GABAA receptor modulation in dorsal root ganglia in vivo affects chronic pain after nerve injury

Neuropathic pain (NPP) due to sensory nerve injury is, in part, the result of peripheral sensitization leading to a long-lasting increase in synaptic plasticity in the spinal dorsal horn. Thus, activation of GABA-mediated inhibitory inputs from sensory neurons could be beneficial in the alleviation of NPP symptoms. Dorsal root ganglia (DRG) conduct painful stimulation from the periphery to the spinal cord. Long-lasting down-regulation in GABA tone or sensitivity in DRG neurons has been reported in animals with neuropathy. To determine the function of GABA in DRG in the development of NPP, we examined how the acute pharmacological GABA(A)-receptor modulation of L5 DRG in vivo affects the development of NPP in rats with crush injury to the sciatic nerve. Direct application of muscimol and gaboxadol, GABA(A) agonists, to L5 DRG immediately after injury induced dose-dependent alleviation, whereas bicuculline and picrotoxin, GABA(A) antagonists, worsened NPP postaxonal injury. The pain-alleviating effects of muscimol and gaboxadol were blocked by bicuculline. Muscimol, applied at the time of injury, caused complete and long-lasting abolishment of NPP development. However, when muscimol was applied after NPP had already developed, its pain-alleviating effect, although significant, was short-lived. Using a fluorescent tracer, sodium fluorescein, we confirmed that local DRG application results in minimal spread into the corresponding dorsal horn of the ipsilateral spinal cord. GABA(A) receptors in DRG are important in the development of NPP after peripheral nerve injury, making timely exogenous GABAergic manipulation at the DRG level a potentially useful therapeutic modality.     

自体外周血干细胞移植治疗周围神经损伤

背景：关于神经干细胞对周围神经损伤的治疗已有多篇报道,但外周血干细胞对周围神经损伤治疗鲜有报道。 目的：探讨自体外周血干细胞移植治疗周围神经损伤使失神经骨骼肌重获神经再支配的临床应用。 方法：应用外周血干细胞治疗周围神经损伤6例,同时与周围神经损伤单纯行神经断端吻合或神经移植10例比较。2组患者术后常规肌注鼠神经生长因子一两个疗程,同时给予针灸、理疗、经皮电刺激治疗及功能康复训练。 结果与结论：两组患者随访均超过6个月。干细胞移植组运动神经传导速度和感觉神经传导速度的恢复率要明显高于单纯神经吻合组。提示周围神经损伤后给予修复局部用外周血干细胞移植能够使远端失神经骨骼肌早期重新获得神经再支配。     

Spinal balloon nucleoplasty: a hypothetical minimally invasive treatment for herniated nucleus pulposus

Low back pain is the most common cause of disability under the age of 45. The annual incidence of back pain is estimated to be 5% and the lifetime prevalence is 80%. Majority of the patients with persistent symptoms are suffering from radiculopathy that is mainly caused by a herniated nucleus pulposus (HNP). HNP can heal spontaneously due to spontaneous resorption. Besides pressure nucleus pulposus, without any compression, may induce similar changes when applied epidurally to the nerve roots. Nevertheless, combination of chronic mechanical compression and application of nucleus pulposus causes a more pronounced nerve injury. When dual pathophysiology (pressure and inflammatory reaction), spontaneous resorption, and natural course of HNP are taken into account, any treatment modality that eliminates both the pressure and contact of the nucleus pulposus with the nerve root via creating extra time for healing to take place might prove beneficial. These requirements can be provided by spinal balloon nucleoplasty (SBN), which can be used in combination with other treatment modalities such as chymopapain injection. In this hypothetical method, epidural access to the subarachnoid space is established via epidural needles, thereafter a specially designed balloon tipped catheter is advanced. When the catheter is ideally placed with the help of CT or MRI, the balloon at the tip is inflated to relieve pressure and to prevent contact of the nerve root with HNP. The answer to the question, will SBN find a place in clinical practice? is obscure. But a homology can be established with uterine fibroid embolization, which has found clinical use in a period of 30 years approximately.     

周围神经损伤修复及功能恢复评价

目的：评价修复周围神经缺损的各种生物型人工材料的性能、应用以及功能恢复评定方法,寻找适宜的周围神经替代物。 方法：以“神经导管,周围神经损伤修复,生物材料,许旺细胞”为关键词,采用计算机检索2004-01/2010-11相关文章。纳入与生物材料以及组织工程神经相关的文章;排除重复研究或Meta分析类文章。以28篇文献为主,重点讨论周围神经修复生物型人工材料的种类、性能以及适宜的功能恢复评定方法。 结果：以脱细胞神经基质以及人工合成可降解材料为主体的复合型生物工程材料可作为较理想的支架材料应用于周围神经组织工程。脱细胞神经支架解决了自体神经来源受限、移植物排斥反应等问题,韧性与可塑性接近自体神经,微环境更利于周围神经再生。人工合成可降解材料具有生物降解、可塑性、一定的通透性等优势,且已有商品化成品出现。若将上述材料分别合理构建复合材料,有可能得到性能良好的组织工程神经移植物。周围神经修复后功能恢复评定方法主要以大体与形态学观察、组织学、神经肌肉机能学评定为主,辅以分子生物学技术。各类评定方法的应用有利于筛选出最适宜的周围神经损伤修复材料与构建方案。 结论：周围神经损伤修复生物型人工材料研究发展迅速,但仍没有超越自体神经移植的支架材料。脱细胞神经基质以及人工合成可降解材料复合构建支架可作为较好的周围神经支架,但仍需要与种子细胞、神经营养因子等联合构建,以取得良好的促进再生效果。当前,对周围神经损伤修复效果的评定更加注重于神经肌肉功能的恢复,迫切需要筛选出最佳的修复材料以及构建方案以满足组织工程神经移植以及功能康复的要求,达到对周围神经损伤后形态、结构修复与功能重建的目的。     

腓总神经损伤致踝关节功能障碍的伤残评定结果分析

目的 分析48例腓总神经损伤所致的踝关节功能障碍者的伤残评定结果。方法 选取2017年11月~2018年11月48例鉴定结果为“腓总神经损伤”所导致的踝关节功能障碍进行伤残程度鉴定的案例,结合肌电图检查结果和影像学检查结果,对其伤残程度评定结果进行分析。结果 伤残患者以男性居多,多为交通事故所致;判断腓总神经完全损伤占29.17%,腓总神经部分损伤者占70.83%;影像学结果发现,除2例医疗事故外,腓总神经损伤并伴有股骨骨折伤者占8.69%;伴有胫骨平台呈现骨折且有同侧腓骨小头有粉碎性骨折占21.74%;伴有胫骨及腓骨呈现多处骨折占26.09%;伴有腓骨呈现多处骨折占26.09%;伴有小腿软组织因遗物残存致肌肉挫裂者占17.39%。踝关节功能鉴定发现,踝关节明显无法正常背屈,对行走功能造成严重影响者占25.00%;呈现踝关节无法正常背屈及跖屈者占25.00%;踝关节呈现背屈功能障碍,未出现跖屈功能障碍者占33.33%;未出现踝关节背屈功能及跖屈功能障碍者占16.67%。48例样本伤残评定结果中,腓总神经完全损伤者14例,其中评定达七级伤残者3例,九级伤残者11例;腓总神经部分损伤者34例,其中评定为十级伤残者33例,未达伤残标准者1例。结论 腓总神经出现完全受损者最终导致的踝关节功能障碍更严重,伤残评定等级较腓总神经部分损伤者更高,另外,在对腓总神经损伤所致的踝关节功能障碍鉴定中需考虑患者的症状。     

生物材料构建神经导管修复周围神经损伤的临床应用

背景：显微外科技术及周围神经损伤修复技术的发展与神经导管材料密切相关。神经导管的构建特别是生物材料构建神经导管材料还有待进一步开发研究。 目的：探讨生物材料构建的神经导管在周围神经损伤修复中的应用及数据分析。 方法：SCI数据库中2001/2010检索有关神经导管在周围神经损伤修复中的应用的文献,检索词为“神经导管(nerve conduit);生物材料(biomaterials);周围神经损伤(peripheral nerve injury);神经再生(nerve regeneration);壳聚糖神经导管(chitosan/chitin nerve conduit);高分子神经导管(polymer/macromolecule nerve conduit);胶原神经导管(collagen nerve conduit)”,共检索文献183篇。 结果与结论：神经导管修复法是在神经断端之间留有一段间隙,利用神经导管在神经的远端和近端之间桥接,并创造相对密闭的环境,以充分发挥远端神经的趋化作用,同时阻隔外部的影响,减少瘢痕的产生。目前,已被用于制备神经导管材料分为非神经组织、非生物降解材料、可生物降解材料。随着分子生物学及其他相关技术的发展,探索寻找理想的材料构建神经导管来治疗周围神经损伤研究始终在进行中。     

Biomedical engineering strategies for peripheral nerve repair: surgical applications, state of the art, and future challenges

Damage to the peripheral nervous system is surprisingly common and occurs primarily from trauma or a complication of surgery. Although recovery of nerve function occurs in many mild injuries, outcomes are often unsatisfactory following severe trauma. Nerve repair and regeneration presents unique clinical challenges and opportunities, and substantial contributions can be made through the informed application of biomedical engineering strategies. This article reviews the clinical presentations and classification of nerve injuries, in addition to the state of the art for surgical decision-making and repair strategies. This discussion presents specific challenges that must be addressed to realistically improve the treatment of nerve injuries and promote widespread recovery. In particular, nerve defects a few centimeters in length use a sensory nerve autograft as the standard technique; however, this approach is limited by the availability of donor nerve and comorbidity associated with additional surgery. Moreover, we currently have an inadequate ability to noninvasively assess the degree of nerve injury and to track axonal regeneration. As a result, wait-and-see surgical decisions can lead to undesirable and less successful "delayed" repair procedures. In this fight for time, degeneration of the distal nerve support structure and target progresses, ultimately blunting complete functional recovery. Thus, the most pressing challenges in peripheral nerve repair include the development of tissue-engineered nerve grafts that match or exceed the performance of autografts, the ability to noninvasively assess nerve damage and track axonal regeneration, and approaches to maintain the efficacy of the distal pathway and targets during the regenerative process. Biomedical engineering strategies can address these issues to substantially contribute at both the basic and applied levels, improving surgical management and functional recovery following severe peripheral nerve injury.     

Biodegradable Conduit Small Gap Tubulization for Peripheral Nerve Mutilation: A Substitute for Traditional Epineurial Neurorrhaphy

Nerve regeneration and re-innervation are usually difficult after peripheral nerve injury. Epineurium neurorrhaphy to recover the nerve continuity is the traditional choice of peripheral nerve mutilation without nerve defects, whereas the functional recovery remains quite unsatisfactory. Based on previous research in SD rats and Rhesus Monkeys, a multiple centers clinical trial about biodegradable conduit small gap tubulization for peripheral nerve mutilation to substitute traditional epineurial neurorrhaphy was carried out. Herein, the authors reviewed the literature that focused on peripheral nerve injury and possible clinical application, and confirmed the clinical possibilities of biodegradable conduit small gap tubulization to substitute traditional epineurial neurorrhaphy for peripheral nerve mutilation. The biodegradable conduit small gap tubulization to substitute traditional epineurial neurorrhaphy for peripheral nerve mutilation may be a revolutionary innovation in peripheral nerve injury and repair field.     

Comparison of sympathetic sprouting in sensory ganglia in three animal models of neuropathic pain

Sympathetic postganglionic fibers sprout in the dorsal root ganglion (DRG) after peripheral nerve injury. Therefore, one possible contributing factor of sympathetic dependency of neuropathic pain is the extent of sympathetic sprouting in the DRG after peripheral nerve injury. The present study compared the extent of sympathetic sprouting in the DRG as well as in the injured peripheral nerve in three rat neuropathic pain models: (1) the chronic constriction injury model (CCI); (2) the partial sciatic nerve ligation injury model (PSI); and (3) the segmental spinal nerve ligation injury model (SSI). All three methods of peripheral nerve injury produced behavioral signs of ongoing and evoked pain with some differences in the magnitude of each pain component. The density of sympathetic fibers in the DRG was significantly higher at all examined postoperative times than controls in the SSI model, while it was somewhat higher than controls only at the last examined postoperative time (20 weeks) in the CCI and PSI models. Therefore, data suggest that, although sympathetic changes in the DRG may contribute to neuropathic pain syndromes in the SSI model, other mechanisms seem to be more important in the CCI and PSI models at early times following peripheral nerve injury.     

TNF-α and neuropathic pain - a review

Tumor necrosis factor alpha (TNF-α) was discovered more than a century ago, and its known roles have extended from within the immune system to include a neuro-inflammatory domain in the nervous system. Neuropathic pain is a recognized type of pathological pain where nociceptive responses persist beyond the resolution of damage to the nerve or its surrounding tissue. Very often, neuropathic pain is disproportionately enhanced in intensity (hyperalgesia) or altered in modality (hyperpathia or allodynia) in relation to the stimuli. At time of this writing, there is as yet no common consensus about the etiology of neuropathic pain - possible mechanisms can be categorized into peripheral sensitization and central sensitization of the nervous system in response to the nociceptive stimuli. Animal models of neuropathic pain based on various types of nerve injuries (peripheral versus spinal nerve, ligation versus chronic constrictive injury) have persistently implicated a pivotal role for TNF-α at both peripheral and central levels of sensitization. Despite a lack of success in clinical trials of anti-TNF-α therapy in alleviating the sciatic type of neuropathic pain, the intricate link of TNF-α with other neuro-inflammatory signaling systems (e.g., chemokines and p38 MAPK) has indeed inspired a systems approach perspective for future drug development in treating neuropathic pain.     

周围神经端侧吻合的研究进展

在周围神经损伤的修复中 ,对于神经长段缺损或近端无法寻找时 ,神经端侧吻合因其操作简便 ,既不损伤供体神经 ,又能恢复受损神经功能 ,已成为一种潜力巨大的神经修复方法。本文通过对神经端侧吻合后神经再生机制、影响因素及其面临的问题进行综述 ,以期为进一步的研究及临床应用提供参考资料。     

The role of immunophilin ligands in nerve regeneration

Tacrolimus (FK506) is a widely used immunosuppressant in organ transplantation. However, it also has neurotrophic activity that occurs independently of its immunosuppressive effects. Other neurotrophic immunophilin ligands that do not exhibit immunosuppression have subsequently been developed and studied in various models of nerve injury. This article reviews the literature on the use of tacrolimus and other immunophilin ligands in peripheral nerve, cranial nerve and spinal cord injuries. The most convincing evidence of enhanced nerve regeneration is seen with systemic administration of tacrolimus in peripheral nerve injury, although clinical use is limited due to its immunosuppressive side effects. Local tacrolimus delivery to the site of nerve repair in peripheral and cranial nerve injury is less effective but requires further investigation. Tacrolimus can enhance outcomes in nerve allograft reconstruction and accelerates reinnervation of complex functional allograft transplants. Other non-immunosuppressive immunophilins ligands such as V-10367 and FK1706 demonstrate enhanced neuroregeneration in the peripheral nervous system and CNS. Mixed results are found in the application of immunophilin ligands to treat spinal cord injury. Immunophilin ligands have great potential in the treatment of nerve injury, but further preclinical studies are necessary to permit translation into clinical trials.     

曲安奈德与甲基泼尼松龙影响周围神经再生的比较

背景：有研究证实甲基泼尼松龙在周围神经损伤后应用可促进神经再生;而曲安奈德在周围神经损伤方面的治疗效果尚未见报道。 目的：对比观察曲安奈德与甲基泼尼松龙在兔周围神经损伤后神经再生中的作用。 方法：36只新西兰大白兔随机数字表法分为曲安奈德组,甲基泼尼松龙组和对照组。兔双侧胫神经切断后行端端缝合,吻合口周围各组分别用曲安奈德注射液、甲基泼尼松龙注射液、生理盐水局部注射。 结果与结论：曲安奈德组和甲基泼尼松龙组步态、足底溃疡及愈合情况均优于对照组,且均较少出现神经吻合口周围粘连,镜下观察吻合口周围再生神经纤维较多,结缔组织增生较少;在神经传导速度、有髓神经纤维再生率、小腿三头肌湿质量比等方面明显优于对照组(P < 0.01)。曲安奈德组和甲基泼尼松龙组在上述各指标中无明显差异(P > 0.05)。提示周围神经损伤修复中局部应用曲安奈德或甲级泼尼松龙处理神经吻合口,能有效防止周围神经粘连,促进周围神经再生。     

Autoimmune diseases of the peripheral nervous system

Autoimmune-mediated diseases targeting the peripheral nerve represent a group of disorders often associated with high clinical disability. At present, therapeutic options are limited. The application of innovative and cutting-edge technologies to the study of immune-mediated disorders of the peripheral nervous system (PNS) have generated a better understanding of underlying principles of the organization of the immune network present in the peripheral nerve and its dialogue with the systemic immune system. These insights may foster the development of specific and highly effective therapies for autoimmune diseases of the peripheral nerve. Of great interest in this context is the application of monoclonal antibodies, such as rituximab or alemtuzumab, which in small observational studies provided promising clinical results. But also other immunomodulatory or immunosuppressive drugs used in other indications currently find their way to PNS autoimmunity. Clearly, prospective controlled clinical trials are warranted before making firm conclusions on the feasibility of these innovative therapeutic approaches for treating immune-mediated disease of the peripheral nerve.     

可降解神经套接管制备及临床试验流程专家共识

周围神经损伤是一种常见临床疾病,损伤后的有效修复是减少损伤并发症、改善预后的重要措施.临床上治疗单纯横断伤或微小缺损的神经损伤多采用显微外科对位缝合方式吻合神经断端,但临床修复效果难达到预期.基于周围神经选择性再生学说,研究者发现小间隙套接缝合的修复效果明显好于传统的神经外膜缝合方法.因此,研发一种用来桥接周围神经断端...     

Injury of Peripheral Muscles in Smokers with Chronic Obstructive Pulmonary Disease

Muscle injury has clinical relevance in diseased individuals because it is associated with muscle dysfunction in terms of decreased strength and/or endurance. This study was aimed at answering three questions: whether the presence of chronic obstructive pulmonary disease (COPD) is associated with peripheral muscle injury; whether muscle injury is associated with some of the relevant functional impairment in the muscles; and whether muscle injury can be solely justified by deconditioning. Twenty-one male COPD patients were eligible for the study. Seven healthy volunteers recruited from the general population were included as controls. Function of the quadriceps muscle was assessed through specific single-leg exercise (strength and endurance). Cellular (light microscopy) and subcellular (electron microscopy) techniques were used to evaluate muscle injury on biopsies from the vastus lateralis muscle. Signs of injury were found in muscles from both control and COPD patients, not only in cases showing severe airflow obstruction but also in the mild or moderate stages of the disease. Current smoking and presence of COPD were significantly associated with increased injury of the muscle as assessed by light and electron microscopy techniques. The authors conclude that peripheral muscle injury is evident in mild, moderate, and severe stages of COPD even in the absence of respiratory failure, hypercapnia, chronic steroid treatment, low body weight, or some coexisting disease. These findings support the theory that systemic factors with deleterious effect are acting on peripheral muscles of smokers with COPD, increasing the susceptibility of the muscle fibers to membrane and sarcomere injury.     

Injury of peripheral muscles in smokers with chronic obstructive pulmonary disease

Muscle injury has clinical relevance in diseased individuals because it is associated with muscle dysfunction in terms of decreased strength and/or endurance. This study was aimed at answering three questions: whether the presence of chronic obstructive pulmonary disease (COPD) is associated with peripheral muscle injury; whether muscle injury is associated with some of the relevant functional impairment in the muscles; and whether muscle injury can be solely justified by deconditioning. Twenty-one male COPD patients were eligible for the study. Seven healthy volunteers recruited from the general population were included as controls. Function of the quadriceps muscle was assessed through specific single-leg exercise (strength and endurance). Cellular (light microscopy) and subcellular (electron microscopy) techniques were used to evaluate muscle injury on biopsies from the vastus lateralis muscle. Signs of injury were found in muscles from both control and COPD patients, not only in cases showing severe airflow obstruction but also in the mild or moderate stages of the disease. Current smoking and presence of COPD were significantly associated with increased injury of the muscle as assessed by light and electron microscopy techniques. The authors conclude that peripheral muscle injury is evident in mild, moderate, and severe stages of COPD even in the absence of respiratory failure, hypercapnia, chronic steroid treatment, low body weight, or some coexisting disease. These findings support the theory that systemic factors with deleterious effect are acting on peripheral muscles of smokers with COPD, increasing the susceptibility of the muscle fibers to membrane and sarcomere injury.     

Studies of vasoactive intestinal polypeptide expression in injured peripheral neurons using capsaicin, sympathectomy and mf mutant rats

The increased expression of vasoactive intestinal polypeptide (VIP) in injured peripheral neurons was studied. In contrast to substance P, there was a marked increase, and maintained fast axonal transport, of VIP in rat sciatic nerve after peripheral axotomy. Local capsaicin application to the nerve trunk failed to inhibit the injury-induced VIP increase, and capsaicin even increased VIP levels when applied locally to uninjured nerves. Pharmacological sympathectomy showed that some of the peripheral VIP increase may occur in post-ganglionic sympathetic fibres. The VIP increase after injury appeared unaffected in the mf mutant rat, in spite of its loss of lumbar dorsal root ganglion cells. VIP-staining fibres in the epi- and peri-neurium and perivascular plexuses of sciatic nerve showed an increase in number in parallel with the changes of the nerve VIP content. These findings suggest that sensory and sympathetic nerve fibres expressing VIP after injury play a role in the regulation of blood flow to nerves, and in the pathophysiological processes in nerve and dorsal spinal cord which follow peripheral nerve injury.     

以组织工程建构技术修复周围神经损伤的难点

背景：组织工程构建技术是近年来周围神经损伤修复的重要方法之一,在周围神经治疗领域有着良好的前景。 目的：总结近年来利用组织工程学构建技术对周围神经损伤修复的研究进展。 方法：应用计算机检索万方数据库、CNKI和PubMed数据库中1995年1月至2011年12月关于组织工程构建技术的文章,在标题和摘要中以“组织工程,神经导管支架,生物活性,周围神经损伤”或“Tissue engineering,Nerve scaffold,Bioactivity,Peripheral nerve defect”为检索词进行检索,初检得到156篇文献,最终纳入56篇文献进行综述。 结果与结论：周围神经损伤组织工程修复的两个要素是神经支架材料的选择和生物功能化。构建神经的支架材料包括可降解和非可降解两大类,通常需要具有三维多孔结构和相应的孔隙率及比表面积,其力学性能、表面活性、生物相容性和导电性等直接影响神经损伤修复的效果;生物功能化的主要生物活性因子包括支持细胞,种子蛋白和神经营养因子,将这些生物活性因子接种在神经导管支架材料上,促进受损神经的修复与功能替代。组织工程技术应用于周围神经损伤修复与再生的研究重点在于导管、细胞与生长因子的综合应用。组织工程技术与生物技术的联合应用将成为周围神经损伤修复的研究热点。