P2X4受体结构及其参与神经病理性痛机制的研究进展

神经病理性痛是神经系统炎症或损伤后引发的一种慢性疼痛,其发病机制复杂,目前仍缺乏有效的治疗药物。近年来针对P2X4受体的蛋白结构及配体结合相关的重要部位开展了大量研究,发现表达于脊髓背角小胶质细胞的P2X4受体在神经病理性痛的发生和发展过程中具有重要的作用,提示其可能参与了神经病理性痛的发病。本文就P2X4受体的结构及其参与神经病理性痛的可能机制作一综述,试图为靶向P2X4受体研发新型抗神经病理性痛药物提供新的线索。     

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。     

NMDAR/PSD-95/nNOS复合物在神经病理性疼痛中的研究进展

神经病理性疼痛是一种常见的慢性疼痛疾病,发病机制复杂且临床治疗效果欠佳。最近研究表明, N-甲基-D-天冬氨酸受体/突触后致密蛋白95/神经元型一氧化氮合酶（NMDAR/PSD-95/nNOS）复合物在神经病理性疼痛中发挥重要作用。研究发现,如果不直接抑制NMDAR或nNOS,选择性阻断NMDAR/PSD-95或者nNOS/PSD-95的相互作用,可以在不影响NMDAR和nNOS生理功能的前提下抑制神经病理性疼痛中NO的病理性释放,可能获得没有明显副作用的安全有效的神经病理性疼痛的治疗药物。故本文对NMDAR/PSD-95/nNOS复合物在神经病理性疼痛中的研究进展进行综述。     

神经病理性疼痛发生机制的研究进展

为了获得高效治疗神经病理性疼痛的方法,本研究对近几年国内外神经病理性疼痛机制与治疗方面的研究进行分析。大量动物模型实验研究证实,脊髓背角星形胶质细胞激活、C-纤维的敏化调节、嘌呤受体信号的激活以及TNF-α细胞因子释放等途径或机制共同作用导致神经病理性疼痛的发生。针对这些机制的研究可指导临床从不同途径阻断疼痛的发生及发展过程,从而治疗该类疼痛,并可为通过减少外周刺激、提高疼痛阈值、阻断疼痛感觉传导等相应手段治疗神经病理性疼痛提供重要理论依据。     

神经病理性疼痛的研究进展

本文从神经病理性疼痛的动物模型、发病机制、临床用药3个方面叙述了神经病理性疼痛的研究进展。     

环氧合酶在神经病理性疼痛中作用的研究进展

环氧合酶(COX)是前列腺素(PG)合成的限速酶，至今已发现其至少具有三个亚型：COX-1，COX-2及COX-3。神经病理性疼痛是由于外周或中枢神经系统的直接损伤和功能紊乱而引起的疼痛，其发病机制不明，缺乏有效治疗措施。COX抑制剂已在炎性疼痛治疗方面得到了广泛应用，但其在神经病理性疼痛的治疗中尚处于起步阶段。研究表明，PG特别是脊髓所产生的PG，作为致痛物质在神经病理性疼痛中起作用。虽然COX-2在中枢的表达较COX-1强得多，但两者在神经病理性疼痛中的地位都不容忽视。前者在神经病理性疼痛的早期发展中起主要作用，而后者与神经病理性疼痛的维持有关。COX抑制剂可能通过减少PG的合成或改变神经病理性疼痛后中枢可塑性和敏感性等途径而起到治疗神经病理性疼痛的作用。     

电压门控性钠通道亚型和神经病理性疼痛

神经病理性疼痛是神经系统损伤引起的一种慢性疼痛。感觉神经元上的电压门控性钠通道在多种由外周神经损伤引起的神经病理性疼痛中具有重要的作用。近年来,随着对钠通道亚型在神经病理性疼痛发病机制中作用的阐明,发展特异性的钠通道亚型阻断药物将成为治疗神经病理性疼痛的重要研究方向。     

基于炎症信号通路的生物碱治疗神经病理性疼痛的研究进展

神经病理性疼痛是由神经系统原发性损害和功能障碍所激发或引起的疼痛,炎症作为神经病理性疼痛发展的重要病机之一,是生物体对组织损伤做出的一种正常生理反应。炎症介导的神经病理性疼痛发展机制与外周神经敏化、中枢神经敏化息息相关,包括神经炎症反应、氧化应激反应、离子通道改变、胶质细胞的活化。常见的中药成分马钱子碱、小檗碱、去氢紫堇鳞茎碱、川芎嗪、氧化苦参碱、青藤碱均可缓解神经病理性疼痛。生物碱可通过多条途径影响神经病理性疼痛,其发挥的抗炎作用影响着外周神经敏化和中枢神经敏化,是治疗神经病理性疼痛的重要机制之一。因此生物碱介导的炎症反应具有良好的抗神经元损伤作用,对神经病理性疼痛产生一定的治疗作用。总结了炎症参与神经病理性疼痛和生物碱抗炎镇痛的机制,拟从分子层面阐释生物碱发挥抗神经病理性疼痛的作用机制。     

周围神经卡压性病理性疼痛的研究进展

神经病理性疼痛是神经系统损伤引起的一种慢性疼痛,其机制涉及异位放电、交感一感觉耦联、解剖重构、脊髓背角神经元的敏感化、中枢抑制性神经元功能下降、高位中枢的敏感化等。药物治疗仍然是目前主要的治疗方法。虽然各种治疗已经在动物试验中取得了许多进展,但是距离临床应用还是有很大的距离。本文就神经病理性疼痛的机制和治疗的进展进行综述,旨在为神经病理性疼痛临床治疗提供参考。     

神经病理性疼痛治疗药物的研究进展

神经病理性疼痛治疗药物的研究是目前药物设计及研究领域的热点和难点之一。本文对目前临床应用及正在研究中的、作用机制不同的及疗效较好的治疗神经病理性疼痛的药物类型及其适应证等作了综述，并对当前的研究现状及趋势作一展望。     

神经病理痛动物模型及其在P2X受体介导痛觉研究中的应用

神经病理痛是临床上常见病症,对人身心健康危害较大,其发病机制尚不清楚,目前无有效的治疗手段,加之慢性神经病理痛持续时间长,其研究成为疼痛领域的热点和重点。该文综述的多种神经病理痛的动物模型,复制了人类神经病理痛的各种症状,是研究神经病理痛的有效手段。三磷酸腺苷(ATP)是一种重要的疼痛信号物质,ATP可作用于P2X受体产生效应。应用神经病理痛动物模型,观察到P2X受体在神经病理痛的痛觉形成、传导和调节中有着重要作用,有望成为神经病理痛治疗的新作用位点。     

Periodate oxidized ATP (oATP) reduces hyperalgesia in mice: involvement of P2X7 receptors and implications for therapy

Some inflammatory mediators play an important role not only in the pathogenesis of the inflammatory pain, but also in that of neuropathic and visceral pain. We previously showed the antihyperalgesic effect of oATP, the inhibitor of the P2X7 receptors for the pro-nociceptive ATP, in experimental inflammation. Here we show the antihyperalgesic effect of oATP in mouse models of neuropathic and visceral pain, other than in a model of arthritic pain mimicking rheumatoid arthritis in humans. We also show that mice lacking P2X7 receptors (KO) are resistant to hyperalgesic thermal stimuli following the induction of arthritic, neuropathic and visceral pain. Local (injection into the right hind paw) pre-treatment with oATP is able to prevent the successive induction of ATP-dependent hyperalgesia in wild type mice. In addition, KO mice are not insensitive to intraplantar treatment with ATP. Our data suggest that, even if oATP is able to inhibit purinoceptors different from P2X7, the latter are the more important involved in pain transmission.     

Purinergic system, microglia and neuropathic pain

Extracellular nucleotides play pivotal roles in the regulation of neuronal and glial functions in the nervous system through P2X receptors (P2XRs) and P2Y receptors (P2YRs). A growing body of evidence shows that microglia express several subtypes of P2XRs and P2YRs, and that these receptors play a key role in pain signaling in the spinal cord under pathological conditions, such as following peripheral nerve injury (neuropathic pain). Following peripheral nerve injury, dorsal horn microglia become activated and show upregulated expression of purinergic receptors, and interference with the function or expression of these receptors strongly suppresses neuropathic pain. This article highlights recent advances that further increase our understanding of the mechanisms by which microglial purinergic receptors contribute to the pathogenesis of neuropathic pain.     

Expression of opioid receptors and c-fos in CB1 knockout mice exposed to neuropathic pain

The development of neuropathic pain is associated with multiple changes in gene expression occurring in the dorsal root ganglia (DRG) and spinal cord. The goal of this study was to evaluate whether the disruption of CB1 cannabinoid receptor gene modulates the changes induced by neuropathic pain in the expression of mu- (MOR), delta- (DOR) and kappa-opioid receptors (KOR) mRNA levels in the DRG and spinal cord. The induction of c-fos expression in the lumbar and sacral regions of the spinal cord was also evaluated in these animals. Opioid receptors mRNA levels were determined by using real-time PCR and Fos protein levels by immunohistochemistry. Nerve injury significantly reduced the expression of MOR in the DRG and the lumbar section of the spinal cord from CB1 cannabinoid knockout (KO) mice and wild-type littermates (WT). In contrast, mRNA levels of DOR and KOR were not significantly changed in any of the different sections analysed. Furthermore, sciatic nerve injury evoked a similar increase of c-fos expression in lumbar and sacral regions of the spinal cord of both KO and WT. In all instances, no significant differences were observed between WT and KO mice. These data revealed specific changes induced by neuropathic pain in MOR expression and c-fos levels in the DRG and/or spinal cord that were not modified by the genetic disruption of CB1 cannabinoid receptors.     

Sigma-1 receptors and animal studies centered on pain and analgesia

Introduction: Neuropathic pain is difficult to relieve with standard analgesics and tends to be resistant to opioid therapy. Sigma-1 receptors activated during neuropathic injury may sustain pain. Neuropathic injury activates sigma-1 receptors, which results in activation of various kinases, modulates the activity of multiple ion channels, ligand activated ion channels and voltage-gated ion channels; alters monoamine neurotransmission and dampens opioid receptors G-protein activation. Activation of sigma-1 receptors tonically inhibits opioid receptor G-protein activation and thus dampens analgesic responses. Therefore, sigma-1 receptor antagonists are potential analgesics for neuropathic and adjuvants to opioid therapy.

Areas covered: This article reviews the importance of sigma-1 receptors as pain generators in multiple animal models in order to illustrate both the importance of these unique receptors in pathologic pain and the potential benefits to sigma-1 receptor antagonists as analgesics.

Expert opinion: Sigma-1 receptor antagonists have a great potential as analgesics for acute neuropathic injury (herpes zoster, acute postoperative pain and chemotherapy induced neuropathy) and may, as an additional benefit, prevent the development of chronic neuropathic pain. Antagonists are potentially effective as adjuvants to opioid therapy when used early to prevent analgesic tolerance. Drug development is complicated by the complexity of sigma-1 receptor pharmacodynamics and its multiple targets, the lack of a specific sigma-1 receptor antagonist, and potential side effects due to on-target toxicities (cognitive impairment, depression).     

Role of molecules expressed in spiral microglia in neuropathic pain]

Physiological pain is an essential experience that alerts us to the presence of external or internal stimuli that are damaging or are potentially tissue-damaging. By contrast, pathological pain is not tied to the presence of tissue-damaging stimuli. One type of pathological pain-neuropathic pain--is often a consequence of nerve injury or of diseases such as diabetes, HIV AIDS or cancer, that damage peripheral nerves. Neuropathic pain can be agonizing, persistent over long periods, and, unfortunately, is often resistant to known pain-killers. Recent advances in our understanding of the mechanisms producing neuropathic pain have been made by defining causal roles of spinal microglia in the pathogenesis of neuropathic pain as several molecules including P2X4 receptors, which are present in activated microglia, have been found to be required molecular mediators. We expect that understanding the key roles of these molecules in spinal microglia may lead to new strategies for the management of neuropathic pain, strategies not previously anticipated by a neuron-centric view of pain plasticity in the dorsal horn.     

作用于5-羟色胺受体的抗偏头痛药物的研究进展

偏头痛是世界范围内致残的主要原因。5-羟色胺（5-HT）受体在偏头痛中发挥不可替代的作用，其中5-HT1、5-HT2、5-HT3和5-HT7受体是在偏头痛、神经性疼痛中研究最多的受体。偏头痛的早期治疗药物包括特异性药物，如曲坦类药物和麦角类生物碱。拉米地坦作为一种5-HT1F受体激动剂在不同人群中具有较好优势。总结了5-HT受体参与偏头痛的发病机制和药物作用机制，归纳了作用于5-HT受体的抗偏头痛药物曲坦类药物、麦角类生物碱和拉米地坦，以期为偏头痛治疗提供新的思路。     

神经病理性疼痛的治疗和药物发现现状

神经病理性疼痛(neuropathic pain,NP)是一直困扰人类的医学难题,严重影响人民生活质量.尽管近年来关于NP的研究取得了很大进展,但是依旧有很多患者对现有的治疗无效.目前药物治疗依旧是缓解疼痛的主要方法,然而药物不良反应阻碍了疗效的发挥,寻找新型药物靶点及减少现有药物的不良反应迫在眉睫.本综述将主要阐述神...     

Therapeutic applications of conotoxins that target the neuronal nicotinic acetylcholine receptor.

Pain therapeutics discovered by molecular mining of the expressed genome of Australian predatory cone snails are providing lead compounds for the treatment of neurological diseases such as multiple sclerosis, shingles, diabetic neuropathy and other painful neurological conditions. The high specificity exhibited by these novel compounds for neuronal receptors and ion channels in the brain and nervous system indicates the high degree of selectivity that this class of neuropeptides can be expected to show when used therapeutically in humans. A lead compound, ACV1 (conotoxin Vc1.1 from Conus victoriae), has entered Phase II clinical trials and is being developed for the treatment for neuropathic pain. ACV1 will be targeted initially for the treatment of sciatica, shingles and diabetic neuropathy. The compound is a 16 amino acid peptide [Sandall et al., 2003. A novel alpha-conotoxin identified by gene sequencing is active in suppressing the vascular response to selective stimulation of sensory nerves in vivo. Biochemistry 42, 6904-6911], an antagonist of neuronal nicotinic acetylcholine receptors. It has potent analgesic activity following subcutaneous or intramuscular administration in several preclinical animal models of human neuropathic pain [Satkunanathan et al., 2005. Alpha conotoxin Vc1.1 alleviates neuropathic pain and accelerates functional recovery of injured neurons. Brain. Res. 1059, 149-158]. ACV1 may act as an analgesic by decreasing ectopic excitation in sensory nerves. In addition ACV1 appears to accelerate the recovery of injured nerves and tissues.