Effect and Safety of Remifentanil Patient-Controlled Analgesia Compared with Epidural Analgesia in Labor: An Updated Meta-Analysis of Randomized Controlled Trials.

PURPOSE: The study was aimed to systematically assess the effect and safety of remifentanil patient-controlled analgesia (rPCA) versus epidural analgesia (EA) during labor. METHODS: Eligible trials were retrieved from PubMed, EMBASE, ScienceDirect, and Cochrane Library before April 2020. The primary outcomes were patient satisfaction with pain relief and average visual analog scale (VAS) pain scores during labor; the secondary outcomes were rate of spontaneous delivery, oxygen desaturation, maternal hyperthermia, and neonatal Apgar scores <7 at 1 and 5 min. RESULTS: Eleven studies involving 3,039 parturients were included. We found that parturients receiving rPCA were similarly satisfied with pain relief compared to those receiving EA (standardized mean difference: -0.19; 95% confidence interval [CI]: -0.57, 0.18), though had significantly higher VAS pain scores during labor (weighted mean difference: 1.41; 95% CI: 0.32, 2.50). The rate of spontaneous delivery was comparable. rPCA increased the risk of maternal oxygen desaturation (risk ratio [RR]:3.23, 95% CI: 1.98, 5.30). There was no statistical significance regarding hyperthermia (RR: 0.49, 95% CI: 0.24, 1.01). No significant difference was found for neonatal Apgar scores <7 at 1 and 5 min. CONCLUSION: rPCA could be an optional alternative for pain relief to EA without worsening maternal satisfaction with pain relief, delivery modes, or neonatal morbidity. However, rPCA was associated with higher pain intensity during labor and higher incidence of maternal oxygen desaturation. The routine use of rPCA in labor must be armed with close respiratory monitoring. Continued well-designed studies are required to provide more robust evidence.

Dexmedetomidine attenuates neuronal injury after spinal cord ischaemia-reperfusion injury by targeting the CNPY2-endoplasmic reticulum stress signalling.

Dexmedetomidine (Dex) has been proven to exert protective effects on multiple organs in response to ischaemia-reperfusion injury, but the specific mechanism by which this occurs has not been fully elucidated. The purpose of this study was to investigate whether Dex attenuates spinal cord ischaemia-reperfusion injury (SCIRI) by inhibiting endoplasmic reticulum stress (ERS). Our team established a model of SCIRI and utilized the endoplasmic reticulum agonist thapsigargin. Dex (25 g/kg) was intraperitoneally injected 30 minutes before spinal cord ischaemia. After 45 minutes of ischaemia, the spinal cord was reperfused for 24 hours. To evaluate the neuroprotective effect of Dex on SCIRI, neurological function scores were assessed in rats and apoptosis of spinal cord cells was determined by TUNEL staining. To determine whether the endoplasmic reticulum apoptosis pathway CNPY2-PERK was involved in the neuroprotective mechanism of Dex, the expression levels of related proteins (CNPY2, GRP78, PERK, CHOP, caspase-12, caspase-9 and caspase-3) were detected by western blot analysis and RT-PCR. We observed that Dex significantly increased the neurological function scores after SCIRI and decreased apoptosis of spinal cord cells. The expression of ERS-related apoptosis proteins was significantly increased by SCIRI but was significantly decreased in response to Dex administration. Taken together, the results of this study indicate that Dex may attenuate SCIRI by inhibiting the CNPY2-ERS apoptotic pathway.

LPS Pretreatment Attenuates Cerebral Ischaemia/Reperfusion Injury by Inhibiting Inflammation and Apoptosis.

BACKGROUND/AIMS: Lipopolysaccharide (LPS) pretreatment has a strong neuroprotective effect on cerebral ischaemia/reperfusion injury (IRI), but the mechanism has not been fully elucidated to date. This study investigated the effect of LPS pretreatment on the pathway mediated by endoplasmic reticulum (ER) stress-CCAAT/enhancer-binding protein- homologous protein (CHOP) and the role of this pathway on cerebral ischaemia/reperfusion (I/R)-induced inflammation and apoptosis. METHODS: Healthy male BALB/c mice were randomised into four groups as follows: sham operation group (sham group, n=30); LPS group (BALB/c mice treated with LPS, n=30); ischaemia/reperfusion group (I/R group, n=30) and I/R+LPS group (BALB/c mice treated with LPS before ischaemia, n=30). The mice were pre-treated with LPS (0.2 mg/kg) intra-peritoneally for three days prior to cerebral ischaemia. After 24 hours, the neurological deficit score, TTC staining and TUNEL assay were used to assess the neuroprotective effect of the LPS pretreatment against cerebral IRI. To assess whether the ER stress-CHOP pathway participated in the LPS-pretreatment neuroprotective mechanism, the expression levels of related proteins (GRP78, CHOP, caspase-12 and caspase-3) from the ischaemic cortical penumbra were detected via a western blot analysis. An immunohistochemical study was used to detect the expression and location of CHOP in the cortical penumbra. To further assess the protective effect of the LPS pretreatment, the concentrations of inflammatory factors (TNF-α, IL-6, IL-1ß and IL-10) in the cortical penumbra were measured by ELISA, and ER stress-CHOP pathway inflammation-related caspase-11 was analysed through western blot analysis. RESULTS: As demonstrated by the experiments, the pretreatment with LPS significantly reduced the neurological deficit score and the infarct size of cerebral IRI. The expression levels of ER stress-CHOP pathway related proteins (GRP78, CHOP, caspase-12 and caspase-3) from the cortical penumbra were significantly decreased by LPS, as well as the level of apoptosis in the cells in the brain. Immunohistochemistry showed that the expression of CHOP significantly decreased after the LPS pretreatment. Furthermore, the concentrations of inflammatory factors (TNF-α, IL-1ß, IL-6) were reduced after the LPS pretreatment, whereas the anti-inflammatory cytokine IL-10 was upregulated. In addition, ER stress-CHOP pathway inflammation-related caspase-11 expression was significantly suppressed after the pretreatment with LPS. CONCLUSIONS: LPS pretreatment significantly ameliorates the effects of cerebral IRI by inhibiting inflammation and apoptosis, and the potential mechanism of the neuroprotective effect may be associated with the ER stress-CHOP mediated signalling pathway.

Sigma-1 receptor regulates the endoplasmic reticulum stress pathway in the protective mechanism of dexmedetomidine against hyperoxia-induced lung injury.

Perioperative hyperoxia therapy is of great significance to save the lives of patients, but little is known about the possible mechanisms that induce hyperoxia-induced acute lung injury (HALI) and the measures for clinical prevention and treatment. In this experiment, the models were established with a feeding chamber with automatic regulation of oxygen concentration. The results showed that with the increase in inhaled oxygen concentration and the prolongation of exposure time, the severity of lung injury also increases significantly, reaching the diagnostic indication of HALI after 48 h of inhaling 95 % oxygen concentration. Subsequently, according to the dynamic changes of apoptosis in lung specimens, and the expression changes in Sig-1R-regulated ER stress pathway proteins (Sig-1R, GRP78, p-PERK, ATF6, IRE1, Caspase-12, ATF4, CHOP, Caspase-3 and p-JNK), it was confirmed that the Sig-1R-regulated ER stress signaling pathway was involved in the occurrence of HALI. To explore the preventive and therapeutic effects of routine clinical medication on HALI during the perioperative period, our research group selected dexmedetomidine (Dex) with lung protection. The experimental results revealed that Dex partially reversed the changes in the expression levels of Sig-1R-regulated ER stress pathway proteins. These results preliminarily confirmed that Dex may inhibit apoptosis induced by high oxygen concentration through the Sig-1R-regulated ER stress signaling pathway, thus playing a protective role in HALI.

[Participation of glucocorticoid receptors in morphine tolerance development through the signal pathway of extracellular signal-regulated kinase].

OBJECTIVE: To investigate the mechanism of glucocorticoid receptors (GR) participating in morphine tolerance development via the extracellular signal-regulated kinase (ERK) signal pathway. METHODS: Forty healthy male SD rats were implanted with intrathecal catheters and then randomized into 4 groups: Group C received an intrathecal injection of 10 µl saline, Group M 10 µg morphine, Group MR 10 µg morphine followed by 2 µg GR antagonist RU38486 and Group MD 10 µg morphine followed by 4 µg GR agonist dexamethasone (DEX) respectively. Each intrathecal drug was administered twice daily for 7 days. Tail-flick test was employed to evaluate the thermal hyperalgesia. After tail-flick test at Day 8, the lumbar intamescentias were isolated by Western blot to examine the protein expressions of Mu opioid receptor (MOR), GR and pERK. And terminal deoxynucleotidyl transferase mediated X-dUTP nick end labeling (TUNEL) stain was performed. RESULTS: DEX and RU38486 enhanced and inhibited morphine induced hyperalgesia to heat respectively. Compared with Group M (count of spinal dorsal horn apoptotic cells 5.4 ± 1.1, protein expression: MOR 37 ± 5, GR 20 ± 6, pERK(1) 39 ± 4, pERK(2) 41 ± 5), apoptotic cells decreased in Group MR (3.2 ± 0.4) (P < 0.01) and increased in Group MD (16.0 ± 1.6) (P < 0.01); the protein expressions of MOR (28 ± 5), GR (12 ± 6), pERK(1)(33 ± 4) and pERK(2)(34 ± 5) were down-regulated in Group MR (P < 0.01) while up-regulated in Group MD (55 ± 6, 28 ± 9, 49 ± 6, 59 ± 5) (P < 0.01). CONCLUSION: The activity of glucocorticoid receptors affects the morphine-induced spinal neural apoptosis and the expression of spinal pERK in morphine tolerance.

Berberine Attenuates Cerebral Ischemia-Reperfusion Injury Induced Neuronal Apoptosis by Down-Regulating the CNPY2 Signaling Pathway.

Berberine (BBR) has a neuroprotective effect against ischemic stroke, but its specific protective mechanism has not been clearly elaborated. This study explored the effect of BBR on the canopy FGF signaling regulator 2 (CNPY2) signaling pathway in the ischemic penumbra of rats. The model of cerebral ischemia-reperfusion injury (CIRI) was established by the thread embolization method, and BBR was gastrically perfused for 48 h or 24 h before operation and 6 h after operation. The rats were randomly divided into four groups: the Sham group, BBR group, CIRI group, and CIRI + BBR group. After 2 h of ischemia, followed by 24 h of reperfusion, we confirmed the neurologic dysfunction and apoptosis induced by CIRI in rats (p < 0.05). In the ischemic penumbra, the expression levels of CNPY2-regulated endoplasmic reticulum stress-induced apoptosis proteins (CNPY2, glucose-regulated protein 78 (GRP78), double-stranded RNA-activated protein kinase-like ER kinase (PERK), C/EBP homologous protein (CHOP), and Caspase-3) were significantly increased, but these levels were decreased after BBR treatment (p < 0.05). To further verify the inhibitory effect of BBR on CIRI-induced neuronal apoptosis, we added an endoplasmic reticulum-specific agonist and a PERK inhibitor to the treatment. BBR was shown to significantly inhibit the expression of apoptotic proteins induced by endoplasmic reticulum stress agonist, while the PERK inhibitor partially reversed the ability of BBR to inhibit apoptotic protein (p < 0.05). These results confirm that berberine may inhibit CIRI-induced neuronal apoptosis by downregulating the CNPY2 signaling pathway, thereby exerting a neuroprotective effect.

CaSR activates PKCδ to induce cardiomyocyte apoptosis via ER stress­associated apoptotic pathways during ischemia/reperfusion.

Endoplasmic reticulum (ER) stress can be activated by ischemia/reperfusion (I/R) injury in cardiomyocytes. Persistent ER stress, with an increase in intracellular Ca2+ ([Ca2+]i) concentration, leads to apoptosis. Protein kinase C (PKC) has a key role in myocardial damage by elevation of [Ca2+]i. The calcium­sensing receptor (CaSR), a G protein­coupled receptor, can increase the release of [Ca2+]i from the ER through the inositol triphosphate receptor (IP3R). Intracellular calcium overload has been demonstrated to cause cardiac myocyte apoptosis during I/R. However, the associations between PKC, CaSR and ER stress are not clear. The present study examined the hypothesis that activation of PKCδ by CaSR participates in ER stress­associated apoptotic pathways within myocardial I/R. Rat hearts were subjected to 30 min of ischemia in vivo, followed by reperfusion for 120 min. GdCl3 (a CaSR activator) was used to elevate the intracellular Ca2+ concentration, but the Ca2+ concentration in the ER was significantly decreased during I/R. Following exposure to GdCl3, expression levels of CaSR, glucose­regulated protein 78 (GRP78), Caspase­12, phosphorylated JNK and Caspase­3 were increased, and the ratios of apoptotic myocardial cells were significantly increased. By contrast, following exposure to rottlerin, a PKCδ inhibitor, the expression levels of these proteins and the ratio of apoptotic myocardial cells were significantly reduced. The present study also demonstrated that PKCδ translocated into the ER to induce an ER stress response and participate in the ER stress­related apoptosis pathway. These results confirmed that CaSR activated PKCδ to induce cardiomyocyte apoptosis through ER stress­associated apoptotic pathways during I/R in vivo.

Dexmedetomidine inhibits neuronal apoptosis by inducing Sigma-1 receptor signaling in cerebral ischemia-reperfusion injury.

Dexmedetomidine is known to alleviate cerebral ischemia-reperfusion injury (CIRI). We established a rat model of CIRI, which exhibited higher neurological deficit scores and a greater number of apoptotic cells in the cerebral ischemic penumbra than controls. Dexmedetomidine reversed the neuronal apoptosis and improved neurological function in this model. We then examined Sigma-1 receptor (Sig-1R) expression on the endoplasmic reticulum (ER) in brain tissues at different reperfusion time points. Sig-1R expression increased with CIRI and decreased with increasing reperfusion times. After 24 hours of reperfusion, dexmedetomidine upregulated Sig-1R expression, and ER stress proteins (GRP78, CHOP, JNK and Caspase-3) were detected in brain tissues with Western blotting. Moreover, GRP78 expression followed a pattern similar to Sig-1R. Dexmedetomidine induced GRP78 expression but inhibited CHOP, Caspase-3 and phosphorylated-JNK expression in brain tissues. A Sig-1R-specific inhibitor reduced GRP78 expression and partially inhibited the upregulation of GRP78 by dexmedetomidine. The inhibitor also increased CHOP and Caspase-3 expression and partially reversed the inhibitory effects of dexmedetomidine on these pro-apoptotic ER stress proteins. These results suggest that dexmedetomidine at least partially inhibits ER stress-induced apoptosis by activating Sig-1R, thereby attenuating brain damage after 24 hours of ischemia-reperfusion.

Spinal glucocorticoid receptor­regulated chronic morphine tolerance may be through extracellular signal­regulated kinase 1/2.

Opioid use has been limited in the treatment of chronic pain due to their side effects, including analgesic tolerance. Previous studies demonstrated that glucocorticoid receptors (GRs) may be involved in the development of chronic morphine tolerance; however, the mechanism remains unknown. It was hypothesized that the expression of spinal phosphorylated mitogen­activated protein kinase [MAPK; phosphorylated extracellular signal­regulated kinase (ERK)] is regulated through the spinal GRs, following chronic treatment with morphine. In the first experiment, the experimental rats were randomly divided into four groups: Control, morphine, morphine+GR antagonist mifepristone (RU38486) and morphine+GR agonist dexamethasone (Dex). Each group was treated with continuous intrathecal (IT) injection of the drugs for 6 days. The expression of GRs and MAPK 3/1 (p­ERK 1/2) in the spinal dorsal horn was detected by western blot analysis and immunofluorescence staining. In the second experiment, the MAPK inhibitor PD98059 was added and the rats were randomly divided into four groups: Control, morphine, PD98059+morphine and PD98059+morphine+Dex. The continuous IT injection lasted for 7 days in each group. For all experiments, the tail flick test was conducted 30 min following administration every day to assess the thermal hyperalgesia of the rats. The experimental results demonstrated that there was a co­existence of GRs and p­ERK 1/2 in the spinal cord dorsal horn by double immunofluorescence staining. The GR antagonist RU38486 attenuated the morphine analgesia tolerance by inhibiting the expression of GR and increasing the expression of p­ERK. The MAPK inhibitor PD98059 increased the effect of morphine tolerance and prolonged the duration of morphine tolerance. The present results suggest that spinal GRs may serve an important role in the development of morphine tolerance through the ERK signaling pathway.