Dopamine receptor D2 regulates GLUA1-containing AMPA receptor trafficking and central sensitization through the PI3K signaling pathway in a male rat model of chronic migraine

BackgroundThe pathogenesis of chronic migraine remains unresolved. Recent studies have affirmed the contribution of GLUA1-containing AMPA receptors to chronic migraine. The dopamine D2 receptor, a member of G protein-coupled receptor superfamily, has been proven to have an analgesic effect on pathological headaches. The present work investigated the exact role of the dopamine D2 receptor in chronic migraine and its effect on GLUA1-containing AMPA receptor trafficking.MethodsA chronic migraine model was established by repeated inflammatory soup stimulation. Mechanical, periorbital, and thermal pain thresholds were assessed by the application of von Frey filaments and radiant heat. The mRNA and protein expression levels of the dopamine D2 receptor were analyzed by qRT‒PCR and western blotting. Colocalization of the dopamine D2 receptor and the GLUA1-containing AMPAR was observed by immunofluorescence. A dopamine D2 receptor agonist (quinpirole) and antagonist (sulpiride), a PI3K inhibitor (LY294002), a PI3K pathway agonist (740YP), and a GLUA1-containing AMPAR antagonist (NASPM) were administered to confirm the effects of the dopamine D2 receptor, the PI3K pathway and GULA1 on central sensitization and the GLUA1-containing AMPAR trafficking. Transmission electron microscopy and Golgi-Cox staining were applied to assess the impact of the dopamine D2 receptor and PI3K pathway on synaptic morphology. Fluo-4-AM was used to clarify the role of the dopamine D2 receptor and PI3K signaling on neuronal calcium influx. The Src family kinase (SFK) inhibitor PP2 was used to explore the effect of Src kinase on GLUA1-containing AMPAR trafficking and the PI3K signaling pathway.ResultsInflammatory soup stimulation significantly reduced pain thresholds in rats, accompanied by an increase in PI3K-P110β subunit expression, loss of dopamine receptor D2 expression, and enhanced GLUA1-containing AMPA receptor trafficking in the trigeminal nucleus caudalis (TNC). The dopamine D2 receptor colocalized with the GLUA1-containing AMPA receptor in the TNC; quinpirole, LY294002, and NASPM alleviated pain hypersensitivity and reduced GLUA1-containing AMPA receptor trafficking in chronic migraine rats. Sulpiride aggravated pain hypersensitivity and enhanced GLUA1 trafficking in CM rats. Importantly, the anti-injury and central sensitization-mitigating effects of quinpirole were reversed by 740YP. Both quinpirole and LY294002 inhibited calcium influx to neurons and modulated the synaptic morphology in the TNC. Additional results suggested that DRD2 may regulate PI3K signaling through Src family kinases.ConclusionModulation of GLUA1-containing AMPA receptor trafficking and central sensitization by the dopamine D2 receptor via the PI3K signaling pathway may contribute to the pathogenesis of chronic migraine in rats, and the dopamine D2 receptor could be a valuable candidate for chronic migraine treatment.Supplementary InformationThe online version contains supplementary material available at 10.1186/s10194-022-01469-x.     

A novel robust nomogram based on peripheral monocyte counts for predicting lymph node metastasis of prostate cancer

Accurate methods for identifying pelvic lymph node metastasis(LNM)of prostate cancer(PCa)prior to surgery are still lacking.We aimed to investigate the predicti...     

羟喜树碱对家兔毒性作用的研究

目的以健康家兔为实验对象研究抗癌药羟喜树碱的毒性作用与剂量的相关性,为进一步对羟喜树碱毒性作用的防治研究提供参考。方法选择新西兰兔,经耳廓静脉连续推注羟喜树碱14d,观察不同剂量(2.1mg/kg组,1·05mg/kg组,0·52mg/kg组)对家兔免疫功能、肾脏、肝脏和心脏的毒性作用及生化指标的变化。结果三组WBC,RBC,IgG,IgM,AST,CK0·52mg/kg组,LDH2·1mg/kg组均较用药前明显下降(P<0·05和0·01);ALT则显著增高(P<0·01)用药后21d时PLT与LDH1·5mg/kg组较用药前明显下降(P<0·05和0·01)。用药后14,21d时LDH0·52mg/kg组较用药前明显下降(P<0·05和0·01)。结论羟喜树碱可引起家兔明显的肝组织、免疫功能、造血功能的损伤和轻度心脏毒性。但对其损伤机制有待进一步研究。     

简易腹腔镜模拟器在腹腔镜模拟培训中的应用研究

目的:本研究拟利用自主开发的腹腔镜模拟器进行实证研究,检验简易模拟器能否在腹腔镜技能教学中起到好的效果。方法:招募陆军军医大学2018级、2019级临床五年制本科学员24名,随机分为研究组与对照组,进行4周的模拟培训,每周3次,每次1学时。培训内容为基本的腹腔镜技能（fundamental laparoscopic s...     

急性心肌梗死48例QT离散度临床意义

目的探讨急性心肌梗死患者溶栓治疗前后QT离散度及校正的QT离散度的变化与恶性心律失常、猝死等心脏事件发生率的相关性。方法将48例急性心肌梗死患者溶栓治疗后根据其是否再通分为两组,分别观察溶栓治疗前后的QT离散度及校正的QT离散度,记录其恶性心律失常、猝死等心脏事件的发生率,并进行统计分析。结果经溶栓治疗后急性心肌梗死患者再通者29例,未通者19例。溶栓再通组于再通后24h内QT离散度迅速降至正常水平,未通组于溶栓治疗后7d方逐渐接近正常水平。溶栓治疗第3d末,再通组QT离散度及校正的QT离散度与治疗前比较差异均有极显著性(t=2.825,2.719,P均<0.01),未通组与治疗前比较均无显著性差异(P>0.05),两组间比较差异均有极显著性(t=2.713,2.941,P均<0.01)。心脏事件发生组QT离散度及校正的QT离散度均极显著高于未发生组(t=2.819,2.691,P均<0.01)。结论QT离散度与心肌梗死后局部心肌复极电活动的不均一性有关;QT离散度及校正的QT离散度越大,恶性心律失常发生率越高。     

肝硬化合并肠功能紊乱的临床治疗观察

目的探讨肝硬化合并肠功能紊乱的有效治疗方法。方法将50例肝硬化合并肠功能紊乱患者,随机分成治疗组(26例)与对照组(24例),治疗组在对照组治疗方案的基础上给予口服贝飞达、双迪28d,同时给予心理干预治疗。观察两组治疗前后临床症状及主要的肝功能指标。结果对照组肠道功能改善总有效率70%,治疗组总有效率92%,治疗组疗效优于对照组(P<0.05)。两组患者治疗后主要肝功能指标均明显改善,治疗组治疗后ALT、T-BiL值低于对照组(P<0.05)。结论肝硬化合并肠功能紊乱的患者给予微生态制剂、肠动力药及心理干预治疗可有效改善患者临床症状,并降低肝功能指标。     

经皮气管切开术在危重症患者中的临床应用

目的总结近年来我科经皮气管切开术在临床应用时遇到的困难及教训。方法应用PT技术21例,并与常规气管切开术32例作对照研究。结果PT可明显缩短手术时间、减少术中及术后的出血量且创伤小,拔管后切口愈合快。结论PT是危重患者快速建立长久人工气道的好方法,患者痛苦小,两者并发症的发生无明显差别,但PT不能完全取代正规气管切开术。     

缬沙坦对大鼠心室肌细胞L-型钙通道电流的影响

目的研究AT1受体拮抗剂缬沙坦对正常大鼠心室肌细胞L-钙电流(Ica-L)的影响。方法采用全细胞膜片钳技术,观察0.4μmol/L的缬沙坦引起单个大鼠心室肌细胞L型钙通道电流变化。结果0.4μmol/L缬沙坦使正常大鼠心室肌细胞L型钙电流峰值明显降低(P<0.01),I-V曲线上移,但不改变其激活电位、峰值电位和反转电位。不影响通道稳态激活曲线,使稳态失活曲线左移。结论0.4μmol/L缬沙坦可直接阻断大鼠心室肌细胞L型钙通道,改变心室肌细胞的电生理特性,可能是其抗心律失常的机制之一。     

Type 2 Diabetes,Fasting Glucose,Hemoglobin A1c Levels and Risk of Primary Open-Angle Glaucoma: A Mendelian Randomization Study

PurposeTo evaluate the potential causal associations between type 2 diabetes and fasting glucose and HbA1c levels and the risk of primary open-angle glaucoma (POAG) in European and East Asian populations.MethodsWe selected genetic variants (P < 5 × 10⁻⁸) for type 2 diabetes (898,130 Europeans; 433,540 East Asians), fasting glucose, and HbA1c (196,991 Europeans; 36,584 East Asians) from three meta-analyses of genome-wide association studies (GWAS). The GWAS for POAG provided summary statistics (192,702 Europeans; 46,523 East Asians). Mendelian randomization (MR) analysis was accomplished using the inverse variance–weighted method, weighted-median method, MR Egger method, and MR-Pleiotropy RESidual Sum and Outlier test.ResultsGenetically predicted type 2 diabetes was potentially positively associated with POAG in the European ancestry (body mass index [BMI]–unadjusted: odds ratio [OR] = 1.07, 95% confidence interval [CI], 1.01–1.14, P = 0.028; BMI-adjusted: OR = 1.07, 95% CI, 1.01–1.15, P = 0.035), but not in the East Asian ancestry (BMI-unadjusted: OR = 1.01, 95% CI, 0.95–1.06, P = 0.866; BMI-adjusted: OR = 1.00, 95% CI, 0.94–1.05, P = 0.882). There was no evidence to support a causal association of fasting glucose (European: OR = 1.19, P = 0.157; East Asian: OR = 0.94, P = 0.715) and HbA1c (European: OR = 1.27, P = 0.178; East Asian: OR = 0.85, P = 0.508) levels with POAG.ConclusionsThe causal effect of type 2 diabetes on the risk of POAG is different in European and East Asian populations. The point estimates of fasting glucose and Hb1Ac with POAG are large but not statistically significant, which prompts the question of statistical power.     

Simulations and Experiments on the Micro-Milling Process of a Thin-Walled Structure of Al6061-T6

Aluminum alloy (Al6061-T6) is an alloy with strong corrosion resistance, excellent disassembly, and moderate strength, which is widely used in the fields of construction, automobile, shipping, and aerospace manufacturing. Researching on the influence of machining precision and surface quality on the micro-milling process of thin-walled structures of Al6061 is highly significant. Combined with the two simulations (DEFORM-3D simulation and interactive finite element numerical simulation (FEM)) and milling experimental verification, the deformations, errors, and surface quality of milling thin-walled Al6061 were analyzed. The simulations and experimental results show that the deformation of milling a micro thin-walled structure was caused by the vertical stiffness of the thin-walled structure and the cutting force. Surface micromorphology further characterized and showed a poorer quality area, top burr, and concave defects, which directly affect machining quality. It is necessary to improve the surface quality, reduce the surface defects, and increase the stiffness at the top of thin-walled structures in future work.