神经病理性疼痛的药物治疗研究进展

神经病理性疼痛是一种神经系统损伤引起的慢性疼痛,严重影响患者的生活质量。药物治疗仍是现用治疗神经病理性疼痛的主要方法。本文综述了现用于治疗神经病理性疼痛主要药物的分子药理机制及其临床运用特点,并在总结疼痛的发生机制的基础上对靶向治疗药物的研发进行了展望。     

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。     

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。     

加巴喷丁用于神经病理性疼痛治疗的研究进展

研究表明加巴喷丁(gabapentin)可作用于脊髓背角神经原突触后钙离子通道，从而可能阻断了神经病理性疼痛产生的过程。临床证实加巴喷丁对糖尿病神经病变和带状疱疹后神经痛的治疗效果，是治疗神经病理性疼痛有效的药物。     

调控环磷腺苷信号通路治疗病理性疼痛

病理性疼痛是困扰人类健康的一种常见疾患,寻找合适的治疗靶点控制病理性疼痛是目前疼痛研究的一个重要方向。近年的研究发现,活化的炎细胞、神经胶质细胞在病理性疼痛中发挥重要作用。环磷腺苷是存在于多种细胞内的第二信使,有文献报道促进环磷腺苷通路能抑制炎细胞及胶质细胞活性,进而治疗病理性疼痛。该文对环磷腺苷通路抑制炎细胞及胶质细胞活化的机制,以及磷酸二酯酶抑制剂治疗病理性疼痛的研究现状做一综述。     

胶质细胞活化在病理性疼痛发展过程中的意义：对药物研发的启示

近年来有关胶质细胞在病理性疼痛发生和发展过程中的作用越来越受到了重视。目前认为小胶质细胞和星形胶质细胞在外周神经或组织损伤后被激活并产生各种炎性介质,成为病理性疼痛发生发展过程中重要的致痛因素,针对胶质细胞活化及其后产生的炎性介质有可能研发出新型抗病理性疼痛药物。本文就此方面的研究进展做一综述,试图为靶向胶质细胞研发新型抗病理性疼痛药物提供新的线索。     

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。     

丝裂原活化的蛋白激酶:一个治疗病理性痛潜在的药物新靶点

病理性痛(pathological pain)是临床上常见的疼痛,通常分为炎性痛(inflammatory pain)和神经病理性痛(neuro-pathic pain),具有痛觉过敏和痛觉异常等疼痛神经可塑性特点;丝裂原活化的蛋白激酶(mitogen-activated proteins kinases,MAPKs)作为一种关键细胞信号分子,包括细胞外信号调节激酶(ERK)、p38和c-Jun氨基末端激酶(JNK)3条主要激活通路,在病理性痛觉信号转导和神经可塑性调控中起重要作用。在不同动物模型中,抑制MAPKs信号通路,可明显减轻炎症痛和神经病理性痛,这为MAPKs抑制剂开发成为治疗病理性痛的药物提供了可能,MAPKs已成为治疗病理性痛药物作用的一个重要的潜在的靶点。     

慢性心力衰竭的药物治疗（一）

心力衰竭是一种复杂的临床综合征,为各种心脏病的严重阶段。心肌重构是导致心力衰竭发生、发展的基本机制。治疗心衰的关键是阻断神经内分泌的过度激活,阻断心肌重构。心衰的标准治疗药物包括利尿剂、ACEI类、β受体阻断药、地高辛及醛固酮受体拮抗剂。近年来抗心力衰竭新药包括血管扩张剂基因重组人脑利钠肽、内皮素受体阻断药、血管升压素受体拮抗剂、新的正性肌力药钙增敏剂以及肾素抑制剂等。     

A型肉毒毒素作用于神经胶质细胞缓解神经病理性疼痛机制的研究进展

神经病理性疼痛是一个重要的临床问题,常规药物治疗效果不佳。A型肉毒毒素可缓解多种疼痛,其镇痛作用被认为与神经胶质细胞相关。本文概要介绍A型肉毒毒素作用于神经胶质细胞缓解神经病理性疼痛机制的研究进展,进一步探究A型肉毒毒素在神经病理性疼痛治疗上的临床潜力。     

CNS response to a thermal stressor in human volunteers and rats may predict the clinical utility of analgesics

fMRI was used to test the hypothesis that global brain activation following a stressor (a thermal stimulus) that activates multiple brain circuits in healthy subjects can predict which drugs have higher potential for clinical utility for neuropathic pain. The rationale is that a drug will modulate multiple neural circuits that are activated by the system‐specific stressor (e.g., pain). In neuropathic pain, some brain circuits have altered function, but most brain systems are “normal.” Thus, the manner in which a drug effect on neural circuits is modulated by the stressor may provide insight into the clinical utility based on the readout of brain activation in response to the stimulus. Six drugs with known clinical efficacy (or lack thereof) in treating neuropathic pain were selected and the CNS response to each drug in the presence or absence of a pain stimulus was examined. The present results suggest that it is possible to identify potentially effective drugs based on patterns of brain activation in healthy human subjects and indicate that CNS activity is a more sensitive measure of drug action than standard psychophysical measures of pain intensity. This approach was repeated in rats and showed that a similar fMRI paradigm segregates these drugs in a similar manner suggesting a potential “translational tool” in evaluating drug efficacy for neuropathic pain. The sensitivity of this paradigm using fMRI allows clinical screening in small groups of healthy subjects, suggesting it could become a useful tool for drug development as well as for elucidating the mechanisms of neuropathic disease and therapy. Drug Dev. Res. 68:23–41, 2007. © 2007 Wiley‐Liss, Inc.     

Pregabalin in Neuropathic Pain: Evidences and Possible Mechanisms

Pregabalin is an antagonist of voltage gated Ca2+ channels and specifically binds to alpha-2-delta subunit to produce antiepileptic and analgesic actions. It successfully alleviates the symptoms of various types of neuropathic pain and presents itself as a first line therapeutic agent with remarkable safety and efficacy. Preclinical studies in various animal models of neuropathic pain have shown its effectiveness in treating the symptoms like allodynia and hyperalgesia. Clinical studies in different age groups and in different types of neuropathic pain (peripheral diabetic neuropathy, fibromyalgia, post-herpetic neuralgia, cancer chemotherapy-induced neuropathic pain) have projected it as the most effective agent either as monotherapy or in combined regimens in terms of cost effectiveness, tolerability and overall improvement in neuropathic pain states. Preclinical studies employing pregabalin in different neuropathic pain models have explored various molecular targets and the signaling systems including Ca2+ channel-mediated neurotransmitter release, activation of excitatory amino acid transporters (EAATs), potassium channels and inhibition of pathways involving inflammatory mediators. The present review summarizes the important aspects of pregabalin as analgesic in preclinical and clinical studies as well as focuses on the possible mechanisms.     

神经痛的药物作用靶点及其机制

目的对近年来出现的治疗神经痛的药物作用靶点及其机制作以综述。方法在查阅30篇文献的基础上,对神经痛的治疗靶点进行整理和归纳。结果目前治疗神经痛的药物作用靶点主要有5-羟色胺受体、去甲肾上腺素受体、阿片受体、大麻素受体、离子通道、免疫相关物质等等。以这些靶点设计的药物均已证明可在一定程度上缓解神经痛。结论为进一步开发治疗神经痛的靶向药物提供参考。     

Ibudilast (AV-411). A new class therapeutic candidate for neuropathic pain and opioid withdrawal syndromes

The treatment of neuropathic pain is a major unresolved medical challenge. Present pharmacotherapies only have modest efficacy and numerous side effects. The use of opioid analgesics is additionally coupled with dependence and withdrawal syndromes. Ibudilast (AV-411) is a non-selective phosphodiesterase inhibitor that is also known to suppress glial cell activation. It has been used clinically for other indications with a good safety profile. As glial cell activation is considered to crucially contribute to neuropathic pain as well as opioid dependence and withdrawal, the authors conceived that ibudilast may be useful for treating these conditions. Preclinical data indicate that ibudilast crosses the blood-brain barrier, is well tolerated, is active on oral administration, reduces glial activation and attenuates pain symptoms in diverse rat models of neuropathic pain. In addition, it enhances acute morphine analgesia and attenuates morphine tolerance and withdrawal. Thus ibudilast may improve opioid efficacy and is a promising therapeutic candidate for neuropathic pain, with a novel mechanism of action.     

Ibudilast (AV-411)

The treatment of neuropathic pain is a major unresolved medical challenge. Present pharmacotherapies only have modest efficacy and numerous side effects. The use of opioid analgesics is additionally coupled with dependence and withdrawal syndromes. Ibudilast (AV-411) is a non-selective phosphodiesterase inhibitor that is also known to suppress glial cell activation. It has been used clinically for other indications with a good safety profile. As glial cell activation is considered to crucially contribute to neuropathic pain as well as opioid dependence and withdrawal, the authors conceived that ibudilast may be useful for treating these conditions. Preclinical data indicate that ibudilast crosses the blood–brain barrier, is well tolerated, is active on oral administration, reduces glial activation and attenuates pain symptoms in diverse rat models of neuropathic pain. In addition, it enhances acute morphine analgesia and attenuates morphine tolerance and withdrawal. Thus ibudilast may improve opioid efficacy and is a promising therapeutic candidate for neuropathic pain, with a novel mechanism of action.     

Cytokine Modulation is Necessary for Efficacious Treatment of Experimental Neuropathic Pain

Neuropathic pain originates from a damage or disease affecting the somatosensory system. Its treatment is unsatisfactory as it appears refractory to most analgesics. Animal models of neuropathic pain are now available that help to clarify the underlying mechanisms. Recently it has been recognized that inflammatory and immune mechanisms in the peripheral and in the central nervous system play a role in the onset and the maintenance of pain. In response to nervous tissue damage, activation of resident or recruited immune cells leads to the production of inflammatory mediators, as cytokines. In models of neuropathic pain, such as nerve injury and diabetes induced neuropathy, the time course of the expression of the proinflammatory cytokines TNF-α,IL-1β and IL-6 and of the antiinflammatory cytokine IL-10 has been well characterized both in the peripheral (sciatic nerve, dorsal root ganglia) and the central (spinal cord) nervous system. These cytokines appear activated/modulated in the nervous tissue in parallel with the occurrence of painful behaviour, i.e. allodynia and hyperalgesia. Novel therapeutic approaches efficacious to reduce painful symptoms, for example treatments with the non specific purinergic antagonist PPADS, the phytoestrogen genistein and a cell stem therapy with murine adult neural stem cells also re-established a balance between pro and antinflammatory mediators in the peripheral and central nervous system. These data suggest a pivotal role of immune system and inflammation in neuropathic pain. The modulation of inflammatory molecules appears to be a common trait accomplished throughout different mechanisms by different drugs that might converge in neuropathic pain modulation.     

Choice of intrathecal drug in the treatment of neuropathic pain – new research and opinion

ABSTRACT

Introduction: The choice of the proper intrathecal drug to treat neuropathic pain has been subject to much debate in recent years.

Areas Covered: Currently, the United States Food and Drug Administration (USFDA) has approved two drugs for chronic intrathecal use for the treatment of pain; however, there has been substantial growth in the development of other intrathecal drugs that can be used for neuropathic pain. We performed a PubMed literature search looking at intrathecal drug research for neuropathic pain between January 2005 to May 2019 and discuss current practices and mechanisms in treating these complex patients.

Expert Opinion: On-label intrathecal drugs are recommended if efficacious with acceptable side effects. In those suffering from neuropathic pain, clinical evidence suggests additional drug algorithms for treating these patients are necessary. There is ample room for growth in the development and approval of novel drugs for intrathecal delivery to manage neuropathic pain.     

Cellular and molecular mechanisms driving neuropathic pain: recent advancements and challenges

Introduction: Current pharmacotherapeutics for neuropathic pain offer only symptomatic relief without treating the underlying pathophysiology. Additionally, they are associated with various dose-limiting side effects. Pain research in the past few decades has revolved around the role of oxidative-nitrosative stress, protein kinases, glial cell activation, and inflammatory signaling cascades but has failed to produce specific and effective therapies.

Areas covered: This review focuses on recent advances in cellular and molecular mechanisms of neuropathic pain that may be translated into future therapies. We discuss emerging targets such as WNT signaling mechanisms, the tetrahydrobiopterin pathway, Mrg receptors, endogenous lipid mediators, micro-RNAs and their roles in pain regulation. Recent evidence is also presented regarding genetic and epigenetic mechanisms of pain modulation.

Expert opinion: During chronic neuropathic pain, maladaptation occurs in the peripheral and central nervous systems, including a shift in microglial phenotype from a surveillance state to an activated state. Microglial activation leads to an altered expression of cell surface proteins, growth factors, and intracellular signaling molecules that contribute to development of a neuroinflammatory cascade and chronic pain sensitization. Specific targeting of these cellular and molecular mechanisms may provide the key to development of effective neuropathic pain therapies that have minimal side effects.     

Chemokine mediated neuron-glia communication and aberrant signalling in neuropathic pain states

Treatment of neuropathic pain is problematic; response to current pharmacological interventions is often poor and associated with undesirable side-effects, thus the identification of new targets for treating this condition is needed. Here we collect evidence demonstrating the potential of chemokines as mediators of neuron-glia communication and contributors to pain signalling. The expression of chemokines such as CX3CL1, CCL2 and CCL21 and their receptors CX3CR1, CCR2 and CXCR3 is altered in the spinal cord under neuropathic pain conditions and chemokine receptor antagonists attenuate neuropathic pain behaviour. By understanding the mechanisms of chemokine-mediated communication we may expose glial targets as a novel approach for the treatment of neuropathic pain.