电压门控钠通道在神经病理性痛中的作用

电压门控钠通道(VGSC)在神经病理性痛的发生和维持中起重要作用。非特异性的通道阻断剂是神经病理性痛的一种治疗手段,但由于可能产生严重的副作用而限制了其使用。最近研究揭示了几种主要在外周感觉神经系统中表达的VGSC的亚型与神经病理性痛密切相关,发展特异性的通道亚型阻断剂将成为治疗神经病理性痛的重要研究方向。     

外周神经损伤引起的神经病理性痛：对神经损伤的一种适应不良反应

外周神经损伤可引起对神经系统的一种适应不良反应,其产生神经病理性痛的主要特点为痛觉增敏和异常疼痛。目前文献报道多种机制涉及此反应,包括离子通道改变引起的异常放电、突触易化、多种轴突水平抑制作用缺失导致的中枢敏化、神经元细胞的凋亡以及异常的突触连接等结构的改变,另外神经损伤引起的神经免疫之间的相互作用在神经病理性痛的持续性发展中发挥着不可替代的作用。了解外周神经损伤引起的神经病理性的发病机制将对我们寻找治疗靶点和治疗策略提供坚实的理论基础。     

异位电活动的特点及其与慢性神经病理性痛的关系

外周神经损伤后 ,受累的背根神经节 (DRG)神经元及损伤部位发放大量异位放电 ,这种放电被认为是慢性神经病理性痛发生发展的基础之一 ,但近期这一理论受到越来越多实验的挑战。本文以脊神经结扎 (SNL)模型为例 ,从三个方面就异位放电的特点及其与慢性神经病理性痛的关系进行论述 :首先介绍异位放电的特点 ;然后根据现有的实验资料分析异位放电发生的可能分子机制 ,着重讨论电压依赖性钠离子通道在异位放电中的作用 ;最后 ,从正反两方面分析了损伤的外周神经产生的异位放电在慢性神经病理性痛发生发展过程中的作用。     

神经病理性疼痛研究进展

神经病理胜疼痛是指神经系统的损伤或功能障碍引起的疼痛,占到了各类慢性疼痛的30%以上。第四军医大学完成的—项研究成果成功揭示了神经病理性痛的发生机制,创建两种能够分别模拟神经病理性痛不同临床表现的动物模型为研究神经病理性痛和制定治疗策略奠定了基础。     

小胶质细胞在神经病理性疼痛中的作用

神经病理性疼痛对患者的生理和心理健康都有着极大的影响。近几年来的研究表明,外周神经炎症或损伤激活的小胶质细胞通过表达及释放一系列介质分子,在神经病理性疼痛的产生和传递通路中发挥重要的调制作用。激活的小胶质细胞与神经元之间信息交互传递从而影响痛敏行为的这一崭新模式极大地推进了人们对于疼痛的理解。同时也为以小胶质细胞作为靶点,开辟镇痛药物治疗的新方法提供了理论依据。     

神经传导速度对糖尿病痛性周围神经病的诊断价值

目的:探讨糖尿病痛性周围神经病的神经传导特点及神经传导速度在糖尿病痛性周围神经病中的诊断价值.方法:对18例痛性周围神经病患者进行病史采集及神经系统查体.采用肌电诱发电位仪,测定患者的正中神经、尺神经、胫神经、腓总神经及腓肠神经的运动感觉神经传导速度.结果:18例患者中男性13例,女性5例.年龄40-89岁.主要表现为双足烧灼样、针刺样、过电样疼痛.神经系统查体:针刺觉减弱7例,痛觉过敏3例,音叉震动觉减弱12例,跟腱反射减弱/消失15例.18例患者中有14例神经传导速度检查结果异常,腓肠神经感觉神经检查结果异常率高,83.3％,对诊断有帮助.结论:糖尿病痛性周围神经病变出现疼痛症状时已经存在大纤维受累,故神经传导速度异常阳性率高.神经传导速度不能早期发现糖尿病痛性周围神经病,探索一种简单易行的早期筛查方法意义重大.     

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

为研究γ-氨基丁酸转运体在神经病理性痛中的作用,实验用坐骨神经慢性挤压伤致神经病理性痛模型大鼠,以清醒大鼠分别对辐射热刺激和机械性触觉刺激的缩腿潜伏期和机械阈值为指标,分为NS组、N5组、N10组、N20组、N40组5组,分别在坐骨神经结扎前和结扎后第三天鞘内给予生理盐水或不同剂量的γ-氨基丁酸转运体特异性抑制剂NO-711(5、10、20、40μg),观察鞘内注射NO-711对大鼠热痛敏和触诱发痛的影响.结果表明,NO-711可显著抑制神经病理性痛大鼠的热痛觉过敏和触诱发痛(P＜0.05,P＜0.01),其抑制作用持续时间最长分别可达2h(N40组)和4 h(N20组),其抗热痛敏作用呈剂量依赖性.坐骨神经结扎前鞘内给予不同剂量的NO-711可不同程度地延迟坐骨神经结扎所致的热痛觉过敏的发生,但不能延迟结扎所致的触诱发痛的发生.结果表明γ-氨基丁酸转运体抑制剂在神经病理性痛大鼠具有抗热痛敏和抗触诱发痛的作用.     

cAMP反应元件结合蛋白介导磷酸化细胞外信号调节激酶在神经病理性痛形成中的作用

采用行为学、免疫组织化学和Western blot方法,观察鞘内注射细胞外信号调节激酶(extracellular signal-regulate kinase,ERK)信号转导通路阻滞剂对慢性压迫性损伤(chronic constriction injury,CCI)大鼠痛行为及脊髓背角内磷酸化cAMP反应元件结合蛋白(phosphorylated cAMP response-element binding protein,pCREB)和Fos表达变化的影响,探讨ERK／CREB转导通路在神经病理性疼痛中的作用。结果表明,CCI可明显增加双侧脊髓背角pCREB、损伤侧脊髓背角浅层Fos阳性神经元表达,以CCI后3与5d时尤为显著。鞘内沣射促分裂原活化蛋白激酶激酶(mitogen-activated protein kinase kinase,MEK)阻滞剂U0126及ERK反义寡核苷酸在减轻大鼠痛行为的同时,能明显抑制双侧脊髓背角内pCREB的表达,同时,Fos阳性神经元的表达也明显减少。大鼠痛行为及脊髓背角pCREB和Fos的表达在时相上一致。上述结果提示pCREB参与pERK介导的神经病理性疼痛。     

趋化因子介导的神经炎症反应和神经病理性疼痛

各种疾病引起的神经系统的损伤或功能障碍致使全球数以百万计的人们患有神经性病理性疼痛。目前的方法对神经病理性疼痛的疗效不佳且有副作用,需要开发有效的治疗方法。近年来人们逐渐认识到,脊髓中胶质细胞（如小胶质细胞和星形胶质细胞）能通过释放强效的神经调质,如促炎细胞因子和趋化因子,在神经性病理性疼痛的产生和维持中起重要作用。近期的证据显示,趋化因子是疼痛调控中的新成员。该文综述了一些趋化因子和受体（如CCL2／CCR2、CXCL1／CXCR2、CX3CL1／CX3CR1、CCL21／CXCR3）作为神经元和胶质细胞相互调控的介质参与神经病理性疼痛的调节。靶向趋化因子介导的神经炎症反应将成为治疗神经病理性疼痛的新方向。     

脊髓p38丝裂原活化蛋白激酶激活参与坐骨神经压迫性损伤所致神经病理性痛

本研究旨在观察脊髓p38丝裂原活化蛋白激酶（p38 mitogen-activated protein kinase,p38 MAPK）在坐骨神经压迫性损伤所致神经病理性痛中的作用。雄性Sprague-Dawley大鼠鞘内置管后,4-0丝线松结扎左侧坐骨神经制作慢性压迫性损伤（chronic constriction injury,CCI）模型。CCI后第5天,鞘内注射不同剂量的p38 MAPK特异性抑制剂SB203580,并在给药前及给药后不同时间点,分别用von Frey机械痛敏监测仪和热辐射刺激仪监测大鼠损伤侧后爪机械和热刺激反应闽值,用免疫印迹技术（Western blot）观察给药前后脊髓磷酸化p38 MAPK（p-p38 MAPK）和磷酸化环磷酸腺苷反应元件结合蛋白（phosphorylated cAMP response element binding protein,pCREB）表达变化。结果发现：坐骨神经压迫性损伤引起脊髓p-p38 MAPK蛋白表达明显增加;鞘内注射SB203580能剂量依赖性逆转CCI引起的机械性痛觉异常和热痛觉过敏及脊髓水平p-p38 MAPK表达的增加,也明显抑制CCI引起的脊髓pCREB表达的增加。结果提示,脊髓水平p38 MAPK激活参与坐骨神经压迫性损伤所致神经病理性痛的发展,其作用可能通过pCREB介导。     

Microglial activation in different models of peripheral nerve injury of the rat

Pain and pain modulation has been viewed as being mediated entirely by neurons. However, new research implicates spinal cord glia as key players in the creation and maintenance of pathological pain. Sciatic nerve lesions are one of the most commonly studied pain-related injuries. In our study we aimed to characterize changes in microglial activation in the rat spinal cord after axotomy and chronic constriction injury of the sciatic nerve and to evaluate this activation in regard to pain behavior in injured and control groups of rats. Microglial activation was observed at ipsilateral side of lumbar spinal cord in all experimental groups. There were slight differences in the level and extent of microglial activation between nerve injury models used, however, differences were clear between nerve-injured and sham animals in accordance with different level of pain behavior in these groups. It is known that activated microglia release various chemical mediators that can excite pain-responsive neurons. Robust microglial activation observed in present study could therefore contribute to pathological pain states observed following nerve injury.     

Effects of dextromethorphan and oxycodone on treatment of neuropathic pain in mice

Background

Neuropathic pain is a very troublesome and difficult pain to treat. Although opioids are the best analgesics for cancer and surgical pain in clinic, only oxycodone among opioids shows better efficacy to alleviate neuropathic pain. However, many side effects associated with the use of oxycodone render the continued use of it in neuropathic pain treatment undesirable. Hence, we explored whether dextromethorphan (DM, a known N-methyl-D-aspartate receptor antagonist with neuroprotective properties) could potentiate the anti-allodynic effect of oxycodone and underlying mechanisms regarding to glial cells (astrocytes and microglia) activation and proinflammatory cytokines release in a spinal nerve injury (SNL) mice model.

Results

Oxycodone produced a dose-dependent anti-allodynic effect. Co-administration of DM at a dose of 10 mg/kg (i.p.) (DM10) which had no anti-allodynic effect by itself enhanced the acute oxycodone (1 mg/kg, s.c.) effect. When the chronic anti-allodynic effects were examined, co-administration of DM10 also significantly enhanced the oxycodone effect at 3 mg/kg. Furthermore, oxycodone decreased SNL-induced activation of glial cells (astrocytes and microglia) and plasma levels of proinflammatory cytokines (IL-6, IL-1β and TNF-α). Co-administration of DM10 potentiated these effects of oxycodone.

Conclusion

The combined use of DM with oxycodone may have therapeutic potential for decreasing the effective dose of oxycodone on the treatment of neuropathic pain. Attenuation of the glial activation and proinflammatory cytokines in the spinal cord may be important mechanisms for these effects of DM.     

Structural hybridization of pyrrolidine-based T-type calcium channel inhibitors and exploration of their analgesic effects in a neuropathic pain model

Highly effective and safe drugs for the treatment of neuropathic pain are urgently required and it was shown that blocking T-type calcium channels can be a promising strategy for drug development for neuropathic pain. We have developed pyrrolidine-based T-type calcium channel inhibitors by structural hybridization and subsequent assessment of in vitro activities against Ca_v3.1 and Ca_v3.2 channels. Profiling of in vitro ADME properties of compounds was also carried out. The representative compound 17h showed comparable in vivo efficacy to gabapentin in the SNL model, which indicates T-type calcium channel inhibitors can be developed as effective therapeutics for neuropathic pain.     

Effective neuropathic pain relief through sciatic nerve administration of GAD65-expressing rAAV2

Recently, we demonstrated that the administration of GAD65-expressing rAAV2 to DRG attenuates peripheral neuropathy by inducing GABA release in the spinal cord. However, the direct injection to DRG is invasive and may therefore cause nerve injury and other side effects.To circumvent this surgical intervention, we explored the potential of a much simpler and less invasive route of sciatic nerve administration. Using a neuropathic pain model, we introduced rAAV2-GAD65 through sciatic nerve and examined its therapeutic potency in pain-related behavior tests. Both GFP and GAD65 expression indicated that effective transgene delivery to the DRG can be accomplished via sciatic nerve administration. Equally importantly, the GABA concentration in the spinal cord increased significantly after GAD65 introduction, and pain symptoms were dramatically reduced and persistently controlled. The implication is that the sciatic nerve is a highly promising route for delivering rAAV2 to the DRG, and thus represents a much less invasive, clinically viable gene therapy option.     

轴突导向因子参与神经病理痛的研究进展

轴突导向因子协同引导轴突延伸,准确地进行轴突的投射。神经系统损害发生后,这些因子及其各自受体相互作用,通过激活磷酸激酶,影响突触可塑性从而诱发和维持神经病理痛。     

Estrogen alleviates neuropathic pain induced after spinal cord injury by inhibiting microglia and astrocyte activation

Neuropathic pain after spinal cord injury (SCI) is developed in about 80% of SCI patients and there is no efficient therapeutic drug to alleviate SCI-induced neuropathic pain. Here we examined the effect of estrogen on SCI-induced neuropathic pain at below-level and its effect on neuroinflammation as underlying mechanisms. Neuropathic pain is developed at late phase after SCI and a single dose of 17β-estradiol (100, 300?μg/kg) were administered to rats with neuropathic pain after SCI through intravenous injection. As results, both mechanical allodynia and thermal hyperalgesia were significantly reduced by 17β-estradiol compared to vehicle control. Both microglia and astrocyte activation in the lamina I and II of L4-5 dorsal horn was also inhibited by 17β-estradiol. In addition, the levels of p-p38MAPK and p-ERK known to be activated in microglia and p-JNK known to be activated in astrocyte were significantly decreased by 17β-estradiol. Furthermore, the mRNA expression of inflammatory mediators such as Il-1β, Il-6, iNos, and Cox-2 was more attenuated in 17β-estradiol-treated group than in vehicle-treated group. Particularly, we found that the analgesic effect by 17β-estradiol was mediated via estrogen receptors, which are expressed in dorsal horn neurons. These results suggest that 17β-estradiol may attenuate SCI-induced neuropathic pain by inhibiting microglia and astrocyte activation followed inflammation.     

miR-32-5p-mediated Dusp5 downregulation contributes to neuropathic pain

Previous studies have demonstrated that microRNAs (miRNAs) play important roles in the pathogenesis of neuropathic pain. In the present study, we found that miR-32-5p was significantly upregulated in rats after spinal nerve ligation (SNL), specifically in the spinal microglia of rats with SNL. Functional assays showed that knockdown of miR-32-5p greatly suppressed mechanical allodynia and heat hyperalgesia, and decreased inflammatory cytokine (IL-1β, TNF-α and IL-6) protein expression in rats after SNL. Similarly, miR-32-5p knockdown alleviated cytokine production in lipopolysaccharide (LPS)-treated spinal microglial cells, whereas its overexpression had the opposite effect. Mechanistic investigations revealed Dual-specificity phosphatase 5 (Dusp5) as a direct target of miR-32-5p, which is involved in the miR-32-5p-mediated effects on neuropathic pain and neuroinflammation. We demonstrated for the first time that miR-32-5p promotes neuroinflammation and neuropathic pain development through regulation of Dusp5. Our findings highlight a novel contribution of miR-32-5p to the process of neuropathic pain, and suggest possibilities for the development of novel therapeutic options for neuropathic pain.     

Nerve Growth Factor of Red Nucleus Involvement in Pain Induced by Spared Nerve Injury of the Rat Sciatic Nerve

Nerve growth factor (NGF), a member of the neurotrophin family, is essential for the development and maintenance of sensory neurons and for the formation of central pain circuitry. The current study was designed to evaluate the expression of NGF in the brain of rats with spared nerve injury (SNI), using immunohistochemical technique. The results showed that the level of NGF in the Red nucleus (RN) of SNI rats was apparently higher than that of sham-operated rats. To further study the effect of NGF in the development of neuropathic pain, different doses of anti-NGF antibody (20, 2.0 and 0.2 μg/ml) were microinjected into the RN contralateral to the nerve injury side of SNI rats. The data suggested that the higher doses of anti-NGF antibody (20 and 2.0 μg/ml) significantly attenuated the mechanical allodynia of neuropathic rats, while the 0.2 μg/ml antibody showed no analgesic effect. These results suggest that the NGF of RN is involved in the development of neuropathic allodynia in SNI rats.     

Synthesis and the 5-HT6 receptor antagonistic effect of 3-arylsulfonylamino-5,6-dihydro-6-substituted pyrazolo[3,4]pyridinones for neuropathic pain treatment

A novel series of 3-arylsulfonylamino-5,6-dihydro-6-substituted-1H-pyrazolo[3,4-c]pyridine-7-ones was designed and synthesized as 5-HT₆ ligands. Among the derivatives synthesized, the lead compound, 12b, having piperidine functionality at the 6-position and (1-naphthyl)sulfonamino at the 3-position of the core structure showed the most potent 5-HT₆ inhibitory activity in vitro, good stability without CYP liability, and good neuropathic pain alleviation activity in a rat animal model.