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不同频度电针治疗大鼠慢性神经源性痛的疗效比较
慢性疼痛,尤其是慢性神经源性疼痛持续时间长,恢复较慢,对人身心健康危害很大,且难以控制.因此慢性神经源性痛的研究成为疼痛领域的研究热点与重点.本所在正常大鼠镇痛模型和慢性炎症痛模型中观察到,多次电针或TENS的镇痛作用不仅与刺激参数有关,而且主要取决于两次电针之间的时间间隔.本实验将大鼠右侧L5/L6脊神经结扎造成慢性神经源性痛模型,用引起缩足的机械刺激阈值(50%)来评价机械性痛觉超敏.用大鼠5 min内在5±1℃冷板上的抬脚次数来反映冷诱发的持续性疼痛.
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神经源性痛诱发大鼠背根神经节细胞电生理学变化
动作电位的异常爆发和编码是痛觉信号传递的电生理学基础.越来越多的证据表明,外周感觉神经元的敏化是慢性痛发生的重要机制之一.本次实验通过结扎大鼠单侧L5和L6脊神经诱发神经源性痛,经Von Frey Hair机械痛敏测量法筛选后,运用全细胞膜片电流钳技术研究急性分离的背根神经节(dorsal root ganglion,DRG)细胞电生理学特征,结果发现:①对照组大鼠背根神经节小直径神经元(细胞直径<30μm)的动作电位阈值为-11.12±1.06 mV(n=11),神经源性痛后小直径神经元动作电位阈值降低了7.82 mV(-18.98±0.69,n=9),二者有显著性差异(P<0.01);与对照组相比,神经源性痛后中等直径DRG神经元(30 μm≤细胞直径≤40μm)兴奋性升高,其动作电位爆发阈从-14.55±1.81 mV(n=8)降低至-19.44±2.22 mV(n=9),差异显著(P<0.05).
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重视糖尿病神经病变机制研究与临床治疗方法探讨
约50%的糖尿病患者并发糖尿病神经病理性疼痛(diabetic neuropathic pain,DNP),是患者病死率增加的主要原因之一,其临床主要表现为神经病理性疼痛症状.疼痛多为轻中度痛感,部分患者出现严重的持续性疼痛,影响患者的生存质量.但因诊断标准不一,所以糖尿病并发神经病变的发病率报道也不一.资料显示美国的发病率大约为50%,而在我国则为85%,显著高于美国.
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重视癌性神经病理性疼痛的诊疗与研究
癌性神经病理性疼痛(malignant neuropathic pain,MNP)的病因和形成机制复杂,镇痛药物治疗难以满意控制,一直是临床治疗的难点.<肿瘤学年鉴>杂志刊登了迄今为止有关MNP发病率的大样本多中心流行病学调查结果.该调查由西班牙学者完成,共调查了8615例癌症患者,2567例伴疼痛,发生率为30%;其中33%临床诊断为神经病理性疼痛,按DN4(Douleur Neuropathique 4 questions)量表筛查,366例符合诊断标准,占癌痛患者的19%.这一关于MNP发病率的报告,明显高于国内外镇痛专家的经验判断.
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神经病理痛的诊断及分类
神经病理痛的流行病学及影响根据NeuPSIG(神经病理痛特别兴趣组,Spe-cial Interest Group on Neuropathic Pain)的定义,神经病理痛是一种由躯体感觉系统受损或病变直接导致的疼痛,已经成为健康的一大难题.然而,这种常见的疼痛类型却常常得不到诊断或治疗不足,并且造成痛苦、残疾,生活质量下降以及大量的花费.
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Electroacupuncture has traditionally been used to treat pain, but its effect on pain following brachial plexus injury is still unknown. In this study, rat models of an avulsion injury to the left brachial plexus root (associated with upper-limb chronic neuropathic pain) were given electroacu-puncture stimulation at bilateralQuchi(LI11),Hegu(LI04),Zusanli(ST36) andYanglingquan (GB34). After electroacupuncture therapy, chronic neuropathic pain in the rats’ upper limbs was signiifcantly attenuated. Immunolfuorescence staining showed that the expression of β-endorphins in the arcuate nucleus was signiifcantly increased after therapy. Thus, experimental ifndings indi-cate that electroacupuncture can attenuate neuropathic pain after brachial plexus injury through upregulatingβ-endorphin expression.
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The use of iodine-125 (125I) in cancer treatment has been shown to relieve patients’ pain. Consid-ering dorsal root ganglia are critical for neural transmission between the peripheral and central nervous systems, we assumed that125I could be implanted into rat dorsal root ganglia to provide relief for neuropathic pain.125I seeds with different radioactivity (0, 14.8, 29.6 MBq) were im-planted separately through L4-5 and L5-6 intervertebral foramen into the vicinity of the L5 dorsal root ganglion. von Frey hair results demonstrated the mechanical pain threshold was elevated after implanting125I seeds from the high radioactivity group. Transmission electron microscopy revealed that nuclear membrane shrinkage, nucleolar margination, widespread mitochondrial swelling, partial vacuolization, lysosome increase, and partial endoplasmic reticulum dilation were visible at 1,440 hours in the low radioactivity group and at 336 hours in the high radio-activity group. Abundant nuclear membrane shrinkage, partial fuzzy nuclear membrane and endoplasmic reticulum necrosis were observed at 1,440 hours in the high radioactivity group. No signiifcant difference in combined behavioral scores was detected between preoperation and postoperation in the low and high radioactivity groups. These results suggested that the mechan-ical pain threshold was elevated after implanting125I seeds without inlfuencing motor functions of the hind limb, although cell injury was present.
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Acupuncture has been used to treat neuropathic pain for a long time, but its mechanisms of action remain unknown. In this study, we observed the effects of electroacupuncture and manual acu-puncture on neuropathic pain and on ephrin-B/EphB signaling in rats models of chronic constriction injury-induced neuropathic pain. The results showed that manual acupuncture and elec-puncture significantly reduced mechanical hypersensitivity fol owing chronic constriction injury, es-pecial y electroacupuncture treatment. Real-time PCR results revealed that ephrin-B1/B3 and EphB1/B2 mRNA expression levels were significantly increased in the spinal dorsal horns of chronic constriction injury rats. Electroacupuncture and manual acupuncture suppressed the high sion of ephrin-B1 mRNA, and elevated EphB3/B4 mRNA expression. Electroacupuncture signifi-cantly enhanced the mRNA expression of ephrin-B3 and EphB3/B6 in the dorsal horns of neuro-pathic pain rats. Western blot results revealed that electroacupuncture in particular, and manual acupuncture, significantly up-regulated ephrin-B3 protein levels in rat spinal dorsal horns. The re-sults of this study suggest that acupuncture could activate ephrin-B/EphB signaling in neuropathic pain rats and improve neurological function.
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癌性神经病理性疼痛药物治疗进展
神经病理性疼痛(neuropathic pain,NeP)是来自外周或中枢神经系统的病变或功能紊乱所引起的疼痛.感染、外伤、代谢性疾病、化疗、手术、放射性损伤、神经毒素、神经压迫以及肿瘤浸润均可以导致NeP.本文简单介绍了癌性神经病理性疼痛(malignant neuropathic pain,MNP)的相关内容,并对国内外学者在MNP药物治疗方面的分析及研究进行概括并简要总结和评述,综述如下.
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BACKGROUND:Ferula sinkiangensis K.M. Shen is composed of volatile oil, resin and gum that have the anti-inflammatory, anti-alergic, antispasmodic and analgesic effects. But its analgesic mechanism is unclear. OBJECTIVE: To observe the effect ofFerula sinkiangensis K.M. Shen on heat pain, mechanical pain, Fos protein expression and astrocyte activation in spinal cord of rats with neuropathic pain. METHODS: Eighty adult Sprague-Dawley rat models of chronic sciatic nerve injury were randomly divided into five groups and then intragasticaly administeredFerula sinkiangensis K.M. Shen at low, moderate and high doses (0.075, 0.15, 0.30 g/kg), celecoxib or physiological saline. Heat pain and mechanical pain were measured at 1 day before operation and at 1, 2, 3, 5, 7, 14 days after operation. The spinal cord tissue at S4-5 segments was harvested and Fos protein expression and astrocyte activation in the spinal cord of rats were observed by immunohistochemical staining method. RESULTS AND CONCLUSION: After 1 and 5 days of medication, behavioral pain scores of rats in the low-, moderate-, and high-doseFerula sinkiangensis K.M. Shen groups were significantly higher than that in the physiological saline group (P < 0.01). The largest reduction in heat pain threshold was measured in the moderate-doseFerula sinkiangensis K.M. Shen group compared to the other groups (P < 0.01). The most significant reduction in rat mechanical pain threshold was measured in the high-doseFerula sinkiangensis K.M. Shen group than in the other groups (P < 0.01). At each time point post-operation, the number of Fos protein-positive cels in the low-, moderate- and high-doseFerula sinkiangensis K.M. Shen and celecoxib groups was significantly lower than that in the physiological saline group (P < 0.05); the number of Fos protein-positive cels in the moderate- and high-doseFerula sinkiangensis K.M Shen groups was significantly higher than that in the celecoxib group (P< 0.05). At each time point post-operation, the number of astrocytes in the spinal cord tissue of rats in the high-doseFerula sinkiangensis K.M. Shen and celecoxib groups was significantly lower than that in the physiological saline group (P< 0.05). There was significant difference in the number of astrocytes between the moderate- and high-doseFerula sinkiangensis K.M shen groups and celecoxib group (P< 0.05). These results confirm thatFerula sinkiangensis K.M. Shen may effectively aleviate the neuropathic pain of rats, and the mechanism of which may be related to the activation of Fos protein and astrocytes in the spinal cord.
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H-89对坐骨神经结扎大鼠触诱发痛和脊髓背角磷酸化CREB表达的影响
Objective To investigate the effects of a highly selective cAMP-dependant protein kinase(PKA)inhibitor, H-89, on tactile allodynia, as well as cyclic AMP response element binding protein (CREB) phosphorylation in the ipsilateral spinal dorsal horn neurons induced by chronic constriction injury(CCI) of the sciatic nerve in rats. Methods In part one, after CCI model had been successfully established, twenty eight female SD rats weighing (250+ 20)g were randomly allocated to one of four groups( n= 7): control group received solvent; H1, H2 and H4 group received H-89 1,2,and 4 nmol respectively. Drugs were delivered via L5-6 acute puncture after briefly anesthetized with isoflurane. Mechanical withdrawal threshold (MWT) were determined at before and 15, 30, 60 min after drug-delivery. In part two, five groups ( n= 6), including a sham group( sham surgery received solvent), and four CCI groups received drugs( H1, H2, H4group) or solvent(DMSO group) as described above were euthanatized 30 min after drug delivery to investigate the effect of H-89 on CREB phosphorylation in the superficial neurons of the ipsilateral spinal dorsal horn. CREB phosphorylated (pCREB) neurons were detected by immunohistochemistry. Results MWT increased after drug administration, but there were no statistical significance in the 1 nmol group, compared to baseline or control group( P 》0.05). 15 min after drug delivery, MWT significantly increased( P 《 0.01, compared to baseline or control group) in the 4 nmol group. The number of pCREB positive neurons in the L4-5 spinal dorsal horn and their gray level were reduced by H-89 administration( P 《0.01, compared to DMSO group). Conclusion PKA inhibitor H-89 can attenuate tactile allodynia induced by chronic constriction injury of the sciatic nerve in rats, and inhibit CREB phosphorylation in the spinal dorsal horn neurons following CCI, indicating PKA/CREB signaling pathway plays an important role in the maintance of neuropathic pain.
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丝裂原活化蛋白激酶家族与病理性疼痛
病理性疼痛包括炎性痛和神经病理性痛.炎性痛是由创伤、细菌或病毒感染及外科手术等引起的外周组织损伤导致的炎症而引起的疼痛;神经病理性疼痛是由于外周或中枢神经系统的直接损伤或功能紊乱引起的疼痛,其共同的临床表现有自发性疼痛、痛觉过敏、触诱发痛等.许多脊髓或高级中枢神经病理生理的改变都可引起或参与病理性神经痛的形成.目前的研究认为,脊髓背角神经元及脊髓胶质细胞丝裂原活化蛋白激酶家族活化与病理性疼痛有关[1,2].现就MAPKs在病理性疼痛的发生、发展过程中所起的作用作一综述.
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cAMP反应元件结合蛋白与神经病理性疼痛
神经病理性疼痛(neuropathic pain)是指由于外周或者中枢神经系统的直接损伤或功能紊乱引起的疼痛.常表现为自发性和诱发性疼痛.其确切机制尚不清楚.目前研究认为与初级感觉神经元的异常兴奋;交感神经的芽生和交感-感觉耦联;初级传入末梢在脊髓背角的异常分布;中枢敏感以及大脑皮层的功能重塑等有关[1,2].这种慢性改变涉及基因表达的改变,基因表达的关键是基因转录的调控.cAMP反应元件结合蛋白(cAMP response-element binding protein,CREB)是转录/翻译因子家族的一员,通过与顺式作用元件结合,改变DNA的局部构象而影响基因转录水平.近年来研究发现,CREB在神经病理性疼痛的发生发展过程中具有重要作用.
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胶质细胞在糖尿病神经病理性疼痛中作用的研究进展
糖尿病神经病理性疼痛(diabetic neuropathic pain,DNP)是糖尿病患者中常见的慢性并发症之一,临床上以肢体自发性疼痛、感觉过敏、异常疼痛、灼热、麻木、冰凉为特征,严重影响患者的生活质量[1].国际疼痛研究协会提出糖尿病神经病理性疼痛的定义:糖尿病周围感觉运动性神经异常直接引起的疼痛,其临床症状:发病部位为远端对称性袜状或手套样分布,开始多累及下肢:足趾、足、小腿,如上行至膝时可累及上肢远端.DNP是临床上极为棘手的问题,治疗上通过对症治疗来缓解疼痛,但不能阻止病程的发展,这种典型的病理性疼痛,其产生的机理尚不清楚.
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神经病理性疼痛外周和中枢机制研究进展
神经病理性疼痛是指中枢及外周神经组织由于多种原因受到损伤或出现功能障碍而引起的一种慢性病理性疼痛[1].常见病因包括代谢性疾病(如糖尿病、尿毒症)、带状疱疹和HIV感染、外伤以及药物或化学制剂(如酒精、化疗和抗HIV药物)应用等.神经病理性疼痛根据有无诱因可表现为诱发性疼痛或自发性疼痛,诱发性疼痛又可分为痛觉过敏或痛觉超敏.神经病理性疼痛是一种存在广泛而又难以治愈的临床症状,越来越受到人们的重视,现就近年来在神经病理性疼痛发病机制方面进行研究取得的进展作一综述.
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加巴喷丁治疗神经病理性疼痛的理论与临床应用
加巴喷丁(Gabapentin,又名Neurontin)是近年来广泛应用于治疗癫痫的药物,亦是当前国外临床应用与研究的热点课题.国内对此药的认识刚刚起步,而且被定为抗癫痫类药物,实际上它是属于一种治疗神经病理性疼痛的镇痛药.国内已有文章介绍[1].加巴喷丁于1993年首先在英国上市用于治疗癫痫大发作,同年美国FDA批准其临床应用.
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Recently, considerable progress in our understanding of the mechanisms of neuropathic pain has been made because of development of several suitable animal models. Neuronal sensitization is believed to play an important role in the pathogenesis of neuropathic pain following peripheral nerve injury.There is much evidence that nitric oxide (NO) is involved in the development and maintenance of pain following peripheral nerve injury. The main focus of this article will be on the recent development in understanding the importance of NO acting as a mediator or messenger in the nociceptive signal processing of neuropathic pain. This information suggests a specific avenue for development of more effective clinical medication for neuropathic pain following nerve injury.
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牛痘疫苗致炎皮肤提取物在30例糖尿病神经痛中的应用观察
糖尿病神经病变是糖尿病常见的长期并发症之一,26%~50%的患者可出现神经病变,其中以感觉神经病变即疼痛性糖尿病神经病变(painf ul dia-betic neuropathy PDN )或糖尿病神经病理性疼痛(diabetic neuropathic pain DNP )为常见。DNP患者可因为慢性疼痛而活动减少,出现睡眠障碍和抑郁症状,降低正常工作和其他社会活动的能力,削弱心理和社会功能以及生活质量[1、2]。糖尿病患者在临床上常常见到即使血糖控制在正常范围内,采用综合治疗措施,但疼痛仍然难以缓解,故顽固性DPN疼痛已成为疼痛治疗领域里一大难题及热点。
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化疗药物紫杉醇在神经病理性痛发生中的作用
1. 化疗药物紫杉醇的概述紫杉醇(Paclitaxel,商品名为Taxol~R)是一种可从紫杉属植物Taxus brevifolia的树皮中提取的多萜醇类单体药物成分(图1).对紫杉醇生物活性的研究始于上个世纪七十年代早期,随着研究的深入,人们发现紫杉醇可以中断细胞分裂周期.
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从神经病理性疼痛新定义探索诊断和治疗的新思路
神经病理性疼痛(neuropathic pain,NP)的定义于2008年由国际疼痛学会神经病理性疼痛学组(IASP NeuPSIG)修改为“躯体感觉系统损伤或疾病所直接导致的疼痛”.与IASP 1994年的传统定义相比:①用“疾病”取代旧定义的“功能障碍”;②将“神经系统的损伤或疾病”明确限定为“躯体感觉系统的损伤或疾病”.两处重大修改对NP病因诊断与治疗具有重要指导意义.