β synthesis, while morphine-induced IL-1β release was via P2X4R. Morphine-induced IL-1β release is mediated by endocytosis of TLR4. These results indicated that TLR4 and P2X4R pathways mediated IL-1β synthesis and release in microglia followed chronic morphine. TLR4 internalization is the main mechanism of morphine-induced microglia activation and IL-1β release.

Background:Neuropathic pain is characterised by spontaneous ongoing or shooting pain and evoked amplified pain responses after noxious or non-noxious stimuli. Neuropathic pain develops as a result of lesions or disease affecting the somatosensory nervous system either in the periphery or centrally. Melanocortin 4 receptor (MC4R) plays an important role in the initiation of neuropathic pain but the underlying mechanisms are still unclear.Methods:Adult male Wistar rats were given chronic constriction injury (CCI) or sham operations. Part of CCI rats were intrathecally treated with HS014 (MC4R antagonist) or SB203580 (p38MAPK inhibitor). On the third, seventh and fourteenth day, the thermal threshold of operated paws was tested. In addition, the MC4R or phosphorylated p38MAPK (p-p38MAPK) levels of lumbar spinal cord were tested with ELISA (enzyme-linked immunosorbent assay), western blot and immunohistochemistry.Results:Here we demonstrate that (1) both HS014 and SB203580 reduced CCI reduced hyperalgesia (2) p-p38MAPK was increased after CCI with a time course parallel to that of the MC4R change, (3) The p38 activation was prevented by blocking MC4R with an antagonist HS014, but MC4R-IR was not prevented by SB203580. (4) MC4R and p-p38MAPK were located in the same cells.Conclusion:The mechanisms of neuropathic pain mediated by MC4R is related to the inhibition of p38MAPK activation. P38MAPK may be a downstream of MC4R.

The purpose of this study was to test the hypothesis that general anesthesia (GA) plus thoracic epidural anesthesia (TEA) has no impact on the outcomes of off-pump coronary artery bypass surgery (OPCABs) compared to GA followed by patient-controlled TEA (PCTEA), while GA plus TEA leads to a higher requirement for vasoactive drug use.Sixty-four patients, American Society of Anesthesiologists physical status II and III, who were scheduled for elective OPCABs, were offered an epidural catheter inserted at the T2-3 interspace and then randomized into 1 of 2 groups according to whether TEA was applied intraoperatively. The TEA(perio) group received GA plus TEA, while the TEA(post) group received GA alone. All groups had postoperative PCTEA. The number of requirements for vasoactive drugs and the extubation times were recorded. The analgesic effect was monitored by visual analog scale (VAS) pain scores. Heart rate, blood pressure, and blood gases were also monitored. The data are presented as mean values ± standard deviation, or medians with quartiles.The proportion of vasoactive drug use was significantly higher in the TEA(perio) group intraoperatively (before or during completion of anastomoses: 59.4 vs. 20.7%, p = 0.004; after completion of anastomoses: 53.1 vs. 17.2%, p = 0.007). There was no statistically significant difference in extubation times or VAS scores between the 2 groups.We conclude that GA plus TEA has no impact on the outcomes of OPCABs, while its use leads to a higher requirement for vasoactive drug use. GA followed by PCTEA facilitates the anesthesia administration, while it does not affect the extubation time and the postoperative analgesic effect.

Melanocortin 4 receptor (MC4R) is implicated in the initiation and maintenance of neuropathic pain. Although the effect of MC4R on neuropathic pain is known, it remains unclear how MC4R mediates neuropathic pain. In vitro MC4R activates mitogen-activated kinase (MAPK). Accordingly, we investigate whether MC4R activates the p38MAPK cascade in vivo to trigger pain behavior of Wistar rats after chronic constriction injury (CCI). Intrathecal injection of MC4R antagonist HS014 (5 μg/day) at the moment of CCI for seven days attenuated thermal hyperalgesia and mechanical allodynia. Similarly, intrathecal injection of a p38 inhibitor (SB203580, 10 mg/day) at the moment of CCI for seven days was also effective. To assess whether the effects of HS014 were mediated via increased p38MAPK activation, ipsilateral L4 and L5 dorsal root ganglion (DRG) were analyzed for MC4R and phosphorylated p38MAPK (p-p38MAPK) after CCI alone or CCI combined with HS014 treatment or SB203580 treatment. After CCI, DRG p-p38MAPK and MC4R were elevated by three, seven, and 14 days. Treatment with SB203580 blocked p38 activation. Both MC4R and phosphorylated p38 localized in DRG neurons. These data suggest a sequential role for MC4R and p38 in the induction and maintenance of neuropathic pain. MC4R plays an important role in the establishment of neuropathic pain following CCI, seemingly dependent on p38 activation.

Alterations in the spinal cord microenvironment in a neuropathic pain model in rats comprising right L-4 spinal nerve lesion were examined following 1, 2, 4 and 10 weeks using albumin and glial fibrillary acidic protein (GFAP) immunoreactivity. Rats subjected to nerve lesion showed pronounced activation of GFAP indicating astrocyte activation, and exhibited marked leakage of albumin, suggesting defects of the blood-spinal cord barrier (BSCB) function in the corresponding spinal cord segment. The intensities of these changes were most prominent in the gray matter of the lesioned side compared to the contralateral cord in both the dorsal and ventral horns. The most marked changes in albumin and GFAP immunoreaction were seen after 2 weeks and persisted with mild intensities even after 10 weeks. Distortion of nerve cells, loss of neurons and general sponginess were evident in the gray matter of the spinal cord corresponding to the lesion side. These nerve cell and glial cell changes was mainly evident in the areas showing leakage of endogenous albumin in the spinal cord. These novel observations indicate that chronic nerve lesion has the capacity to induce a selective increase in local BSCB permeability that could be instrumental in nerve cell and glial cell activation. These findings may be relevant to our current understanding on the pathophysiology of neuropathic pain.