氯胺酮对神经病理性疼痛大鼠行为学及坐骨神经的影响

目的 探讨氯胺酮对神经病理性疼痛(NP)大鼠行为学和坐骨神经的影响.方法 24只SD大鼠随机均分为假手术组(S组)、坐骨神经慢性压迫性损伤(CCI)模型组(NP组)和CCI模型+氯胺酮处理组(NPK组).S组大鼠仅分离坐骨神经;NP组和NPK组建立CCI模型.S组和NP组分别于术后7～14 d每天腹腔注射生理盐水10 ...     

苦参碱对神经病理性疼痛小鼠疼痛行为的干预

目的研究苦参碱对坐骨神经缩窄性损伤(CCI)诱导的神经病理性疼痛的镇痛作用。方法建立慢性坐骨神经缩窄性损伤神经病理性疼痛模型,用Von Frey纤维丝、辐射热测痛仪、冷板法、运动协调和自主活动实验的方法测定苦参碱对7.5,15和30 mg·kg的CCI小鼠的机械缩足反射阈值(MWT)、热缩足反射潜伏期(TWL)、抬足次数、在棒时间和自主活动次数的影响。结果 CCI小鼠从术后7d开始到本实验观察的14d表现出明显的机械性痛觉超敏、热痛觉过敏及冷痛觉超敏。与CCI组相比,ip给予苦参碱30 mg·kg-1可提高小鼠损伤侧后足的机械缩足反射阈值(P<0.05);ip给予苦参碱30,15和7.5 mg·kg-1呈剂量依赖性延长小鼠损伤侧后足的热缩足反射潜伏期(P<0.05);ip给予苦参碱30,15和7.5 mg·kg-1呈剂量依赖性地减少小鼠损伤侧后足的冷缩足反射次数(P<0.05);ip给予苦参碱30,15和7.5 mg·kg-1对自主活动次数(P>0.05)和在棒时间(P>0.05)没有明显影响。结论苦参碱对CCI诱发的神经病理性疼痛有良好的镇痛作用。     

维拉帕米增强氯胺酮对小鼠的镇痛作用

目的:观察钙通道拮抗剂维拉帕米对静脉麻醉药氯胺酮镇痛效应的影响。方法:取40只小鼠,雌雄各半,随机分为4组:生理盐水对照组(NS)、氯胺酮处理组(K)、维拉帕米处理组(V)、维拉帕米和氯胺酮联合用药组(V+K),通过醋酸致小鼠扭体法观察小鼠给药后扭体潜伏期和次数的变化。另取40只小鼠,雌雄各半,随机分为上述4组,利用甩尾实验分别观察给药后小鼠对热水和冰水痛阈值的改变。结果:维拉帕米单独用药对小鼠扭体潜伏期和次数、热水和冰水痛阈值均无显著影响;氯胺酮能够延长醋酸致小鼠扭体的潜伏期,并且减少醋酸致小鼠扭体的次数,升高小鼠对热水和冰水甩尾痛阈值;而维拉帕米能够进一步增强氯胺酮延长小鼠扭体潜伏期,减少扭体次数和升高小鼠甩尾痛阈值的效应。结论:维拉帕米能够显著增强氯胺酮对小鼠的镇痛效应。     

安络小皮伞醇提取物对神经病理性疼痛模型大鼠的镇痛作用研究

目的 研究安络小皮伞醇提取物（MAEE）对坐骨神经慢性压迫性损伤（CCI）所致神经病理性疼痛大鼠的镇痛作用并探索其作用机制。方法 40只成年SD大鼠随机分为假手术组、模型组及MAEE高、中、低剂量（800、400、200 mg/kg）组,每组8只。CCI术后14 d,连续ig给药7 d。于1、3、5、7 d给药后2 h测定大鼠机械痛阈（MWT）值和热痛阈（TWL）值,并在停药后连续测定3 d。于给药7 d后,取各组大鼠脊髓L₄-L₆节段,ELISA及实时荧光定量PCR（qRT-PCR）法检测炎症因子肿瘤坏死因子-α（TNF-α）及白细胞介素-1β（IL-1β）的表达,Western blotting法检测MAPK家族蛋白p-ERK、p-p38、p-JNK的表达变化。结果 与模型组比较,连续7 d给予MAEE能够剂量依赖性的缓解CCI诱导的大鼠机械学过敏及热痛学超敏（P<0.05、0.01）;下调CCI大鼠脊髓L₄-L₆节段炎症因子TNF-α和IL-1β的水平以及p-ERK、p-p38、p-JNK的蛋白表达（P<0.05、0.01）。结论 MAEE剂量依赖性的缓解CCI诱导的机械学超敏及热痛学过敏,该作用可能与其抑制CCI大鼠脊髓TNF-α、IL-1β等炎性细胞因子的表达及降低MAPK磷酸化蛋白表达相关。     

Wnt信号通路在神经病理性疼痛中的作用及机制研究进展

神经病理性疼痛(neuropathic pain, NP)作为一种慢性疼痛综合征,严重危害患者生活质量,且发病机制复杂,临床疗法有限,极易复发。越来越多的报道发现Wnt信号通路与神经病理性疼痛的发生和发展密切相关。因此,对Wnt信号通路的进一步研究可能为探索NP的发病机制及发现有效治疗手段提供新思路。本文就Wnt信号通路在神经病理性疼痛中的作用及机制进行综述。     

静脉注射免疫球蛋白对神经病理性疼痛治疗作用的研究进展

静脉注射免疫球蛋白具有多种免疫调节方面的功能,临床上常用于自身免疫性疾病的治疗。近年来,静脉注射免疫球蛋白也应用于许多神经系统疾病的治疗,因为部分神经系统疾病的发病机制与免疫调节相关。神经病理性疼痛是慢性顽固性的疼痛综合征,发病机制复杂,免疫调节也参与神经病理性疼痛的发生。目前发现静脉注射免疫球蛋白可以明显减轻神经病理性疼痛患者的疼痛,给药后无严重不良反应的发生,而且在镇痛的同时可以促进伤口的愈合,提高患者的生活质量。其作用机制可能是免疫球蛋白可以阻断自身抗体与Fc受体结合或中和自身抗体,减轻补体介导的组织损伤作用;还可以通过降低炎性细胞因子表达减轻患者的疼痛。     

癌性神经病理性疼痛概述

1定义及分类临床上疼痛是一种常见的自觉症状,是机体的一种自我保护反应,任何形式的刺激,只要超过痛阈即可引起疼痛。疼痛的表现形式多样,患者在躯体和心理上遭受极大的痛苦,严重影响生活质量。     

原花青素对神经病理性疼痛模型大鼠的镇痛作用研究

目的利用大鼠坐骨神经慢性压迫（CCI）模型,研究原花青素对神经病理性疼痛的镇痛作用。方法应用热板法观察原花青素对正常小鼠基础痛阈的影响。应用Hargreaves法观察不同剂量原花青素腹腔注射对CCI大鼠热痛觉过敏的影响。结果原花青素对正常小鼠基础痛阈无显著性影响（P〉0.05）;原花青素腹腔注射可显著抑制CCI导致的大鼠热痛觉过敏（P〈0.05）。结论原花青素显著抑制CCI所导致的热痛觉过敏,且镇痛作用维持时间长于吗啡。     

治疗神经病理性疼痛新药：mirogabalin

mirogabalin是一种新型的钙离子通道调节剂，于2019年在日本获批上市用于治疗神经病理性疼痛。与普瑞巴林相比，mirogabalin可通过选择性结合电压依赖性钙离子通道α₂δ-1亚单位，表现出更加长效良好的镇痛作用。多项临床试验验证了mirogabalin治疗神经病理性疼痛安全、有效，不良反应较少，患者耐受良好。     

虎杖提取物对神经病理性疼痛模型大鼠的镇痛作用研究

目的：研究虎杖提取物对神经病理性疼痛模型大鼠的镇痛作用,并探讨其作用机制。方法雄性SD大鼠,随机分为对照组和坐骨神经缩狭模型（chronic construction injury, CCI）组。CCI术后14 d,应用Von Frey法测定机械刺激缩足反射阈值（mechanical withdrawal threshold, MWT）,观察口服不同剂量的虎杖提取物对CCI大鼠机械性痛觉超敏的影响。并考察不同剂量虎杖提取物对CCI大鼠脊髓p-ERK、p-P38水平及小胶质细胞活化的影响。结果虎杖提取物可明显升高CCI大鼠术侧的MWT值（P〈0.05）,而对正常大鼠的MWT值没有显著影响（P〉0.05）。同时虎杖提取物可显著抑制CCI模型大鼠脊髓ERK和p38的磷酸化,并显著抑制IBA-1表达增加。结论虎杖提取物对CCI诱导的机械性痛觉超敏具有显著性的抑制作用,且镇痛作用维持时间长于吗啡,其机制可能是通过抑制脊髓水平ERK和p38的磷酸化,及通过抑制小胶质细胞活化而实现。     

Topical amitriptyline and ketamine for post-herpetic neuralgia and other forms of neuropathic pain

Introduction: Neuropathic pain (NP) has several therapeutic options but efficacy is limited and adverse effects occur, such that additional treatment options are needed. A topical formulation containing amitriptyline 4% and ketamine 2% (AmiKet) may provide such an option.

Areas covered: This report summarizes both published and unpublished results of clinical trials with AmiKet. In post-herpetic neuralgia (PHN), AmiKet produces a significant analgesia which is comparable to that produced by oral gabapentin. In diabetic painful neuropathy, AmiKet showed a strong trend towards pain reduction. In mixed neuropathic pain, case series reports suggest a favourable response rate, but are limited by trial characteristics. AmiKet is absorbed minimally following topical administration. Over 700 patients have now received topical AmiKet in clinical regimens, and it is well-tolerated with the adverse effects mainly being application site reactions. Both agents are polymodal, and several mechanisms may contribute to the peripheral efficacy of AmiKet.

Expert opinion: Topical AmiKet has the potential to be a first-line treatment option for PHN, and to be useful in other NP conditions. Furthermore, AmiKet has the potential to be an adjunct to systemic therapies, with the targeting of a peripheral compartment in addition to central sites of action representing a rational drug combination.     

鞘内西地那非能减轻神经病理性疼痛大鼠的痛觉高敏

目的观察鞘内注射西地那非对腰5(L5)脊神经切断大鼠痛觉高敏及对脊髓小胶质细胞活化、炎症细胞因子表达的影响。方法♂SD大鼠120只,随机分为5组(n=24),Ⅰ组:假手术组;Ⅱ组:L5脊神经切断模型鞘内注射生理盐水20μl;Ⅲ～Ⅴ组:L5脊神经切断模型分别鞘内注射3μg/20μl、10μg/20μl、30μg/20μl西地那非组。Ⅰ组仅暴露L5脊神经,Ⅱ～Ⅴ组均切断L5脊神经,术后d 7开始鞘内给药,Ⅰ、Ⅱ组注射20μl生理盐水,Ⅲ～Ⅴ组分别给予上述剂量西地那非,各组每天1次,连续5 d。测定各组大鼠术前1d,术后7、8、10、12 d机械痛阈(mechanical withdrawa1 thresh-old,MWT),术后8、10、12 d取L5脊髓,测定各组大鼠肿瘤坏死因子(tumor necrosis factorα,TNF-α)、白细胞介素1β(in-terleukin-1β,IL-1β)含量和小胶质细胞标记物白细胞分化抗原11b(cluster differentiation antigen 11b,CD11b)的mRNA表达水平。结果①术后7 d,与Ⅰ组相比,各组MWT明显下降(P<0.05),术后8、10、12 d与Ⅱ组相比,Ⅲ～Ⅴ剂量依赖地升高MWT(P<0.05)。②与Ⅰ组相比较,其余各组大鼠术后8、10、12 d TNF-α和IL-1β的水平及CD11b mRNA含量均明显上升(P<0.05),与Ⅱ组相比较,Ⅲ～Ⅴ于术后8、10、12 d明显剂量依赖地抑制了TNF-α和IL-1β及CD11b mR-NA的表达(P<0.05)。结论西地那非能剂量依赖性地缓解大鼠神经病理性痛觉过敏的发展,该效应可能与抑制脊髓小胶质细胞活性,减少TNF-α和IL-1β表达有关。     

γ-氨基丁酸转运体抑制剂NO-711术前鞘内注射对坐骨神经慢性挤压伤大鼠神经病理性痛觉过敏的影响

γ-氨基丁酸是哺乳动物中枢神经系统主要的抑制性神经递质。近年来的研究发现GABA递质受体系统在伤害性信息传递和调节方面起着重要的作用。定位在突触前膜和神经胶质细胞的转运体GAT1是最重要的神经递质转运体之一，能快速摄取GABA从而终止其抑制作用。GABA转运体抑制剂已经被广泛用于癫痫研究，但是这种药是否对疼痛动物或人有镇痛作用仍然不是十分清楚。本实验目的是在大鼠神经病理痛模型建立前鞘内给予NO-711，观察其对大鼠热痛敏和触诱发痛的影响。     

Pentoxifylline decreases allodynia and hyperalgesia in a rat model of neuropathic pain

BACKGROUND AND THE PURPOSE OF THE STUDY: Pentoxifylline (PTX) is a non-specific cytokite pain in several animal models and humans. However, long-term therapeutic effects of PTX on neuropathic pain in a rat model of chronic constriction injury (CCI) are not completely clear. This study was conducted to examine the effect of long-term administration of PTX on neuropathic pain in rats. METHODS : Neuropathic pain was induced by sciatic nerve ligation using of CCI model in rats. Rats were randomly assigned into sham, CCI-saline treated, and CCI-PTX treated (30 or 60 mg/kg ip) groups. PTX or saline administered at 30 min before CCI and daily for 14 days post-CCI. At the days of 3, 7, 11 and 14 following CCI, by using standard methods effects of thermal hyperalgesia, thermal and mechanical allodynia in all groups were examined using the standard methods. RESULTS : The CCI-saline treated group showed a significant increase in mechanical and thermal allodynia, and thermal hyperalgesia as compared with the sham group in the tested days. Administration of the higher dose of PTX (60 mg/kg/day), but not the lower dose (30 mg/kg/day) significantly reduced mechanical and thermal allodynia, as compared with the CCI-saline treated group on days of 3, 7, 11 and 14 (all P values<0.001). Also, both doses of PTX significantly reduced thermal hyperalgesia as compared with the CCI-saline treated group on these days (all P values<0.001). CONCLUSION : Results of this study show that chronic administration of PTX reduces the neuropathic pain in a rat model of CCI. Thus, this drug may have a therapeutic application in the treatment and management of neuropathic pain in humans.     

Blocking sodium channels to treat neuropathic pain

Neuropathic pain remains a large unmet medical need. A number of therapeutic options exist, but efficacy and tolerability are less than satisfactory. Based on animal models and limited data from human patients, the pain and hypersensitivity that characterize neuropathic pain are associated with spontaneous discharges of normally quiescent nociceptors. Sodium channel blockers inhibit this spontaneous activity, reverse nerve injury-induced pain behavior in animals and alleviate neuropathic pain in humans. Several sodium channel subtypes are expressed primarily in sensory neurons and may contribute to the efficacy of sodium channel blockers. In this report, the authors review the current understanding of the role of sodium channels and of specific sodium channel subtypes in neuropathic pain signaling.     

GLT-1激动剂头孢曲松钠对慢性神经病理性痛的影响

目的：探讨头孢曲松钠（Ceftriaxone,Cef）对慢性神经病理性痛过敏及GLT-1表达的影响。方法雄性SD大鼠90只,随机分为Sham组、CCI 14 d组、Cef预防组、 Cef治疗组,后2组设腹腔注射NS组为对照,在不同时间点测定热缩足反射潜伏期;另设CCI 1 d、4 d、7 d组。应用免疫组化观察不同时间点脊髓后角GLT-1表达的变化。结果CCI诱导大鼠产生了热痛敏,腹腔注射NS对CCI诱导的热痛敏无影响。 Cef预防组大鼠CCI侧后肢热缩足反射潜伏期于CCI后第5天、第7天明显延长（ P ＜0°．05）;Cef 治疗组大鼠CCI侧后肢热缩足反射潜伏期在术后第11天、第14天明显延长（ P ＜0．05）。免疫组化检测发现,Cef预防组和Cef治疗组分别抑制和逆转了GLT-1在CCI后期表达的降低。结论 Cef可通过上调GLT-1的表达对慢性神经病理性痛起到预防和治疗作用。     

葛根素对神经病理性痛模型小鼠的镇痛作用

目的探讨葛根素对神经病理性痛模型小鼠的镇痛作用,为临床开发新的镇痛药物奠定基础。方法结扎雌性C57BL/6小鼠单侧胫神经和腓总神经,建立坐骨神经分支选择损伤(spared nerve injury,SNI)神经病理性痛模型,利用机械刺激法和冷盘法分别观察腹腔注射不同剂量葛根素(100,75和25mg·kg-1)对SNI模型小鼠患侧脚掌痛阈的影响。结果 SNI模型小鼠腹腔注射75mg·kg-1葛根素可显著提高患侧脚掌的50%缩足阈值(P<0.01)和降低5min抬足次数(P<0.01),产生明显的镇痛作用,镇痛时间可维持60～70min;100mg·kg-1葛根素腹腔注射后虽然也可产生明显的镇痛作用,但作用时间较短,仅维持10～20min;25mg·kg-1葛根素腹腔注射后没有明显的镇痛作用。结论适当剂量的葛根素对神经病理性痛具有明显的镇痛作用。     

New targets for neuropathic pain therapeutics

Neuropathic pain (NeP) is initiated by a lesion or dysfunction in the nervous system. Unlike physiological pain it serves no useful purpose and is usually sustained and chronic. NeP encompasses a wide range of pain syndromes of diverse aetiologies which together account for > 12 million sufferers in the US. Currently, there are a number of therapies available for NeP, including gabapentin, pregabalin, anticonvulsants (tiagabine HCl), tricyclic antidepressants (amitriptyline, nortriptyline) and acetaminophen/opioid combination products (Vicodin, Tylenol #3). However, these products do not provide sufficient pain relief and a significant proportion of sufferers are refractory (60%). Therefore, there is a need for new therapies that provide more predictable efficacy in all patients with improved tolerability. Over the last decade, understanding of the basic mechanisms contributing to the generation of NeP in preclinical animal models has greatly improved. Together with the completion of the various genome sequencing projects and significant advances in microarray and target validation strategies, new therapeutic approaches are being rigourously pursued. This article reviews the rationale behind a number of these mechanism-based approaches, briefly discusses specific challenges that they face, and finally, speculates on the potential of emerging technologies as alternative therapeutic strategies to the traditional ‘small-molecule’ approach.     

Actions of the endocannabinoid transport inhibitor AM404 in neuropathic and inflammatory pain models

1. Although cannabinoid receptor agonists have analgesic activity in chronic pain states, they produce a spectrum of central cannabinoid CB(1) receptor-mediated motor and psychotropic side-effects. The actions of endocannabinoids, such as anandamide, are terminated by uptake and subsequent intracellular enzymatic degradation. In the present study, we examined the effect of acute administration of the anandamide transport inhibitor AM404 in rat models of chronic neuropathic and inflammatory pain. 2. Systemic administration of AM404 (10 mg/kg) reduced mechanical allodynia in the partial sciatic nerve ligation (PNL) model of neuropathic pain, but not in the complete Freund's adjuvant (CFA) model of inflammatory pain. 3. The effect of AM404 in the PNL model was abolished by coapplication with the selective cannabinoid CB(1) receptor antagonist AM251 (1 mg/kg). AM404 did not produce a reduction in motor performance in either the PNL or CFA models. 4. These findings suggest that acute administration of AM404 reduces allodynia in a neuropathic pain model via cannabinoid CB(1) receptor activation, without causing the undesirable motor disruption associated with cannabinoid receptor agonists.