Effect of stellate ganglion block on postoperative recovery of gastrointestinal function in patients undergoing surgery with general anaesthesia: a meta-analysis.

BACKGROUND: The return of gastrointestinal function is an important sign of postoperative recovery in patients undergoing surgery with general anaesthesia. We aimed to summarize the effects of stellate ganglion block on the recovery of gastrointestinal function as a means of exploring methods through which anaesthesiologists can contribute to postoperative patient recovery. METHODS: We performed a quantitative systematic review of randomized controlled trials published between January 1, 1988, and November 11, 2019, in PubMed, the Cochrane Library, China National Knowledge Infrastructure, Chinese VIP Information, and the Wanfang and SinoMed databases. Study quality was assessed by using the GRADE criteria and bias of included studies were assessed using the revised Cochrane risk-of-bias tool for randomized trials. The time to peristaltic sound resumption, flatus, postoperative eating and the incidence of abdominal bloating in the stellate ganglion block and control groups were compared. The control group consisted of either a stellate ganglion block with normal saline or no treatment. Meta-analysis was performed using Review Manager software. RESULTS: After searching for relevant articles, 281 studies were identified, and five articles with data on 274 patients were eligible. Regarding postoperative flatus time, stellate ganglion block resulted in a mean reduction of 15 h (P = 0.02); then a sensitivity analysis was performed, and the standard mean difference decreased to 6 h (P = 0.007). For gastrointestinal surgery, the mean reduction was 23.92 h (P = 0.0002). As for the evaluation of the recovery of peristaltic sounds, stellate ganglion block promoted the recovery of regular peristaltic bowel sounds an average of 14.67 h earlier than in the control (P = 0.0008). When it comes to nutrients, stellate ganglion block shortened the total parenteral nutrition time by more than 50 h in patients who had undergone gastrointestinal surgery (P<0.00001). Finally, stellate ganglion block prevented the occurrence of postoperative abdominal bloating (P = 0.001).) No complications related to stellate ganglion block were reported. CONCLUSION: Stellate ganglion block may promote postoperative gastrointestinal recovery in patients undergoing various surgeries under general anaesthesia. However, additional trials investigating the use of stellate ganglion block are necessary to confirm our finding. TRIAL REGISTRATION: This meta-analysis has been registered at the International Prospective Register of Systematic Reviews (registration number CRD42020157602).

Resolvin D2 Relieving Radicular Pain is Associated with Regulation of Inflammatory Mediators, Akt/GSK-3ß Signal Pathway and GPR18.

Neuroinflammation induced by protruded nucleus pulposus (NP) has been shown to play a significant role in facilitation of radicular pain. Resolvin D2 (RvD2), a novel member of resolvin family, exhibits potent anti-inflammatory, pro-resolving and antinociceptive effects. But the effect of RvD2 in radicular pain remains unknown. The radicular pain rat models were induced by application of NP to L5 dorsal root ganglion. Each animal received intrathecal injections of vehicle or RvD2 (10 ng µl-1 or 100 ng µl-1). Mechanical thresholds were determined by measuring the paw withdrawal threshold for 7 days. The expressions of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and transforming growth factor-ß1 (TGF-ß1) in ipsilateral lumbar segment of rat spinal dorsal horns were measured by using ELISA and real time-PCR. Western blot was used to measure the expressions of phosphorylated Akt (p-Akt) and phosphorylated glycogen synthase kinase 3 beta (p-GSK-3ß). The expressions and distributions of RvD2 receptor, G-protein-coupled receptor 18 (GPR18), were also explored in the spinal cord of rats by using double-label immunofluorescence. RvD2 treatment caused significant reductions in the intensity of mechanical hypersensitivity and spinal expressions of TNF-α and IL-6. Meanwhile, RvD2 increased the expressions of TGF-ß1 and regulated Akt/GSK-3ß signaling. Furthermore, immunofluorescence showed that GPR18 colocalized with neurons and astrocytes in spinal cord. The results suggested that RvD2 might attenuate mechanical allodynia via regulating the expressions of inflammatory mediators and activation of Akt/GSK-3ß signal pathway. RvD2 might offer a hopeful method for radicular pain therapy.

Efficacy of different doses of dexmedetomidine as a rapid bolus for children: a double-blind, prospective, randomized study.

BACKGROUND: Dexmedetomidine (DEX), a highly sensitive α2-adrenoceptor agonist that possesses anxiolytic, sedative, and analgesic effects, has been documented as a preventative and treatment for emergence agitation (EA). The therapeutic should be given as a loading dose that is infused during a 10 min period, but if a rapid bolus injection is deemed to be hemodynamically appropriate, it would be a more opportune route of administration. So we studied the efficacy of different doses of DEX as a rapid bolus for children to prevent and treat EA. METHODS: One hundred patients were enrolled and randomly divided into five groups: the control group (group D1), the 0.25 µg/kg DEX group (group D2), the 0.5 µg/kg DEX group (group D3), the 0.75 µg/kg DEX group (group D4), and the 1 µg/kg DEX group (group D5). Heart rate (HR), mean blood pressure (MBP) and blood oxygen saturation (SaO2) were recorded immediately before the study drug injection (baseline) and every minute for 5 min thereafter and at the time points of the skin cut and hernial sac pull. EA and pain were assessed in the post -anesthesia care unit, and any complementary medicine and adverse events were recorded too. RESULTS: The incidence of EA was significantly decreased in group D4 and group D5 compared with D1.All groups exhibited similar baseline HR and MBP. After administered, HR and MBP were significantly decreased in all DEX group compared with group D1.In groups D3, D4 and D5, the minimal HR was decreased significantly compared with the groups D1 and duration time of minimal HR significantly prolonged in group D5, but no patient needed treatment. As the dosage increased, the recovery time was significantly prolonged. There were no significant differences in occurrence time of minimal HR, the incidence of complementary medicine and adverse events among groups. CONCLUSION: Rapid intravenous injection (IV) bolus administration of 0.75 and 1.0 µg/kg of DEX could improve the recovery profile by reducing the incidence of EA in children. Although its use resulted in a transient decreases in HR and MBP, DEX was clinically well-tolerated in children. TRIAL REGISTRATION: No. ChiCTR-IPR-17010658 . Registered 17 February 2017.

Propofol Affects Neurodegeneration and Neurogenesis by Regulation of Autophagy via Effects on Intracellular Calcium Homeostasis.

BACKGROUND: In human cortical neural progenitor cells, we investigated the effects of propofol on calcium homeostasis in both the ryanodine and inositol 1,4,5-trisphosphate calcium release channels. We also studied propofol-mediated effects on autophagy, cell survival, and neuro- and gliogenesis. METHODS: The dose-response relationship between propofol concentration and duration was studied in neural progenitor cells. Cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and lactate dehydrogenase release assays. The effects of propofol on cytosolic calcium concentration were evaluated using Fura-2, and autophagy activity was determined by LC3II expression levels with Western blot. Proliferation and differentiation were evaluated by bromodeoxyuridine incorporation and immunostaining with neuronal and glial markers. RESULTS: Propofol dose- and time-dependently induced cell damage and elevated LC3II expression, most robustly at 200 µM for 24 h (67 ± 11% of control, n = 12 to 19) and 6 h (2.4 ± 0.5 compared with 0.6 ± 0.1 of control, n = 7), respectively. Treatment with 200 µM propofol also increased cytosolic calcium concentration (346 ± 71% of control, n = 22 to 34). Propofol at 10 µM stimulated neural progenitor cell proliferation and promoted neuronal cell fate, whereas propofol at 200 µM impaired neuronal proliferation and promoted glial cell fate (n = 12 to 20). Cotreatment with ryanodine and inositol 1,4,5-trisphosphate receptor antagonists and inhibitors, cytosolic Ca chelators, or autophagy inhibitors mostly mitigated the propofol-mediated effects on survival, proliferation, and differentiation. CONCLUSIONS: These results suggest that propofol-mediated cell survival or neurogenesis is closely associated with propofol's effects on autophagy by activation of ryanodine and inositol 1,4,5-trisphosphate receptors.

Selective phosphodiesterase-2A inhibitor alleviates radicular inflammation and mechanical allodynia in non-compressive lumbar disc herniation rats.

PURPOSE: Phosphodiesterase inhibitors possess anti-inflammatory properties. In addition, some studies report that phosphodiesterase 2A (PDE2A) are highly expressed in the dorsal horn of the spinal cord. The present study aimed to investigate whether intrathecal administration of Bay 60-7550, a specific PDE2A inhibitor, could alleviate mechanical allodynia in non-compressive lumbar disc herniation (NCLDH) rats. METHODS: Rat NCLDH models by autologous nucleus pulposus implantation to dorsal root ganglion were established. Vehicle or Bay 60-7550 (0.1, 1.0 mg/kg) was injected by intrathecal catheter at day 1 post-operation. The ipsilateral mechanical withdrawal thresholds were analyzed from the day before surgery to day 7 after surgery. At day 7 post-operation, the ipsilateral lumbar (L4-L6) segments of the spinal dorsal horns were removed, and tumor necrosis factor α (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), cyclic adenosine monophosphate (cAMP), and cyclic guanosine monophosphate (cGMP) expressions were measured by ELISA. Furthermore, PDE2A mRNA and protein expressions in spinal cord were measured by Real-Time PCR and Western blot. RESULTS: Intrathecal administration of the PDE2A inhibitor Bay 60-7550, significantly attenuated mechanical allodynia, down-regulated spinal TNF-α, IL-1ß and IL-6 over-expressions, increased the expression of spinal cAMP, as well as cGMP in a more remarkable manner, and decreased the spinal PDE2A expression in NCLDH rats in a dose-dependent manner. CONCLUSIONS: Bay 60-7550 alleviated mechanical allodynia and inflammation in NCLDH rats, which might be associated with increased cAMP and especially cGMP increase. Thus, spinal PDE2A inhibition might represent a potential analgesic strategy for radiculopathy treatment in non-compressive lumbar disc herniation.

Resolvin D1 Inhibits Mechanical Hypersensitivity in Sciatica by Modulating the Expression of Nuclear Factor-κB, Phospho-extracellular Signal-regulated Kinase, and Pro- and Antiinflammatory Cytokines in the Spinal Cord and Dorsal Root Ganglion.

BACKGROUND: Accumulating evidence indicates that spinal inflammatory and immune responses play an important role in the process of radicular pain caused by intervertebral disk herniation. Resolvin D1 (RvD1) has been shown to have potent antiinflammatory and antinociceptive effects. The current study was undertaken to investigate the analgesic effect of RvD1 and its underlying mechanism in rat models of noncompressive lumbar disk herniation. METHODS: Rat models of noncompressive lumber disk herniation were established, and mechanical thresholds were evaluated using the von Frey test during an observation period of 21 days (n = 8/group). Intrathecal injection of vehicle or RvD1 (10 or 100 ng) was performed for three successive postoperative days. On day 7, the ipsilateral spinal dorsal horns and L5 dorsal root ganglions (DRGs) were removed to assess the expressions of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), IL-10, and transforming growth factor-ß1 (TGF-ß1) and the activation of nuclear factor-κB (NF-κB)/p65 and phospho-extracellular signal-regulated kinase (p-ERK) signaling (n = 30/group). RESULTS: The application of nucleus pulposus to L5 DRG induced prolonged mechanical allodynia, inhibited the production of IL-10 and TGF-ß1, and up-regulated the expression of TNF-α, IL-1ß, NF-κB/p65, and p-ERK in the spinal dorsal horns and DRGs. Intrathecal injection of RvD1 showed a potent analgesic effect, inhibited the up-regulation of TNF-α and IL-1ß, increased the release of IL-10 and TGF-ß1, and attenuated the expression of NF-κB/p65 and p-ERK in a dose-dependent manner. CONCLUSIONS: The current study showed that RvD1 might alleviate neuropathic pain via regulating inflammatory mediators and NF-κB/p65 and p-ERK pathways. Its antiinflammatory and proresolution properties may offer novel therapeutic approaches for the management of neuropathic pain.

Investigation on the Interaction of Hydroxyethyl Starch 130/0.4 (Voluven) and Serum Albumin for Pharmacokinetic and Toxicological Implications.

The interaction of hydroxyethyl starch 130/0.4 (Voluven) with human serum albumin (HSA) has been investigated by fluorescence (steady state and synchronous), Fourier transforms infrared (FT-IR), and circular dichroism (CD) spectroscopies. Analysis of the fluorescence quenching data of HSA by Voluven using the Stern-Volmer method revealed the formation of 1:1 ground-state complex. Evaluation of binding parameters and binding energy indicated that the binding reaction was exothermic. On the basis of fluorescence measurements, it was concluded that electrostatic forces play a crucial role in stabilizing the complex. The binding distance was calculated by using Förster resonance energy transfer (FRET) theory. The conformational changes of HSA were obtained qualitatively as well as quantitatively using synchronous fluorescence, FT-IR, and CD. The HSA underwent partial unfolding in the presence of Voluven.

Spinal anaesthesia with low-dose bupivacaine in marginally hyperbaric solutions for caesarean section: A randomised controlled trial.

BACKGROUND: Conventional hyperbaric spinal anaesthesia solution (SAS) with 8% glucose and low-dose bupivacaine may reduce the incidence of hypotension in caesarean section compared to standard doses, and marginally hyperbaric SAS (≤0.8% glucose) can induce a lower block level and a lower incidence of hypotension in nonobstetric patients than conventional 8% glucose SAS. OBJECTIVE: The objective of this study was to evaluate the clinical efficacy of marginally hyperbaric low-dose bupivacaine solutions used for spinal anaesthesia during caesarean section. DESIGN: A randomised, controlled clinical trial. SETTING: Single medical centre. PATIENTS: One hundred twenty women scheduled for elective caesarean section were randomised into four groups. INTERVENTIONS: Caesarean section after combined spinal-epidural anaesthesia using hyperbaric preparations of low-dose SAS (7.2 mg bupivacaine and 2 µg 1.6 ml sufentanil in one of the following: 8%, 0.8%, 0.5% or 0.33% glucose solution. MAIN OUTCOME MEASURES: The dermatomal sensory block and degree of motor block of the lower extremities and adverse effects of anaesthesia were recorded. RESULTS: The maximum cephalad sensory block level and the incidence of hypotension decreased as the density of SAS fell (T1, T2, T4 and T6, P < 0.001; 48.3, 30, 13.3 and 10.3%, P = 0.003). The incidence of shivering reduced with decreasing density of SAS (P < 0.05). There was no significant difference in the quality of anaesthesia (efficacy of motor block and sensory block) between the groups (P > 0.05). CONCLUSION: Compared with conventional 8% glucose hyperbaric SAS, marginally hyperbaric (0.5 or 0.33% glucose) low-dose bupivacaine solutions led to a significantly lower height of cephalad spread and incidence of hypotension with no impact on the efficacy of spinal anaesthesia for caesarean section.

Ozone (O3) elicits neurotoxicity in spinal cord neurons (SCNs) by inducing ER Ca(2+) release and activating the CaMKII/MAPK signaling pathway.

Ozone (O3) is widely used in the treatment of spinal cord related diseases. Excess or accumulation of this photochemical air can however be neurotoxic. In this study, in vitro cultured Wister rat spinal cord neurons (SCNs) were used to investigate the detrimental effects and underlying mechanisms of O3. Ozone in a dose-dependent manner inhibited cell viability at a range of 20 to 500 µg/ml, with the dose at 40 µg/ml resulting in a decrease of cell viability to 75%. The cell death after O3 exposure was related to endoplasmic reticulum (ER) calcium (Ca(2+)) release. Intracellular Ca(2+) chelator, ER stabilizer (inositol 1,4,5-trisphosphate receptor (IP3R) antagonist and ryanodine receptor (RyR) antagonist) and calcium/calmodulin-dependent protein kinase II (CaMKII) antagonist could effectively block Ca(2+) mobilization and inhibit cell death following 40 µg/ml O3 exposure. In addition, ER Ca(2+) release due to O3 exposure enhanced phospho-p38 and phospho-JNK levels and apoptosis of SCNs through activating CaMKII. Based on these results, we confirm that ozone elicits neurotoxicity in SCNs via inducing ER Ca(2+) release and activating CaMKII/MAPK signaling pathway. Therefore, physicians should get attention to the selection of treatment concentrations of oxygen/ozone. And, approaches, such as chelating intracellular Ca(2+) and stabilizing neuronal Ca(2+) homeostasis could effectively ameliorate the neurotoxicity of O3.

Histone deacetylase inhibitors trichostatin A and suberoylanilide hydroxamic acid attenuate ventilator-induced lung injury.

The pathophysiology of ventilator-induced lung injury (VILI) involves multiple mechanisms including inflammation. Histone deacetylase inhibitors have been shown to exert anti-inflammation activity. The purpose of this study was to examine the protecting roles and mechanisms of the histone deacetylase inhibitors trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA) in ventilator-induced lung injury in normal rat lung. Male Sprague-Dawley rats were divided into four groups: lung-protective ventilation (LV), injurious ventilation (HV), HV+TSA and HV+ SAHA groups. Mechanical ventilation (MV) settings were 7 ml/kg VT and 3cm H2O positive end-expiratorypressure [PEEP], 40 breaths/min for LV group and 42 ml/kg VT, zero end-expiratoryvolume [ZEEP], 40 breaths/min for the HV, HV+TSA and HV+ SAHA groups. After 2 h of MV, acute lung injury (ALI) score, wet-to-dry (W/D) weight ratio and the activity of myeloperoxidase (MPO) were determined. The concentration of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and interleukin-10 (IL-6) in the homogenized lung were measured by ELISA. The expression ICAM-1 was measured by both realtime PCR and Western blot assays. In addition, survival of each group was also assessed. Our results indicated that administration of TSA or SAHA alleviated ventilator-induced lung injury. This was accompanied by reduced neutrophil infiltration, reduced MPO activity, decreased intercellular adhesion molecule-1 (ICAM-1) expression in lung tissue, and lower TNF-alpha, IL-1beta and IL-6 levels. In addition, treatment with HDAC inhibitors significantly prolonged the survival time of ventilator-induced lung injury rats. Our data suggested that TSA and SAHA could significantly alleviate ventilator-induced rat lung injury and prolong the survival time of those rats by attenuate intrapulmonary inflammatory response.

Highly exposed metal atomic active sites in Al2O3/CoNC: Modify reaction pathways by coupling oxygen species.

The catalytic oxidation of formaldehyde (HCHO) at ambient temperature is a highly efficient, cost-effective and environmentally friendly approach for formaldehyde removal. Reactive oxygen (O*) and reactive hydroxyl groups (OH*) are the main active species in the catalytic oxidation reaction of HCHO. Therefore, it is crucial to design catalysts that can simultaneously enhance the surface concentrations of O* and OH*, thereby improving their overall catalytic performance. The present study aimed to design an Al2O3/CoNC catalyst featuring layered carbon nitride coupled with metal oxides possessing domain-limited cobalt (Co) metal active sites, to efficiently remove HCHO (≈100 %, 100 ppm, RH=50 %, GSHV=20,000 mL/(g h)) and ensure stability (more than 90 % formaldehyde removal within 450 h) at ambient temperature. The characterization revealed that the interaction between Al2O3-supported metal and CoNC resulted in enhanced confinement of Co, leading to a higher abundance of edge structures exposing more active sites. Additionally, the presence of highly dispersed Co-NX active sites and increased oxygen vacancies effectively facilitated the adsorption and activation processes of HCHO and O2, as well as the adsorption and desorption dynamics of intermediates during the reaction. These factors collectively contributed to an improved catalytic activity. The results of in situ infrared spectroscopy revealed that the catalyst improved the adsorption and activation of O2 and H2O, leading to the rapid generation of substantial amounts of O* and OH*. This synergistic interaction between Al2O3 and CoNC plays a crucial role in the sustained production of O* and OH*, promoting efficient of intermediate decomposition, and ensuring excellent catalytic activity and stability for HCHO.

Multidisciplinary Guidelines for the Rational Use of Topical Non-Steroidal Anti-Inflammatory Drugs for Musculoskeletal Pain (2022).

(1) Background: Topical non-steroidal anti-inflammatory drugs (NSAIDs) are one of the primary drugs for treating musculoskeletal pain. However, there are currently no evidence-based recommendations about drug selection, drug administration, drug interactions, and use in special populations or other pharmacology-related content of such medications. To this end, the Chinese Pharmaceutical Association Hospital Pharmacy Professional Committee developed multidisciplinary guidelines on using topical NSAIDs to treat musculoskeletal pain. (2) Methods: The guidelines development process followed the World Health Organization guideline development handbook, the GRADE methodology, and the statement of Reporting Items for Practice Guidelines in Healthcare. The guideline panel used the Delphi method to identify six clinical questions to be addressed in the guidelines. An independent systematic review team conducted a systematic search and integration of evidence. (3) Results: Based on the balance between the benefits and harms of an intervention, the quality of the evidence, patient preferences and values, and resource utilization, the guideline panel developed 11 recommendations and nine expert consensuses on using topical NSAIDs to treat acute and chronic musculoskeletal pain. (4) Conclusions: Based on the effectiveness and overall safety of topical NSAIDs, we recommend patients with musculoskeletal pain use topical NSAIDs and suggest high-risk patients use topical NSAIDs, such as those with other diseases or receiving other concurrent treatments. The evidenced-based guidelines on topical NSAIDs for musculoskeletal pain incorporated a pharmacist perspective. The guidelines have the potential to facilitate the rational use of topical NSAIDs. The guideline panel will monitor the relevant evidence and update the recommendations accordingly.

Ozone induces autophagy by activating PPARγ/mTOR in rat chondrocytes treated with IL-1ß.

BACKGROUND: Osteoarthritis (OA) is the main cause of older pain and disability. Intra-articular injections of ozone (O3) commonly have been found to have antioxidative and anti-inflammatory effects to reduce pain and improve function in knee osteoarthritis. It has been reported that reduced autophagy in chondrocytes plays an important role in the development of OA. This study aimed to probe the role of O3 on the autophagy in chondrocytes treated with IL-1ß. METHODS: Primary chondrocytes were isolated from Wistar rats cartilage within 3 days. The OA chondrocytes model was induced via treatment with IL-1ß for 24 h. Then the cells were treated with O3 and GW9662, the inhibitor of PPARγ. Cell viability was assessed by CCK-8. Further, the cells subjected to Western blot analysis, qRT-PCR and immunofluorescence assay. The numbers of autophagosomes were observed via transmission electron microscopy. RESULTS: 30 µg/ml O3 improved the viability of chondrocytes treated with IL-1ß. The decreased level of autophagy proteins and the numbers of autophagosomes improved in IL-1ß-treated chondrocytes with O3 via activating PPARγ/mTOR. In addition, the qRT-PCR results showed that O3 decreased the levels of IL-6, TNF-α and MMP-3, MMP-13 in chondrocytes treated with IL-1ß. CONCLUSIONS: 30 µg/ml O3 improved autophagy via activating PPARγ/mTOR signaling and suppressing inflammation in chondrocytes treated with IL-1ß.

Chinese expert consensus on minimally invasive interventional treatment of trigeminal neuralgia.

Background and purpose: Trigeminal neuralgia is a common condition that is associated with severe pain, which seriously affects the quality of life of patients. When the efficacy of drugs is not satisfactory or adverse drug reactions cannot be tolerated, minimally invasive interventional therapy has become an important treatment because of its simple operation, low risk, high repeatability and low cost. In recent years, minimally invasive interventional treatments, such as radiofrequency thermocoagulation (RF) of the trigeminal nerve and percutaneous microcompression (PMC), have been widely used in the clinic to relieve severe pain in many patients, however, some related problems remain to be addressed. The Pain Association of the Chinese Medical Association organizes and compiles the consensus of Chinese experts to standardize the development of minimally invasive interventional treatment of trigeminal neuralgia to provide a basis for its clinical promotion and application. Materials and methods: The Pain Association of the Chinese Medical Association organizes the Chinese experts to compile a consensus. With reference to the evidence-based medicine (OCEBM) system and the actual situation of the profession, the Consensus Development Committee adopts the nominal group method to adjust the recommended level. Results: Precise imaging positioning and guidance are the keys to ensuring the efficacy and safety of the procedures. RF and PMC are the most widely performed and effective treatments among minimally invasive interventional treatments for trigeminal neuralgia. Conclusions: The pain degree of trigeminal neuralgia is severe, and a variety of minimally invasive intervention methods can effectively improve symptoms. Radiofrequency and percutaneous microcompression may be the first choice for minimally invasive interventional therapy.

Bupivacaine inhibits a small conductance calcium-activated potassium type 2 channel in human embryonic kidney 293 cells.

BACKGROUND: Bupivacaine blocks many ion channels in the heart muscle, causing severe cardiotoxicity. Small-conductance calcium-activated potassium type 2 channels (SK2 channels) are widely distributed in the heart cells and are involved in relevant physiological functions. However, whether bupivacaine can inhibit SK2 channels is still unclear. This study investigated the effect of bupivacaine on SK2 channels. METHODS: The SK2 channel gene was transfected into human embryonic kidney 293 cells (HEK-293 cells) with Lipofectamine 2000. The whole-cell patch-clamp technique was used to examine the effect of bupivacaine on SK2 channels. The concentration-response relationship of bupivacaine for inhibiting SK2 currents (0 mV) was fitted to a Hill equation, and the half-maximal inhibitory concentration (IC50) value was determined. RESULTS: Bupivacaine inhibited the SK2 channels reversibly in a dose-dependent manner. The IC50 value of bupivacaine, ropivacaine, and lidocaine on SK2 currents was 16.5, 46.5, and 77.8µM, respectively. The degree of SK2 current inhibition by bupivacaine depended on the intracellular concentration of free calcium. CONCLUSIONS: The results of this study suggested the inhibitory effect of bupivacaine on SK2 channels. Future studies should explore the effects of SK2 on bupivacaine cardiotoxicity.

Intrathecal injection of ozone alleviates CCI­induced neuropathic pain via the GluR6­NF­κB/p65 signalling pathway in rats.

Ozone is widely used to relieve chronic pain clinically, but the precise mechanisms governing its action have yet to be elucidated. The present study aimed to investigate the mechanisms underlying the pain­alleviating effect of ozone in the chronic constriction injury (CCI) model of sciatic nerve in rats. Pain behaviours of rats were assessed by mechanical allodynia and thermal hyperalgesia. The expression of spinal glutamate receptor 6 (GluR6) and NF­κB/p65 was detected by western blotting and reverse transcription­quantitative PCR. Meanwhile, the expression of spinal IL­1ß, IL­6 and TNF­α was detected by ELISA. GluR6 short interfering (si)RNAs were used intrathecally immediately following CCI once per day. Ozone (10, 20 or 30 µg/ml) or oxygen was injected intrathecally on day 7 after CCI. The expression level of spinal GluR6 increased on day 3 and reached a peak on day 7 after CCI. The expression level of spinal IL­1ß, IL­6, TNF­α and NF­κB/p65 also increased on day 7 after CCI. In addition, pre­intrathecal injection of GluR6 siRNAs inhibited pain behaviours and suppressed the expression of spinal GluR6, IL­1ß, IL­6, TNF­α and NF­κB/p65 in CCI rats on day 7. Intrathecal injection of ozone was also observed to inhibit pain behaviours and suppress the expression of spinal GluR6, IL­1ß, IL­6, TNF­α and NF­κB/p65 in CCI rats on day 7. The present study suggested that GluR6 served a pivotal role in neuropathic pain and that intrathecal injection of ozone may alleviate neuropathic pain via the GluR6­NF­κB/p65 signalling pathway.

Upregulation of antioxidant and autophagy pathways via NRF2 activation protects spinal cord neurons from ozone damage.

Ozone therapy can relieve multiple types of pain but exhibits potential neurotoxicity, the mechanism of which is unclear. The present study aimed to identify the role of nuclear factor (erythroid­derived­2)­related 2 (NRF2) in preventing spinal cord injury caused by ozone overdose. Primary neuronal cells were extracted from newborn Wistar rats and authenticated by immunofluorescence using anti­microtubule­associated protein 2 as a cell type­specific marker. Cell viability assay with different ozone concentrations (0, 10, 20, 30 and 40 µg/ml) was used to determine the concentration that caused primary neuron injury; 30 min of 40 µg/ml ozone therapy notably decreased cell viability to 71%. In order to test the effects of ozone, the cells were divided into five treatment groups [0­, 30­ and 40 µg/ml ozone, tert­butylhydroquinone (tBHQ) + 40 µg/ml ozone (T40) and tBHQ (T0)]. Cells in the T40 and T0 groups received 40 µmol/l tBHQ on the fifth day of SCN cultivation. Reverse transcription­quantitative PCR and western blotting showed that protein expression levels of heme oxygenase­1 (HO­1) and mRNA expression levels of HO­1 and NRF2 were decreased. NRF2, ubiquitin­binding protein p62 and microtubule­associated proteins 1A/1B light chain 3B expression levels were decreased following treatment with 40 µg/ml ozone. Immunofluorescence showed that NRF2 nuclear expression levels also decreased following 40 µg/ml ozone treatment. However, cells in the T40 group did not display decreased NRF2 nuclear expression levels. Normal/Apoptotic/Necrotic Cell Detection kit revealed that necrosis rate increased following treatment with 40 µg/ml ozone; however, the T40 group did not exhibit this increased necrosis. At 40 µg/ml, ozone increased spinal cord neuron (SCN) death in vitro. Moreover, treatment with 40 µg/ml ozone damaged SCNs. The p62/NRF2/antioxidant response element pathway prevented such injury. tBHQ activated this pathway, upregulated autophagy and increased local nuclear NRF2 concentration, thus enhancing the antioxidant system to protect SCNs from injury caused by high concentrations of ozone.

Expert consensus of Chinese Association for the Study of Pain on the non-opioid analgesics for chronic musculoskeletal pain.

Chronic musculoskeletal pain (CMP) is a common occurrence in clinical practice and there are a variety of options for the treatment of it. However, the pharmacological therapy is still considered to be a primary treatment. The recent years have witnessed the emergence of opioid crisis, yet there are no relevant guidelines on how to treat CMP with non-opioid analgesics properly. The Chinese Medical Association for the Study of Pain convened a panel meeting to develop clinical practice consensus for the treatment of CMP with non-opioid analgesics. The purpose of this consensus is to present the application of nonsteroidal anti-inflammatory drugs, serotonin norepinephrine reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, muscle relaxants, ion channel drugs and topical drugs in CMP.

Expert consensus of Chinese Association for the Study of Pain on the application of ozone therapy in pain medicine.

This consensus was compiled by first-line clinical experts in the field of pain medicine and was organized by the Chinese Association for the Study of Pain. To reach this consensus, we consulted a wide range of opinions and conducted in-depth discussions on the mechanism, indications, contraindications, operational specifications and adverse reactions of ozone iatrotechnique in the treatment of pain disorders. We also referred to related previous preclinical and clinical studies published in recent years worldwide. The purpose of this consensus is to standardize the rational application of ozone iatrotechnique in pain treatment, to improve its efficacy and safety and to reduce and prevent adverse reactions and complications in this process.