非药物疗法在慢性疼痛干预中的应用和治疗机制

疼痛是一种由身体组织的真实或潜在损伤引起的不舒服感觉，慢性疼痛为持续时间超过3个月以上的疼痛。慢性疼痛可以由多种疾病引起，发病率高。然而应用药物治疗慢性疼痛存在一定的局限性。非阿片类药物对部分类型的慢性痛，如神经病理性疼痛，疗效不佳。而阿片类镇痛药物则因成瘾和易诱发胃肠道副作用而受限，因此非药物干预治疗逐渐受到关注。目前临床上对于治疗慢性疼痛常用的非药物疗法包括脉冲射频（pulsed radiofrequency,PRF）、脊髓电刺激（spinal cordstimulation, SCS）、光生物调节（photobiomodulation, PBM）和重复经颅磁刺激（repetitive transcranial magnetic stimulation,rTMS）。最新研究揭示了光照和声音的中枢镇痛机制，提示光疗和声疗在临床转化上的潜力。鉴于光照和声音都属于非侵入性治疗，因此这两者在临床应用上具有广阔的前景。本文通过梳理以上非药物镇痛手段的干预方法、优缺点以及镇痛机制，希望为深入理解慢性痛的发病机制提供依据，为优化疼痛的非药物干预手段提供新的思路。     

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。     

基于神经影像技术认识膝骨关节炎慢性疼痛的复杂性

膝骨关节炎(knee osteoarthritis, KOA)慢性疼痛极大影响患者的生活质量及功能活动,明确KOA疼痛的机制及不同疗法的镇痛效应是目前研究的重要任务。近年来,神经影像技术在疼痛的基础和临床研究中发挥了重要作用。随着神经影像技术在KOA慢性疼痛研究中的应用和发展,学者们发现KOA的慢性疼痛不仅包含伤害感受性疼痛,也含有神经病理性疼痛成分。参与KOA疼痛的神经病理性疼痛机制复杂,可能是外周或中枢敏化引起的,但在临床诊疗中未引起足够的重视,针对合并神经病理性疼痛KOA的治疗方法也尚未形成共识。因此,本综述基于磁共振成像(magnetic resonance imaging, MRI)、脑电图(electroencephalogram, EEG)、脑磁图(magnetoencephalogram, MEG)、近红外光谱(near-infrared spectroscopy, NIRS)等神经影像技术研究成果,回顾KOA疼痛引起的大脑病理生理学相关区域变化,梳理疼痛评估和预测方面的最新成果,明确KOA不同疗法的脑中枢镇痛机制,希望为KOA疼痛的治疗提供新思路,以利于制定KOA的早、中期合理治疗方案,促进临床镇痛疗效的提高。     

非药物干预治疗神经精神疾病作用及机制研究

<正>近年来，随着非药物干预技术和方法的更新，其在治疗神经精神疾病中的作用及相关的机制也引起了广泛的关注。非药物干预包括运动、认知、经颅磁刺激、经颅电刺激，声光感觉刺激等^[1-4]。非药物干预在早期预防、减少药物副作用等方面存在优势。多项研究表明，非药物干预在预防和治疗脑缺血、阿尔茨海默病(Alzheimer’s disease,AD)、帕金森病、神经性疼痛、共情缺陷、意识障碍、物质使用障碍等神经精神疾病都有较好效果^[5-24]。     

综述与专论：运动诱发的镇痛效应：脊髓、皮层下和皮层机制

在健康受试者或部分慢性疼痛人群中，一定强度和时长的运动锻炼或针对性的运动疗法，已被广泛验证可以有效提高疼痛阈值并改善疼痛症状。上述运动诱发的镇痛效应（exercise induced hypoalgesia,EIH）被认为与痛觉内源性调控系统在神经系统不同水平上的调控作用紧密联系；合适类型的运动刺激可以在脊髓水平诱发镇痛效应，亦可激活脊髓以上高位中枢神经系统的痛觉内源性调控系统，进而对脊髓水平的伤害性反应进行调控。病理性痛状态下，EIH的产生与运动皮层的激活水平以及痛觉下行抑制作用均有关。研究脊髓、皮层下和皮层水平EIH效应的确切机制，将为非药物运动手段预防疼痛慢性化提供帮助。     

非侵入性电刺激神经调控技术：镇痛效果与镇痛机制

非侵入性电刺激神经调控技术是一种潜力巨大的非药物镇痛手段,具有经济、易操作、安全性高等优点,已被应用于各类临床疼痛的治疗。然而,目前仍缺乏对不同电刺激神经调控技术镇痛特性的深入理解。本文从镇痛效果和镇痛机制两个方面入手,评述非侵入性外周神经电刺激(经皮神经电刺激、经皮迷走神经电刺激)和中枢神经电刺激(经颅直流电刺激、经颅交流电刺激)在镇痛方面的研究结果,总结各技术在缓解急性疼痛和慢性疼痛中常用的刺激参数和其镇痛效果,探讨可能的镇痛机制。最后,本文对比和总结各技术的镇痛特点,讨论了现有研究的若干局限和未来的研究方向。克服这些局限将促进相关技术的临床应用,最终达到帮助患者缓解疼痛的目的,减轻疼痛对患者、其家庭和整个社会带来的健康和经济负担。     

新生儿疼痛的临床研究-254例病例分析

目的：探索新生儿疼痛临床观察,诊断方法及降低疼痛应激的临床对策。方法：对254例新生儿NICU的医疗过程中操作性疼痛进行临床观察,观察其生理表现：迷走神经张力减低,植物神经系统改变;行为表现：包括面部表情（蹙眉、挤眼、鼻唇沟起皱、张口）、哭声、粗大运动及行为状态（睡眠和食欲）的改变等。对新生儿急性疼痛做出评分,得出正确的诊断,并采用综合干预的策略：非药物性干预方法或与局部的药物镇痛法联合使用,或药物镇痛。结果：254例新生儿在NICU的医疗过程中操作性疼痛得到正确的预防,诊断和治疗,对新生儿急性疼痛的再评分显示新生儿生理和行为表现明显改善。结论：NICU内的各种侵袭性操作所致新生儿疼痛,不仅造成婴儿近期的生理、行为紊乱,还将导致严重的远期后果,造成感知行为和神经功能上的损害;预防,诊断和综合干预可降低疼痛应激,有效阻断疼痛危害。     

低剂量氯胺酮对工作记忆的影响

氯胺酮是一种N-甲基-D-天冬氨酸受体（NMDAR）阻滞剂，低剂量氯胺酮具有良好的镇痛、抗炎和抗抑郁作用，近年来受到了广泛的关注。但是低剂量氯胺酮对于高级认知功能的影响尚未全面阐明。工作记忆是涉及众多复杂认知活动的关键功能，有研究显示低剂量氯胺酮急性或慢性使用均会损伤工作记忆，其神经机制也开始受到关注。深入分析低剂量氯胺酮对于工作记忆的影响及其机制对于指导氯胺酮的临床使用具有重要意义。本文首先介绍了低剂量氯胺酮作用于神经系统的药理作用途径，以及工作记忆本身的神经环路机制，进而回顾了近年来关于低剂量氯胺酮对工作记忆的急性和慢性作用的相关研究，并重点分析了低剂量氯胺酮损伤工作记忆的可能的神经机制，希望对低剂量氯胺酮在临床中的合理使用提供科学依据。     

感觉刺激在阿尔茨海默病干预中的应用

阿尔茨海默病（Alzheimer’s disease, AD）是一种神经退行性疾病。药物治疗是目前AD治疗的主要策略，但仅起到延缓或减轻作用。本文旨在综述各种感觉刺激和多感官刺激对AD的影响，并解释可能的机制，为进一步研究提供新思路。对光刺激疗法、气味刺激疗法、声音刺激疗法、节律性刺激、多感官刺激进行了系统分析，结果显示，这些感觉和多感官刺激可以有效改善AD的病理状态，唤起记忆，改善认知和行为。     

秀丽隐杆线虫模型在阿尔茨海默病研究中的应用

阿尔茨海默病（Alzheimer’s disease,AD）是一种与年龄相关的神经退行性疾病,该疾病的病理特征为老年斑（SPs）和神经原纤维缠结（NFTs）的存在。目前,阿尔茨海默病患病率呈现逐年上升的趋势,寻找完全治愈或延缓阿尔茨海默症发展的有效疗法和药物迫在眉睫。秀丽隐杆线虫（Caenorhabditis elegans）的基因和神经元功能与人类具有高度同源性,可作为研究阿尔茨海默病发病机制研究的较好模型。本文综述AD的发病机制假说、秀丽隐杆线虫AD模型以及线虫模型在AD治疗中的应用进展,旨在为后续研究AD提供理论参考。     

Upregulation of miR-183 represses neuropathic pain through inhibiton of MAP3K4 in CCI rat models

Many studies have verified that microRNAs contribute a lot to neuropathic pain progression. Furthermore, nerve-related inflammatory cytokines play vital roles in neuropathic pain progression. miR-183 has been identified to have a common relationship with multiple pathological diseases. However, the potential effects of miR-183 in the process of neuropathic pain remain undetermined. Therefore, we performed the current study with the purpose of finding the functions of miR-183 in neuropathic pain progression using a chronic sciatic nerve injury (CCI) rat model. We demonstrated that miR-183 expression levels were evidently reduced in CCI rats in contrast with the control group. Overexpression of miR-183 produced significant relief of mechanical hyperalgesia, as well as thermal hyperalgesia in CCI rats. Furthermore, neuropathic pain-correlated inflammatory cytokine expression levels containing interleukin-6 (IL-6) and interleukin-1β (IL-1β), cyclooxygenase-2 (COX-2) were obviously inhibited by upregulation of miR-183. Meanwhile, dual-luciferase reporter assays showed MAP3K4 was a direct downstream gene of miR-183. The expression levels of MAP3K4 were modulated by the increased miR-183 negatively, which lead to the downregulation of IL-6, IL-1β, and COX-2, and then reduced neuropathic pain progression, respectively. Overall, our study pointed out that miR-183 was a part of the negative regulator which could relieve neuropathic pain by targeting MAP3K4. Thus it may provide a new clinical treatment for neuropathic pain patients clinical therapy.     

Dissecting out mechanisms responsible for peripheral neuropathic pain: implications for diagnosis and therapy

Peripheral neuropathic pain, that clinical pain syndrome associated with lesions to the peripheral nervous system, is characterized by positive and negative symptoms. Positive symptoms include spontaneous pain, paresthesia and dysthesia, as well as a pain evoked by normally innocuous stimuli (allodynia) and an exaggerated or prolonged pain to noxious stimuli (hyperalgesia/hyperpathia). The negative symptoms essentially reflect loss of sensation due to axon/neuron loss, the positive symptoms reflect abnormal excitability of the nervous system. Diverse disease conditions can result in neuropathic pain but the disease diagnosis by itself is not helpful in selecting the optimal pain therapy. Identification of the neurobiological mechanisms responsible for neuropathic pain is leading to a mechanism-based approach to this condition, which offers the possibility of greater diagnostic sensitivity and a more rational basis for therapy. We are beginning to move from an empirical symptom control approach to the treatment of pain to one targeting the specific mechanisms responsible. This review highlights some of the mechanisms underlying neuropathic pain and the novel targets they reveal for future putative analgesics.     

cDNA microarray analysis of the differential gene expression in the neuropathic pain and electroacupuncture treatment models

Partial nerve injury is the main cause of neuropathic pain disorders in humans. Acupuncture has long been used to relieve pain. It is known to relieve pain by controlling the activities of the autonomic nervous system. Although the mechanism of neuropathic pain and analgesic effects of electroacupuncture (EA) have been studied in a rat model system, its detailed mechanism at the molecular level remains unclear. To identify genes that might serve as either markers or explain these distinct biological functions, a cDNA microarray analysis was used to compare the expression of 8,400 genes among three sample groups. Messenger RNAs that were pooled from the spinal nerves of 7 normal, 7 neuropathic pain, and 7 EA treatment rat models were compared. Sixty-eight genes were differentially expressed more than 2-fold in the neuropathic rat model when compared to the normal, and restored to the normal expression level after the EA treatment. These genes are involved in a number of biological processes, including the signal transduction, gene expression, and nociceptive pathways. Confirmation of the differential gene expression was performed by a dotblot analysis. Dot-blotting results showed that the opioid receptor sigma was among those genes. This indicates that opioid-signaling events are involved in neuropathic pain and the analgesic effects of EA. The potential application of these data include the identification and characterization of signaling pathways that are involved in the EA treatment, studies on the role of the opioid receptor in neuropathic pain, and further exploration on the role of selected identified genes in animal models.     

The beneficial use of ultramicronized palmitoylethanolamide as add-on therapy to Tapentadol in the treatment of low back pain: a pilot study comparing prospective and retrospective observational arms

Background

This pilot study was designed to compare the efficacy of ultramicronized palmitoylethanolamide (um-PEA) as add-on therapy to tapentadol (TP) with TP therapy only in patients suffering from chronic low back pain (LBP).

Methods

This pilot observational study consists in two arms: the prospective arm and the retrospective one. In the prospective arm patients consecutively selected received um-PEA as add-on therapy to TP for 6 months; in the retrospective arm patients were treated with TP only for 6 months. Pain intensity and neuropathic component were evaluated at baseline, during and after 6 months. The degree of disability and TP dosage assumption were evaluated at baseline and after 6 months.

Results

Statistical analysis performed with generalized linear mixed model on 55 patients (30 in the prospective group and 25 in the retrospective group) demonstrated that um-PEA as add-on treatment to TP in patients with chronic LBP, in comparison to TP alone, led to a significantly higher reduction in pain intensity, in the neuropathic component, the degree of disability and TP dosage assumption. No serious side effects were observed.

Conclusion

Overall, the present findings suggest that um-PEA may be an innovative therapeutic intervention as add-on therapy to TP for the management of chronic LBP with a neuropathic component, as well as to improve patient quality of life. Additionally, this combination treatment allowed a reduction in TP dose over time and did not show any serious side effects.

     

Proteomic analysis of differential protein expression in neuropathic pain and electroacupuncture treatment models

Acupuncture has long been used for pain relief. Although recent studies have shown that acupuncture can reduce neuropathic pain, the mechanism of this effect is not clear and little information is available regarding proteins that are involved in the development of neuropathic pain and the effects of acupuncture. We have developed an animal model for neuropathic pain using young adult male Sprague-Dawley rats. The model was confirmed by behavioral tests. Electroacupuncture (EA) treatment was applied to Zusanli (ST36) of neuropathic pain model to examine the analgesic effect of EA. The protein expression profile of the hypothalamus in both neuropathic pain and EA treatment models was analyzed using two-dimensional electrophoresis-based proteomics. We detected thirty-six proteins that were differentially expressed in the neuropathic pain model compared with normal rats and that restored to normal expression levels after EA treatment. Twenty-one of these proteins were identified in the MS-FiT database and are involved in a number of biological processes, including inflammation, enzyme metabolism and signal transduction. Potential applications of our results include the identification and characterization of signaling pathways involved in EA treatment and further exploration of the role of selected identified proteins in the animal model.     

Influence of postoperative analgesics on the development of neuropathic pain in rats

Rodent models of neuropathic pain require extensive tissue manipulation to induce the lesion of interest which results in inflammation and postoperative pain that is unrelated to nerve injury per se. We sought to determine whether acute postoperative pain management affects the development of hallmark signs of neuropathic pain. Analgesic regimens (q 24 h x 3 days) were buprenorphine (0.05 and 0.1 mg/kg of body weight, s.c.), flunixin meglumine (1.1 and 2.5 mg/kg, s.c.), and fentanyl citrate (0.01 and 0.1 mg/kg, i.p.). The spared nerve injury model of neuropathic pain was used, and mechanical and cold allodynia as well as body weight gain were measured for 28 days. Buprenorphine and fentanyl alleviated mechanical sensitivity and prevented weight loss associated with the surgery (0 to 3 days), but opioid-related adverse effects were observed. Flunixin reduced wound inflammation and improved weight gain, but had no effect on nociceptive thresholds. Cold allodynia was unaltered by any treatment. By postoperative day 7, control and treatment groups did not differ with respect to weight gain or nociceptive thresholds. Our findings suggest that postsurgical inflammation and pain behavior can be ameliorated without substantially altering the long-term development of neuropathic pain, provided that the selection of agent(s) and treatment regimen(s) is appropriate and the neuropathic pain of interest is evaluated seven days after surgery.     

Parecoxib and its metabolite valdecoxib directly interact with cannabinoid binding sites in CB1-expressing HEK 293 cells and rat brain tissue

Cyclooxygenase 2 inhibitors (COX 2) such as parecoxib (par) and valdecoxib (val) are used in the treatment of neuropathic pain. Using the radioligand binding assay it was demonstrated that both the prodrug par as well as its active metabolite val have a specific affinity to the cannabinoid (CB) receptor measured in CB1-expressing HEK 293 cells and rat brain tissue. Agonist activity was detected by GTPγS assays, cAMP formation experiments and ex vivo modulation of glutamate and GABA release of the rat brain tissue. In comparison to the specific cannabinoid agonist, WIN 55,212-2, the two COX 2 inhibitors are about 2 orders of magnitude less potent. The data suggest that the analgesic effects of par and its metabolite val in Wistar rats may be at least partially mediated by a direct interaction with the CB1 receptors. The COX 2 inhibitors appear to be a hypothetically useful tool for add-on therapy of neuropathic pain.     

Differential involvement of trigeminal transition zone and laminated subnucleus caudalis in orofacial deep and cutaneous hyperalgesia: the effects of interleukin-10 and glial inhibitors

Background

Understanding the underlying mechanisms of neuropathic pain caused by damage to the peripheral nervous system remains challenging and could lead to significantly improved therapies. Disturbance of homeostasis not only occurs at the site of injury but also extends to the spinal cord and brain involving various types of cells. Emerging data implicate neuroimmune interaction in the initiation and maintenance of chronic pain hypersensitivity.

Results

In this study, we sought to investigate the effects of TGF-β1, a potent anti-inflammatory cytokine, in alleviating nerve injury-induced neuropathic pain in rats. By using a well established neuropathic pain animal model (partial ligation of the sciatic nerve), we demonstrated that intrathecal infusion of recombinant TGF-β1 significantly attenuated nerve injury-induced neuropathic pain. TGF-β1 treatment not only prevents development of neuropathic pain following nerve injury, but also reverses previously established neuropathic pain conditions. The biological outcomes of TGF-β1 in this context are attributed to its pleiotropic effects. It inhibits peripheral nerve injury-induced spinal microgliosis, spinal microglial and astrocytic activation, and exhibits a powerful neuroprotective effect by preventing the induction of ATF3⁺ neurons following nerve ligation, consequently reducing the expression of chemokine MCP-1 in damaged neurons. TGF-β1 treatment also suppresses nerve injury-induced inflammatory response in the spinal cord, as revealed by a reduction in cytokine expression.

Conclusion

Our findings revealed that TGF-β1 is effective in the treatment of neuropathic by targeting both neurons and glial cells. We suggest that therapeutic agents such as TGF-β1 having multipotent effects on different types of cells could work in synergy to regain homeostasis in local spinal cord microenvironments, therefore contributing to attenuate neuropathic pain.     

Modulation of neuropathic-pain-related behaviour by the spinal endocannabinoid/endovanilloid system

Neuropathic pain refers to chronic pain that results from injury to the nervous system. The mechanisms involved in neuropathic pain are complex and involve both peripheral and central phenomena. Although numerous pharmacological agents are available for the treatment of neuropathic pain, definitive drug therapy has remained elusive. Recent drug discovery efforts have identified an original neurobiological approach to the pathophysiology of neuropathic pain. The development of innovative pharmacological strategies has led to the identification of new promising pharmacological targets, including glutamate antagonists, microglia inhibitors and, interestingly, endogenous ligands of cannabinoids and the transient receptor potential vanilloid type 1 (TRPV1). Endocannabinoids (ECs), endovanilloids and the enzymes that regulate their metabolism represent promising pharmacological targets for the development of a successful pain treatment. This review is an update of the relationship between cannabinoid receptors (CB1) and TRPV1 channels and their possible implications for neuropathic pain. The data are focused on endogenous spinal mechanisms of pain control by anandamide, and the current and emerging pharmacotherapeutic approaches that benefit from the pharmacological modulation of spinal EC and/or endovanilloid systems under chronic pain conditions will be discussed.