• 【带疱疹或带痛后的小鼠静态和动态异常性疼痛之间的药理差异。】 复制标题 收藏 收藏
    DOI:10.1254/jphs.08154fp 复制DOI
    作者列表:Sasaki A,Serizawa K,Andoh T,Shiraki K,Takahata H,Kuraishi Y
    BACKGROUND & AIMS: :In the present study, we investigated whether dynamic and static allodynia would be developed in the affected dermatome in murine models of herpetic pain and postherpetic neuralgia and pharmacologically characterized the allodynia. Inoculation with herpes simplex virus type-1 on the femur induced skin lesions in the dermatome including the plantar region of the hind paw from day 5 to day 21 after inoculation. Dynamic allodynia became apparent in the hind paw from day 3 to at least day 42. Static allodynia was not obvious during the stage of herpetic pain and gradually increased after the lesion healing. Mexiletine hydrochloride (30 mg/kg, p.o.) and ketamine hydrochloride (50 mg/kg, i.p.) produced a moderate attenuation of static but not dynamic allodynia. Diclofenac sodium (50 mg/kg, i.p.) did not affect both static and dynamic allodynia. Gabapentin (30 mg/kg, p.o.) markedly inhibited both static and dynamic allodynia. Developmental and pharmacological differences between static and dynamic allodynia suggest that independent mechanisms are responsible for dynamic and static allodynia. This murine model may be useful for the study of the mechanisms of dynamic allodynia of herpetic pain or postherpetic neuralgia and the development of new analgesics effective against the dynamic allodynia.
    背景与目标: : 在本研究中,我们调查了在疱疹性疼痛和带状疱疹后神经痛的鼠模型中受影响的皮刀中是否会出现动态和静态异常性疼痛,并在药理学上对异常性疼痛进行了表征。从接种后的第5天到第21天,在股骨上接种1型单纯疱疹病毒会在包括后爪足底区域在内的皮刀中引起皮肤病变。从第3天到至少第42天,后爪的动态异常性疼痛变得明显。在疱疹性疼痛阶段,静态异常性疼痛不明显,病变愈合后逐渐增加。盐酸美西律 (30 mg/kg,p.o.) 和盐酸氯胺酮 (50 mg/kg,i.p.) 产生静态但动态异常性疼痛的中度衰减。双氯芬酸钠 (50 mg/kg,ip) 不影响静态和动态异常性疼痛。加巴喷丁 (30 mg/kg,p.o.) 显着抑制静态和动态异常性疼痛。静态和动态异常性疼痛之间的发育和药理差异表明,独立机制是导致动态和静态异常性疼痛的原因。该鼠模型可用于研究疱疹性疼痛或带状疱疹后神经痛的动态异常性疼痛的机制,以及开发有效对抗动态异常性疼痛的新型镇痛药。
  • 【与临床关节炎症状解离的持续性异常性疼痛中,可分解的脂质介质失衡。】 复制标题 收藏 收藏
    影响因子 :
    发表时间:2020-09-01
    来源期刊:Pain
    DOI:10.1097/j.pain.0000000000001908 复制DOI
    作者列表:Allen BL,Montague-Cardoso K,Simeoli R,Colas RA,Oggero S,Vilar B,McNaughton PA,Dalli J,Perretti M,Sher E,Malcangio M
    BACKGROUND & AIMS: ABSTRACT:Rheumatoid arthritis-associated pain is poorly managed, often persisting when joint inflammation is pharmacologically controlled. Comparably, in the mouse K/BxN serum-transfer model of inflammatory arthritis, hind paw nociceptive hypersensitivity occurs with ankle joint swelling (5 days after immunisation) persisting after swelling has resolved (25 days after immunisation). In this study, lipid mediator (LM) profiling of lumbar dorsal root ganglia (DRG), the site of sensory neuron cell bodies innervating the ankle joints, 5 days and 25 days after serum transfer demonstrated a shift in specialised proresolving LM profiles. Persistent nociception without joint swelling was associated with low concentrations of the specialised proresolving LM Maresin 1 (MaR1) and high macrophage numbers in DRG. MaR1 application to cultured DRG neurons inhibited both capsaicin-induced increase of intracellular calcium ions and release of calcitonin gene-related peptide in a dose-dependent manner. Furthermore, in peritoneal macrophages challenged with lipopolysaccharide, MaR1 reduced proinflammatory cytokine expression. Systemic MaR1 administration caused sustained reversal of nociceptive hypersensitivity and reduced inflammatory macrophage numbers in DRG. Unlike gabapentin, which was used as positive control, systemic MaR1 did not display acute antihyperalgesic action. Therefore, these data suggest that MaR1 effects observed after K/BxN serum transfer relate to modulation of macrophage recruitment, more likely than to direct actions on sensory neurons. Our study highlights that, in DRG, aberrant proresolution mechanisms play a key role in arthritis joint pain dissociated from joint swelling, opening novel approaches for rheumatoid arthritis pain treatment.
    背景与目标: 摘要: 类风湿性关节炎相关疼痛管理不善,当关节炎症得到药理学控制时,通常会持续。相比之下,在炎症性关节炎的小鼠K/BxN血清转移模型中,后爪伤害性超敏反应发生,踝关节肿胀 (免疫后5天) 在肿胀消退后 (免疫后25天) 持续存在。在这项研究中,血清转移后5天和25天,腰背根神经节 (DRG) 的脂质介体 (LM) 分析显示,感觉神经元细胞体支配踝关节的部位在专门的前移LM谱中发生了变化。持续的无关节肿胀的伤害感受与低浓度的特殊预溶解的LM marresin 1 (MaR1) 和DRG中的高巨噬细胞数量有关。将MaR1应用于培养的DRG神经元以剂量依赖性方式抑制辣椒素诱导的细胞内钙离子增加和降钙素基因相关肽的释放。此外,在受到脂多糖攻击的腹膜巨噬细胞中,MaR1降低了促炎细胞因子的表达。系统性MaR1给药可导致伤害性超敏反应的持续逆转,并减少DRG中的炎性巨噬细胞数量。与用作阳性对照的加巴喷丁不同,系统性MaR1不显示急性抗痛觉过敏作用。因此,这些数据表明,K/BxN血清转移后观察到的MaR1效应与巨噬细胞募集的调节有关,比直接对感觉神经元的作用更可能。我们的研究强调,在DRG中,异常的溶解机制在关节炎关节痛与关节肿胀分离中起着关键作用,为类风湿性关节炎疼痛的治疗开辟了新的途径。
  • 【小干扰RNA介导的Na(V) 选择性敲除1.8抗河豚毒素的钠通道可逆转神经性大鼠的机械性异常性疼痛。】 复制标题 收藏 收藏
    DOI:10.1016/j.neuroscience.2007.01.054 复制DOI
    作者列表:Dong XW,Goregoaker S,Engler H,Zhou X,Mark L,Crona J,Terry R,Hunter J,Priestley T
    BACKGROUND & AIMS: :The biophysical properties of a tetrodotoxin resistant (TTXr) sodium channel, Na(V)1.8, and its restricted expression to the peripheral sensory neurons suggest that blocking this channel might have therapeutic potential in various pain states and may offer improved tolerability compared with existing sodium channel blockers. However, the role of Na(V)1.8 in nociception cannot be tested using a traditional pharmacological approach with small molecules because currently available sodium channel blockers do not distinguish between sodium channel subtypes. We sought to determine whether small interfering RNAs (siRNAs) might be capable of achieving the desired selectivity. Using Northern blot analysis and membrane potential measurement, several siRNAs were identified that were capable of a highly-selective attenuation of Na(V)1.8 message as well as functional expression in clonal ND7/23 cells which were stably transfected with the rat Na(V)1.8 gene. Functional knockdown of the channel was confirmed using whole-cell voltage-clamp electrophysiology. One of the siRNA probes showing a robust knockdown of Na(V)1.8 current was evaluated for in vivo efficacy in reversing an established tactile allodynia in the rat chronic constriction nerve-injury (CCI) model. The siRNA, which was delivered to lumbar dorsal root ganglia (DRG) via an indwelling epidural cannula, caused a significant reduction of Na(V)1.8 mRNA expression in lumbar 4 and 5 (L4-L5) DRG neurons and consequently reversed mechanical allodynia in CCI rats. We conclude that silencing of Na(V)1.8 channel using a siRNA approach is capable of producing pain relief in the CCI model and further support a role for Na(V)1.8 in pathological sensory dysfunction.
    背景与目标: : 河豚毒素抗性 (TTXr) 钠通道Na(V)1.8的生物物理性质及其对周围感觉神经元的限制性表达表明,与现有的钠通道阻滞剂相比,阻断该通道可能在各种疼痛状态下具有治疗潜力,并且可能提供改善的耐受性。然而,Na(V)1.8在伤害感受中的作用不能使用传统的小分子药理学方法来测试,因为目前可用的钠通道阻滞剂不能区分钠通道亚型。我们试图确定小干扰rna (sirna) 是否能够实现所需的选择性。使用Northern印迹分析和膜电位测量,鉴定出几种sirna能够高度选择性地衰减Na(V)1.8信息以及在用大鼠Na(V)1.8基因稳定转染的克隆ND7/23细胞中的功能表达。使用全细胞电压钳电生理证实了通道的功能性敲除。在大鼠慢性收缩神经损伤 (CCI) 模型中,评估了一种显示出Na(V)1.8电流的鲁棒敲除的siRNA探针在逆转已建立的触觉异常性疼痛方面的体内功效。通过留置硬膜外套管递送到腰背根神经节 (DRG) 的siRNA导致腰4和5 (L4-L5) DRG神经元中Na(V)1.8 mRNA表达的显着降低,因此在CCI大鼠中逆转了机械性异常性疼痛。我们得出的结论是,使用siRNA方法沉默Na(V)1.8通道能够在CCI模型中产生疼痛缓解,并进一步支持Na(V)1.8在病理性感觉功能障碍中的作用。
  • 【在神经性疼痛的分级慢性收缩损伤模型中,外周免疫细胞的过继转移可增强异常性疼痛。】 复制标题 收藏 收藏
    DOI:10.1016/j.bbi.2010.11.018 复制DOI
    作者列表:Grace PM,Hutchinson MR,Bishop A,Somogyi AA,Mayrhofer G,Rolan PE
    BACKGROUND & AIMS: :Recent evidence demonstrates that peripheral immune cells contribute to the nociceptive hypersensitivity associated with neuropathic pain by infiltrating the central nervous system (CNS). We have recently developed a rat model of graded chronic constriction injury (CCI) by varying the exposure of the sciatic nerve and control non-nerve tissue to surgical placement of chromic gut. We demonstrate that splenocytes can contribute significantly to CCI-induced allodynia, as adoptive transfer of these cells from high pain donors to low pain recipients potentiates allodynia (P<0.001). The phenomenon was replicated with peripheral blood mononuclear cells (P<0.001). Adoptive transfer of allodynia was not achieved in sham recipients, indicating that peripheral immune cells are only capable of potentiating existing allodynia, rather than establishing allodynia. As adoptively transferred cells were found by flow cytometry to migrate to the spleen (P<0.05) and potentiation of allodynia was prevented in splenectomised low pain recipients, adoptive transfer of high pain splenocytes may induce the migration of host-derived immune cells from the spleen to the CNS as observed by flow cytometry (P<0.05). Importantly, intrathecal transfer of CD45(+) cells prepared from spinal cords of high pain donors into low pain recipients led to potentiated allodynia (P<0.001), confirming that infiltrating immune cells are not passive bystanders, but actively contribute to nociceptive hypersensitivity in the lumbar spinal cord.
    背景与目标: : 最近的证据表明,外周免疫细胞通过浸润中枢神经系统 (CNS) 而导致与神经性疼痛相关的伤害性超敏反应。我们最近通过改变坐骨神经的暴露并控制非神经组织对肠肠的外科手术放置,开发了分级慢性收缩损伤 (CCI) 的大鼠模型。我们证明,脾细胞可以显着促进CCI诱导的异常性疼痛,因为这些细胞从高疼痛供体到低疼痛受体的过继转移会增强异常性疼痛 (P<0.001)。用外周血单个核细胞复制该现象 (P<0.001)。假接受者未实现异常性疼痛的过继转移,这表明外周免疫细胞仅能够增强现有的异常性疼痛,而不是建立异常性疼痛。由于通过流式细胞术发现过继转移的细胞迁移到脾脏 (P<0.05),并且在脾切除的低疼痛受体中防止了异常性疼痛的增强,通过流式细胞术观察到,高疼痛脾细胞的过继转移可能诱导宿主来源的免疫细胞从脾迁移到CNS (P<0.05)。重要的是,鞘内转移从高疼痛供体的脊髓制备的CD45(+) 细胞到低疼痛受体导致增强的异常性疼痛 (P<0.001),证实浸润的免疫细胞不是被动的旁观者,而是积极地促进腰椎脊髓的伤害性超敏反应。
  • 【大麻素受体1型拮抗剂AM251可减轻烧伤后的机械性异常性疼痛和热痛觉过敏。】 复制标题 收藏 收藏
    DOI:10.1097/ALN.0000000000000422 复制DOI
    作者列表:Ueda M,Iwasaki H,Wang S,Murata E,Poon KY,Mao J,Martyn JA
    BACKGROUND & AIMS: BACKGROUND:Burn injury causes nociceptive behaviors, and inflammation-related pathologic pain can lead to glial cell activation. This study tested the hypothesis that burn injury activates glial cells, and cannabinoid receptor 1 (CB1R) antagonist, AM251, will decrease burn pain. METHODS:Anesthetized rats received 0.75-cm third-degree burn on dorsal hind paw. Vehicle or AM251 30 μg intrathecally (older rats, n=6 per group) or, either vehicle, 0.1 or 1.0 mg/kg intraperitoneally (younger rats, n=6 per group), started immediate postburn, was administered for 7 days. Mechanical allodynia and thermal hyperalgesia were tested on ventral paw for 14 days. Microglial and astroglial activity was assessed by immunocytochemistry. RESULTS:Allodynia, observed on burn side from day 1 to 14, was significantly (P<0.05) attenuated by intrathecal and intraperitoneal AM251 (1 mg/kg) starting from 3 to 14 days. Hyperalgesia, observed from day 3 to 12, was completely (P<0.05) reversed by intrathecal and intraperitoneal AM251 (1 mg/kg). AM251 0.1 mg/kg had no effect. Microglial activity (n=3 per time point) increased (P<0.05) 18.5±7.5 and 12.3±1.6 (mean±SD) fold at 7 and 14 days, respectively. Astroglial activity (n=4 per time point) increased 2.9±0.3 fold at day 7 only. Glial activities were unaltered by AM251. CONCLUSIONS:AM251 inhibited nociceptive behaviors after burn even beyond 7-day period of administration. Although many studies have documented the utility of CB1R agonists, this study indicates that endogenous cannabinoids may have an unexpected pronociceptive effect during development of burn pain, explaining why CB1R antagonist, AM251, improves nociceptive behaviors. The decreased nociception with AM251 without altering glial activity indicates that AM251 acts further downstream of activated glial cells.
    背景与目标:
  • 【脊髓中肿瘤坏死因子-α 的上调有助于长春新碱诱导的小鼠机械性异常性疼痛。】 复制标题 收藏 收藏
    DOI:10.1016/j.neulet.2008.09.009 复制DOI
    作者列表:Kiguchi N,Maeda T,Kobayashi Y,Kishioka S
    BACKGROUND & AIMS: :Chronic treatment with vincristine (VCR) causes mechanical allodynia as an adverse effect. We previously reported that peripheral macrophage-derived interleukin-6 played a critical role in VCR-induced allodynia. However, the involvement of glial cell activation and central sensitization in VCR-induced allodynia is still unclear. In this study, we focused on tumor necrosis factor-alpha (TNF-alpha) in spinal cord, and investigated the role of TNF-alpha in VCR-induced allodynia in mice. VCR (0.1mg/kg, i.p.) was administered to mice once per day for 7 days. The expression of TNF-alpha mRNA and the protein in spinal cord was evaluated by quantitative real-time PCR and immunohistochemistry, respectively. In VCR-treated mice, TNF-alpha mRNA gradually increased and was significantly up-regulated on day 7. As measured by immunohistochemistry, microglia and astrocytes were activated in the spinal dorsal horn on day 7 of VCR administration. The immunoreactivity of TNF-alpha was co-localized in some of the activated microglia and astrocytes. In behavioral analysis, a neutralizing antibody of TNF-alpha, which was injected intrathecally on days 0, 3, and 6, significantly attenuated VCR-induced mechanical allodynia on days 4 and 7. These results suggest that VCR treatments elicited the activation of glial cells in spinal cord, and up-regulated TNF-alpha in these cells may play an important role in VCR-induced mechanical allodynia.
    背景与目标: : 长春新碱 (VCR) 的慢性治疗会导致机械性异常性疼痛,这是一种不良反应。我们先前报道了外周巨噬细胞衍生的interleukin-6在VCR诱导的异常性疼痛中起关键作用。然而,神经胶质细胞活化和中枢敏化参与VCR诱导的异常性疼痛仍不清楚。在这项研究中,我们重点研究了脊髓中的肿瘤坏死因子-α (TNF-α),并研究了TNF-α 在VCR诱导的小鼠异常性疼痛中的作用。每天给小鼠一次VCR (0.1 mg/kg,i.p.),持续7天。通过实时定量PCR和免疫组织化学分别评估了TNF-α mRNA和蛋白在脊髓中的表达。在VCR处理的小鼠中,TNF-α mRNA逐渐增加,并在第7天显着上调。通过免疫组织化学测量,在VCR给药的第7天,小胶质细胞和星形胶质细胞在脊髓背角被激活。TNF-α 的免疫反应性共定位在某些活化的小胶质细胞和星形胶质细胞中。在行为分析中,在第0、3和6天鞘内注射的TNF-α 中和抗体在第4天和第7天显着减轻了VCR诱导的机械性异常性疼痛。这些结果表明,VCR治疗可引起脊髓中神经胶质细胞的激活,而这些细胞中TNF-α 的上调可能在VCR诱导的机械性异常性疼痛中起重要作用。
  • 【在逆行标记的突触后背柱神经元中没有FOS标记的情况下,存在神经损伤引起的触觉异常性疼痛。】 复制标题 收藏 收藏
    影响因子 :
    发表时间:2007-05-01
    来源期刊:Pain
    DOI:10.1016/j.pain.2006.10.009 复制DOI
    作者列表:Zhang ET,Ossipov MH,Zhang DQ,Lai J,Porreca F
    BACKGROUND & AIMS: :The dorsal column pathway consists of direct projections from primary afferents and of ascending fibers of the post-synaptic dorsal column (PSDC) cells. This pathway mediates touch but may also mediate allodynia after nerve injury. The role of PSDC neurons in nerve injury-induced mechanical allodynia is unknown. Repetitive gentle, tactile stimulus or noxious pinch was applied to the ipsilateral hindpaw of rats with spinal nerve ligation (SNL) or sham surgery that had previously received tetramethylrhodamine dextran in the ipsilateral n. gracilis. Both touch and noxious stimuli produced marked increases in FOS expression in other cells throughout all laminae of the ipsilateral dorsal horn after nerve injury. However, virtually none of the identified PSDC cells expressed FOS immunofluorescence in response to repetitive touch or pinch in either the nerve-injured or sham groups. In contrast, labeled PSDC cells expressed FOS in response to ureter ligation and labeled spinothalamic tract (STT) cells expressed FOS in response to noxious pinch. Identified PSDC neurons from either sham-operated or SNL rats did not express immunoreactivity to substance P, CGRP, NPY, PKCY, MOR, the NK1 and the NPY-Y1 receptor. Retrogradely labeled DRG cells of nerve injured rats were large diameter neurons, which expressed NPY, but no detectable CGRP or substance P. Spinal nerve injury sensitizes neurons in the spinal dorsal horn to repetitive light touch but PSDC neurons apparently do not participate in touch-evoked allodynia. Sensitization of these non-PSDC neurons may result in activation of projections integral to the spinal/supraspinal processing of enhanced pain states and of descending facilitation, thus priming the central nervous system to interpret tactile stimuli as being aversive.
    背景与目标: : 背柱途径由初级传入的直接投射和突触后背柱 (PSDC) 细胞的上升纤维组成。该途径介导触摸,但也可能介导神经损伤后的异常性疼痛。PSDC神经元在神经损伤引起的机械性异常性疼痛中的作用尚不清楚。重复的轻柔,触觉刺激或有害的捏合作用被应用于患有脊神经结扎 (SNL) 或假手术的大鼠的同侧后爪,这些大鼠先前在同侧gracilis中接受了四甲基罗丹明葡聚糖。神经损伤后,在同侧背角的所有层中,触摸和有害刺激均使其他细胞中的FOS表达显着增加。然而,在神经损伤或假手术组中,几乎没有鉴定出的PSDC细胞响应于重复触摸或捏合而表达FOS免疫荧光。相反,标记的PSDC细胞响应输尿管结扎表达FOS,而标记的脊髓丘脑束 (STT) 细胞响应有害的挤压表达FOS。鉴定出的来自假手术或SNL大鼠的PSDC神经元对p物质,CGRP,NPY,PKCY,MOR,NK1和NPY-Y1受体不表达免疫反应性。神经损伤大鼠逆行标记的DRG细胞为大直径神经元,表达NPY,但未检测到CGRP或p物质。脊神经损伤使脊髓背角的神经元对重复的轻触敏感,但PSDC神经元显然不参与触摸诱发的异常性疼痛。这些非PSDC神经元的敏化可能导致增强的疼痛状态和下降的促进作用的脊髓/脊髓上处理的投影的激活,从而引发中枢神经系统将触觉刺激解释为令人厌恶的。
  • 【带状疱疹后神经痛中疼痛,异常性疼痛和热感觉的关系。】 复制标题 收藏 收藏
    DOI:10.1093/brain/119.2.347 复制DOI
    作者列表:Rowbotham MC,Fields HL
    BACKGROUND & AIMS: In the syndrome of post-herpetic neuralgia (PHN), the nature of the sensory disturbance and its relationship both to the severity and cause of the pain is controversial. To address these issues, sensory mapping and quantitative thermal sensory testing was carried out four times in separate sessions on 35 subjects with established PHN. All subjects had pain affecting the torso or extremities and brush-evoked allodynia. Each session included rating of ongoing pain, mapping of the area of any sensory disturbance and the area of greatest pain, grading of allodynia severity within the area of greatest ongoing pain, and quantitative testing of thermal sensation in both the painful and the contralateral unaffected mirror-image skin. The severity of allodynia was positively correlated with reported ongoing pain severity. As a group, subjects had a sensory deficit to thermal stimuli in PHN skin compared with unaffected mirror-image skin. However, the magnitude of the heat pain sensory deficit was inversely correlated with both pain intensity and severity of allodynia. In fact, 12 subjects had heat hyperalgesia in their region of maximum pain. Compared with the 23 subjects with heat hypoalgesia, the group of 12 heat hyperalgesic subjects had significantly higher pain ratings and allodynia severity. Sensory loss was less strongly, but still inversely related to pain severity for the thermal modalities of innocuous warming, cooling and cold pain. This implies that there is no simple relationship between loss of peripheral nerve function and spontaneous or evoked pain. Rather, the preservation of several sensory modalities in their area of maximal pain suggests that in some PHN patients, activity in primary afferent nociceptors that remain connected to both their peripheral and central targets contributes significantly to ongoing pain. Although other mechanisms are likely to contribute to the pain, the demonstrated responsivity of PHN to topical agents including local anaesthetics, capsaicin, and non-steroidal anti-inflammatory drugs, supports this proposed mechanism of pain generation.

    背景与目标: 在带状疱疹后神经痛 (PHN) 综合征中,感觉障碍的性质及其与疼痛的严重程度和原因的关系是有争议的。为了解决这些问题,在35个已建立PHN的受试者中,分别进行了四次感官映射和定量热感官测试。所有受试者都有影响躯干或四肢的疼痛和刷子诱发的异常性疼痛。每个疗程包括持续疼痛的评分,任何感觉障碍区域和最大疼痛区域的映射,最大持续疼痛区域内的异常性疼痛严重程度的分级,以及对疼痛和对侧未受影响的镜像皮肤的热感觉的定量测试。异常性疼痛的严重程度与报告的持续疼痛严重程度呈正相关。作为一组,与未受影响的镜像皮肤相比,受试者对PHN皮肤的热刺激感觉不足。然而,热痛感觉缺陷的程度与疼痛强度和异常性疼痛的严重程度呈负相关。实际上,有12名受试者在其最大疼痛区域存在热痛觉过敏。与23例热痛觉低下的受试者相比,12例热痛觉过敏受试者的疼痛等级和异常性疼痛严重程度明显更高。感觉损失不那么强烈,但对于无害的变暖,降温和冷痛的热方式,其疼痛程度仍与疼痛严重程度成反比。这意味着周围神经功能丧失与自发性或诱发性疼痛之间没有简单的关系。相反,在其最大疼痛区域保留几种感觉方式表明,在某些PHN患者中,与周围和中心目标保持联系的主要传入伤害感受器的活动显着导致持续的疼痛。尽管其他机制可能会导致疼痛,但已证明PHN对局部药物 (包括局部麻醉剂,辣椒素和非甾体抗炎药) 的反应性支持了这种提出的疼痛产生机制。
  • 【痛苦的幻觉: 预先存在的知识决定了大脑对 “想象的异性障碍” 的激活。】 复制标题 收藏 收藏
    DOI:10.1016/j.jpain.2008.01.340 复制DOI
    作者列表:Krämer HH,Stenner C,Seddigh S,Bauermann T,Birklein F,Maihöfner C
    BACKGROUND & AIMS: UNLABELLED:Allodynia means that innocuous tactile stimulation is felt as pain. Accordingly, cerebral activations during allodynia or touch should markedly differ. The aim of this study was to investigate whether the imagination of allodynia affects brain processing of touch in healthy subjects. Seventeen healthy subjects divided into 2 subgroups were investigated: The first group (n = 7) was familiar with allodynia, based on previous pain studies, whereas the second group (n = 10) had never knowingly experienced allodynia. Using functional magnetic resonance imaging, 2 experimental conditions were investigated. In one condition the subjects were simply touched at their left hand, whereas during the other condition they were asked to imagine pain (allodynia) during tactile stimulation of the right hand and to estimate the imagined pain on a numeric rating scale. Data processing and analysis were performed with the use of SPM5. The group analysis of all subjects revealed that tactile stimulation activated contralateral somatosensory cortices (S1 [primary] and S2 [secondary]), but the imagination of allodynia led to an additional activation of anterior cingulate cortex and bilateral activation of S2, insular cortex, and prefrontal cortices. Subgroup analysis using rating-weighted predictors revealed activation of the contralateral thalamus, anterior cingulate cortex, and amygdala and a bilateral activation of S1, S2, and insular cortex and prefrontal cortices in allodynia-experienced subjects. In contrast, allodynia-inexperienced subjects only activated contralateral S1 and bilateral S2. Just the imagination that touch is painful is able to partly activate the central pain system, but only when the subject has previous experience of this. According to our results, the medial pain system is involved in the encoding of imagined allodynia. PERSPECTIVE:This article reports that pain experience is able to alter central processing of sensory stimuli. Pain knowledge appears to be able to shift "normal" tactile processing to a different quality, resulting in modified brain activity. Therefore, our study may contribute to the current understanding of human pain and will promote future research on this field.
    背景与目标:
  • 【偏头痛和早期异常性疼痛患者曲坦效果的差异。】 复制标题 收藏 收藏
    DOI:10.1111/j.1468-2982.2008.01642.x 复制DOI
    作者列表:Lampl C,Huber G,Haas S,Rittberger E,Diener HC
    BACKGROUND & AIMS: :The aim of this study was to determine whether in migraine patients with and without aura early treatment with various triptans leads to differences in pain reduction after 1 h and in modulating cutaneous allodynia. Thirty-six patients with early manifestation of a clinically recognizable allodynia of the face and non-responders to earlier treatment with sumatriptan 100 mg were included. Patients were randomized to six triptan treatment groups. Significant pain reduction was seen only in the group receiving zolmitriptan nasal spray 5 mg with a mean visual analogue scale (VAS) score of 3.8 (s.d. 1.2) at baseline and 2.4 (s.d. 1.3; P = 0.015) at 1 h after using the triptan and was thus a predictor of a VAS score 3 within 1 h. The study results indicate that migraine headache intensity can be reduced within 1 h by using zolmitriptan 5 mg nasal spray in spite of the presence of early cutaneous allodynia.
    背景与目标: : 这项研究的目的是确定在有和没有先兆的偏头痛患者中,使用各种曲坦药物进行早期治疗是否会导致1小时后疼痛减轻和调节皮肤异常性疼痛的差异。包括36例早期表现为临床可识别的面部异常性疼痛的患者和对舒马曲坦100 mg早期治疗无反应的患者。患者被随机分为六个曲普坦治疗组。仅在基线和2.4 (s.d. 1.3) 平均视觉模拟评分 (VAS) 为3.8 (s.d. 1.2) 的佐米曲普坦鼻喷雾剂5 mg组中观察到明显的疼痛减轻; P = 0.015) 在使用曲坦后1小时,因此是1小时内VAS评分3的预测因子。研究结果表明,尽管存在早期皮肤异常性疼痛,但使用佐米曲坦5 mg鼻喷雾剂可在1小时内降低偏头痛的强度。
  • 【月经相关偏头痛的异常性疼痛: 通过异常性疼痛症状清单 (ASC-12) 进行评分评估。】 复制标题 收藏 收藏
    DOI:10.1111/head.13677 复制DOI
    作者列表:Melhado EM,Thiers Rister HL,Galego DR,de Oliveira AB,Buttarello IA,Belucio IS,Oliveira Marcos JM,Xavier MLT,Peres MFP
    BACKGROUND & AIMS: OBJECTIVE:The aim of this study was to compare the allodynia score in headache attacks related and not related to menstruation in women diagnosed with menstrually related migraine without aura. BACKGROUND:Allodynia is an important symptom in migraine and has been associated with migraine chronification. No study has yet compared prospectively allodynia in menstrual vs non-menstrual attacks within the same cohort of patients. METHODS:This is a prospective cohort study, where participants had the 12-item Allodynia Symptom Checklist (ASC-12) assessed after 1, 2, 4, and 24 hours from the onset of migraine attacks in 2 different conditions, with menstrual migraine attack (MM+) and with non-menstrual migraine attack (MM-). RESULTS:A total of 600 women with headache complaints were screened from March 2013 to July 2014 in a headache outpatient or headache tertiary clinic. From these, 55 participants were recruited, and 32 completed the study. Participants' mean age was 27 years, BMI was 22.1, menarche age 12 years, migraine history was 11.5 years, and most women were young (ranged from 17 to 44 years of age), were in higher school (13/32 = 41%), single (20/32 = 63%), and used contraceptives (22/32 = 69%). Multiple pairwise comparisons of ANCOVA's test showed significant higher ASC-12 scores in MM+ group compared to MM- group at 2 hours [mean, 95% CI of difference: 2.3 (0.31, 4.7), P = .049)]. For the ASC-12 categorical scores (absent, mild, moderate, and severe) MM+ yielded higher scores than MM- at 1 hour (z = -3.08, P = .021) and 4 hours (z = -2.97, P = .03). CONCLUSION:This study demonstrated that in the patents from tertiary headache center assessed, menstrual-related migraine attacks augment allodynia scores in the beginning of attacks compared to non-menstrual migraine attacks.
    背景与目标:
  • 【偏头痛中动态 (刷) 和静态 (压力) 机械异常性疼痛的比较。】 复制标题 收藏 收藏
    DOI:10.1111/j.1468-2982.2006.01121.x 复制DOI
    作者列表:LoPinto C,Young WB,Ashkenazi A
    BACKGROUND & AIMS: :Allodynia has been described in migraine but has not been fully investigated for the different sensory modalities. The aim of this study was to compare the prevalence of dynamic (brush) and static (pressure) mechanical allodynia in migraine patients and to suggest a practical method of testing them in a clinical setting. Patients with International Headache Society-defined episodic migraine (EM) or with transformed migraine (TM) as defined by Silberstein and Lipton were prospectively recruited from the Jefferson Headache Center out-patient clinic. A questionnaire of migraine features and symptoms of allodynia was administered. Brush allodynia (BA) was tested by cutaneous stimulation with a gauze pad and pressure allodynia (PA) was tested using von Frey hairs (VFH). The prevalence of BA and PA in all patients and in the different subgroups was calculated and correlated with migraine features. We recruited 55 migraine patients. Twenty-five had EM and 30 had TM. BA was present in 18 (32.7%) patients and PA in 18-24 (32.7-43.6%). Allodynia to both brush and pressure was found in 13-17 (23.6-30.9%) patients. If a patient had allodynia to one modality only, it was more likely to be PA than BA. Both BA and PA were more common in patients with TM compared with those with EM [BA 46.7% vs. 16.0%; PA (differences significant for the medium and thick VFHs) 50% vs. 20% and 50% vs. 12%, respectively]. Both types of allodynia were also more common in patients with migraine with aura compared with those with migraine without aura (BA 57.1% vs. 17.6%; PA 57.1-61.9% vs. 17.6-32.7%). There was a positive correlation between allodynia score (as obtained by examination) and allodynia index (as obtained by history) for both BA and PA. The incomplete, although considerable, overlap between BA and PA suggests that allodynia to different sensory modalities is associated with sensitization of different neuronal populations. Because PA was more common than BA, it may be a more sensitive indicator of allodynia in migraine. PA can be tested clinically in a practical and systematic manner.
    背景与目标: : 偏头痛中已经描述了异常性疼痛,但尚未对不同的感觉方式进行充分研究。这项研究的目的是比较偏头痛患者的动态 (刷) 和静态 (压力) 机械异常性疼痛的患病率,并提出一种在临床环境中进行测试的实用方法。前瞻性地从杰斐逊头痛中心门诊招募了国际头痛协会定义的发作性偏头痛 (EM) 或Silberstein和Lipton定义的转化偏头痛 (TM) 患者。进行了偏头痛特征和异常性疼痛症状的问卷调查。通过用纱布垫进行皮肤刺激来测试刷性异常性疼痛 (BA),并使用von Frey头发 (VFH) 测试压力异常性疼痛 (PA)。计算了所有患者和不同亚组中BA和PA的患病率,并将其与偏头痛特征相关联。我们招募了55名偏头痛患者。25个有EM,30个有TM。BA存在于18 (32.7%) 例患者中,PA存在于18-24 (32.7-43.6%) 中。在13-17 (23.6-30.9%) 例患者中发现了刷和压力的异常性疼痛。如果患者仅对一种方式有异常性疼痛,则PA比BA更有可能。与EM患者相比,TM患者中BA和PA更为常见 [BA 46.7% vs. 16.0%; PA (中等和厚VFHs的差异显着) 50% 分别为20% 和50% 与12%]。与无先兆偏头痛患者相比,两种类型的异常性疼痛在先兆偏头痛患者中也更常见 (BA 57.1% vs. 17.6%; PA 57.1-61.9% vs. 17.6-32.7%)。BA和PA的异常性疼痛评分 (通过检查获得) 与异常性疼痛指数 (通过病史获得) 之间呈正相关。BA和PA之间不完整 (尽管相当大) 的重叠表明,对不同感觉方式的异常性疼痛与不同神经元群体的敏化有关。由于PA比BA更常见,因此它可能是偏头痛异常性疼痛的更敏感指标。PA可以以实用和系统的方式进行临床测试。
  • 【神经性疼痛患者刷状诱发异常性疼痛的脑处理的fMRI研究。】 复制标题 收藏 收藏
    DOI:10.1016/j.neuroimage.2006.03.024 复制DOI
    作者列表:Schweinhardt P,Glynn C,Brooks J,McQuay H,Jack T,Chessell I,Bountra C,Tracey I
    BACKGROUND & AIMS: :Previous human imaging studies have revealed a network of brain regions involved in the processing of allodynic pain; this includes prefrontal areas, insula, cingulate cortex, primary and secondary somatosensory cortices and parietal association areas. In this study, the neural correlates of the perceived intensity of allodynic pain in neuropathic pain patients were investigated. In eight patients, dynamic mechanical allodynia was provoked and brain responses recorded using functional magnetic resonance imaging (fMRI). Voxels in which the magnitude of fMRI signal correlated linearly with the ratings of allodynic pain across the group were determined in a whole brain analysis using a general linear model. To ensure that activation reflected only allodynic pain ratings, a nuisance variable containing ratings of ongoing pain was included in the analysis. We found that the magnitude of activation in the caudal anterior insula (cAI) correlates with the perceived intensity of allodynic pain across subjects, independent of the level of ongoing pain. However, the peak of activation in the allodynic condition was located in the rostral portion (rAI). This matches the representation of other clinical pain syndromes, confirmed by a literature review. In contrast, experimental pain in healthy volunteers resides predominantly in the cAI, as shown by the same literature review. Taken together, our data and the literature review suggest a functional segregation of anterior insular cortex.
    背景与目标: : 先前的人类影像学研究揭示了参与异型疼痛处理的大脑区域网络; 这包括前额叶区域,岛叶,扣带回皮层,初级和次级体感皮层以及顶叶关联区域。在这项研究中,研究了神经性疼痛患者的异常性疼痛感知强度的神经相关性。在八名患者中,使用功能磁共振成像 (fMRI) 引起了动态机械性异常性疼痛,并记录了大脑反应。在使用一般线性模型的全脑分析中,确定了fMRI信号的大小与全组异常性疼痛的等级线性相关的体素。为了确保激活仅反映异常性疼痛等级,分析中包括了包含持续疼痛等级的滋扰变量。我们发现,尾部前岛岛 (cAI) 的激活程度与整个受试者的异常性疼痛的感知强度相关,而与持续疼痛的水平无关。然而,异常性状态下的激活峰值位于鼻尖部分 (rAI)。这与文献综述证实的其他临床疼痛综合征的表现相匹配。相反,如同一文献综述所示,健康志愿者的实验性疼痛主要发生在cAI中。综上所述,我们的数据和文献综述表明,前岛叶皮层具有功能性分离。
  • 【身体滥用通过神经源性炎症和spino-parabrachio-杏仁核途径激活,导致广泛的慢性机械痛觉过敏,触觉异常性疼痛和冷异常性疼痛。】 复制标题 收藏 收藏
    影响因子 :
    发表时间:2020-08-01
    来源期刊:Pain
    DOI:10.1097/j.pain.0000000000001867 复制DOI
    作者列表:Ohmichi Y,Ohmichi M,Tashima R,Osuka K,Fukushige K,Kanikowska D,Fukazawa Y,Yawo H,Tsuda M,Naito M,Nakano T
    BACKGROUND & AIMS: :Physical disuse could lead to a state of chronic pain typified by complex regional pain syndrome type I due to fear of pain through movement (kinesiophobia) or inappropriate resting procedures. However, the mechanisms by which physical disuse is associated with acute/chronic pain and other pathological signs remain unresolved. We have previously reported that inflammatory signs, contractures, disuse muscle atrophy, spontaneous pain-like behaviors, and chronic widespread mechanical hyperalgesia based on central plasticity occurred after 2 weeks of cast immobilization in chronic post-cast pain (CPCP) rat model. In this study, we also demonstrated dystrophy-like changes, both peripheral nociceptive signals and activation of the central pain pathway in CPCP rats. This was done by the following methods: (1) vascular permeability (Evans blue dye) and inflammatory- and oxidative stress-related messenger RNA changes (real-time quantitative polymerase chain reaction); (2) immunofluorescence of pERK and/or c-Fos expression in the spino-parabrachio-amygdaloid pathway; and (3) blockade of nociceptive-related signals using sciatic nerve block. Furthermore, we demonstrated tactile allodynia using an optogenetic method in a transgenic rat line (W-TChR2V4), cold allodynia using the acetone test, and activation of dorsal horn neurons in the chronic phase associated with chronic mechanical hyperalgesia using c-Fos immunofluorescence. In addition, we showed that nociceptive signals in the acute phase are involved in chronic pathological pain-like behaviors by studying the effects of sciatic nerve block. Thus, we conclude that physical disuse contributes to dystrophy-like changes, spontaneous pain-like behavior, and chronic widespread pathological pain-like behaviors in CPCP rats after 2 weeks of cast immobilization.
    背景与目标: : 由于害怕通过运动 (运动恐惧症) 或不适当的休息程序而引起的疼痛,身体上的不使用可能导致以I型复杂区域疼痛综合征为代表的慢性疼痛状态。然而,身体使用与急/慢性疼痛和其他病理体征相关的机制仍未解决。我们以前曾报道,在慢性铸后疼痛 (CPCP) 大鼠模型中,在石膏固定2周后发生了炎症体征,挛缩,废用肌肉萎缩,自发性疼痛样行为和基于中枢可塑性的慢性广泛的机械痛觉过敏。在这项研究中,我们还证明了CPCP大鼠的营养不良样变化,包括外周伤害感受信号和中枢疼痛途径的激活。这是通过以下方法完成的 :( 1) 血管通透性 (伊文思蓝染料) 和炎症和氧化应激相关的信使RNA变化 (实时定量聚合酶链反应); (2) spino-parabrachio-杏仁核途径中pERK和/或c-Fos表达的免疫荧光; (3) 使用坐骨神经阻滞阻断伤害性相关信号。此外,我们在转基因大鼠品系 (W-TChR2V4) 中使用光遗传学方法证明了触觉异常性疼痛,使用丙酮测试证明了冷异常性疼痛,以及使用c-Fos免疫荧光激活与慢性机械痛觉过敏相关的慢性期背角神经元。此外,通过研究坐骨神经阻滞的作用,我们发现急性期的伤害性信号与慢性病理性疼痛样行为有关。因此,我们得出的结论是,石膏固定2周后,CPCP大鼠的身体使用会导致营养不良样变化,自发性疼痛样行为和慢性广泛的病理性疼痛样行为。
  • 【抗肿瘤坏死因子-α 的抗体可减少硼替佐米诱导的大鼠模型中的异常性疼痛。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Chiorazzi A,Canta A,Meregalli C,Carozzi V,Sala B,Oggioni N,Monbaliu J,VAN DE Velde H,Cavaletti G
    BACKGROUND & AIMS: BACKGROUND:Bortezomib is an anti-neoplastic drug acting against multiple myeloma but its use is associated with the onset of painful peripheral neuropathy. Tumor necrosis factor-α (TNFα) is associated with the development of neuropathic pain; several models have shown that the inactivation of TNFα leads to a reduction in pain stimuli perception. The aim of the present study was to analyze if the administration of an antibody against TNFα is able to prevent the development of bortezomib-induced neuropathic pain. MATERIALS AND METHODS:Nerve conduction velocity was measured and a histopathological examination was performed to assess the extent of peripheral neuropathy. To study the onset of painful neuropathy, the response to mechanical or thermal stimuli was evaluated. RESULTS:This study demonstrated that co-administration of an antibody against TNFα is able to prevent allodynia induced by bortezomib but does not reduce neuropathy. CONCLUSION:Targeting TNFα might be useful in limiting patients' discomfort during bortezomib therapy.
    背景与目标:

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