2020, Vol. 55
2. 中国医学科学院、北京协和医学院药物研究所, 神经科学中心, 北京 100050
2. Neuroscience Center, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
神经病理性疼痛(neuropathic pain, NP)是一种常见的慢性疼痛, 全球患病人数超百万, 严重影响了患者的生活质量[1]。国际疼痛研究学会将神经病理性疼痛定义为“由躯体感觉神经系统的损伤或疾病引起的疼痛”。其临床特征主要表现为自发性疼痛、痛觉过敏、痛觉超敏和感觉异常等[2, 3]。NP常见于脊髓损伤、多发性硬化症及糖尿病和其他代谢紊乱疾病。此外, 癌症患者也常出现神经病理性疼痛, 是癌症对周围神经的直接作用或是化疗的不良反应。
Wnt信号通路在神经系统的发育过程中发挥着多种作用, 已被证实参与了NP的发生和维持[4-7], 而且与中枢敏化、炎症因子的释放等密切相关, 表明Wnt通路可能是NP发病的一个关键机制[8]。本文将从Wnt信号通路的角度阐述神经病理性疼痛的发生和发展。
1 Wnt信号通路概述Wnt (Wingless-related integration site)基因的命名结合了果蝇中发现的Wingless (无翅基因)和小鼠乳腺肿瘤细胞中发现的Integration (Int, 一种原癌基因), 1991年学者一致认为属于Int/Wingless家族的基因应记作Wnt[9]。Wnts是一类分泌型糖蛋白, 目前已有19种Wnt配体被确认[9] (图 1)。Wnts可以激活不同的细胞表面受体, 这些受体与典型和非典型Wnt信号通路相连, 在多种发育和致癌过程中起着至关重要的作用[10]。研究证明, Wnts在神经系统中具有调节突触形成、突触传递和突触可塑性的作用[11], 在哺乳动物中枢神经系统中, 特定的Wnt配体主要在神经元中表达, 如Wnt3a (激活典型通路的Wnt配体)和Wnt5a (激活非典型通路的Wnt配体)[12-14]等。Wnt信号通路包括3条不同的通路, 即典型通路Wnt/β-catenin通路、非典型通路平面细胞极性通路(Wnt/planar cell polarity, Wnt/PCP)和Wnt/Ca2+通路(图 2)。
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Figure 1 Structure of Wnt. SS: Asignal sequence; C: Conserved cysteine residues |
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Figure 2 Wnt signaling pathway in neuropathic pain. The canonical and non-canonical Wnt signaling pathway is activated and involved in the production of neuropathic pain (a, b). Wnt: Wnt ligands; Fzd: Frizzled; LRP: Lipoprotein receptor-related protein; Dvl: Dishevelled; Ror: Receptor tyrosine kinase-like orphan receptor 2; Ryk: Receptor-like tyrosine kinase; CK1: Casein kinase 1; APC: Adenomatous polyosis coli; GSK-3β: Glycogen synthase kinase-3β; RhoA: Ras homolog gene family, member A; ROCK: Rho associated kinases; Rac1: Ras-related C3 botulinum toxin substrate 1; JNK: c-Jun N-terminal kinase; TNK: Tankyrase; PLC: Phospholipases C; PKC: Protein kinase C; CaMK Ⅱ: Calcium/calmodulin-dependent protein kinase; β-cat: β-Catenin; TCF/LEF: T-cell factor/lymphoid enhancer factor; TNF-α: Tumor necrosis factor-α; IL-18: Interleukin-18; IL-1β: Interleukin-1β; IL-6: Interleukin-6; BDNF: Brain-derived neurotrophic factor; NR2B: N-Methyl-D-aspartate receptor 2B; NFAT: Nuclear factor of activated T cells |
Wnt/β-catenin信号通路由Wnt配体、Wnt受体[脂蛋白受体相关蛋白4-6 (lipoprotein receptor-related protein 4-6, LRP4-6)、10种卷曲蛋白受体(frizzled, Fzd)]、蓬乱蛋白(dishevelled, Dsh/Dvl)、轴蛋白(Axin)、腺瘤性结肠息肉病蛋白(adenomatous polyosis coli, APC)、酪蛋白激酶1 (casein kinase 1, CK1)、糖原合成酶激酶-3β (glycogen synthase kinase-3β, GSK-3β)、β-连环蛋白(β-catenin)以及转录因子T细胞/淋巴增强因子(T-cell factor/lymphoid enhancer factor, TCF/LEF)家族转录调节因子等组成[15]。β-catenin是一种多功能蛋白, 通常在细胞质内被Axin、APC、CK1和GSK-3β形成的复合物磷酸化和泛素化而降解。当Wnt/β-catenin通路激活后, Wnt蛋白与Fzd、LRP5/6结合, 并在Fzd细胞质尾部募集Dvl, 阻止Axin、APC、CK1和GSK-3β的复合物产生, 从而导致β-catenin不能被磷酸化而在细胞质中累积, 最终转移至细胞核内取代共抑制因子/转录因子T细胞/淋巴增强因子(Groucho/TCF/LEF)复合物中的Groucho, 与TCF/LEF相互作用来调节靶基因的转录[9]。
1.2 平面细胞极性通路(Wnt/planar cell polarity, Wnt/PCP)平面细胞急性通路不依赖于LRPs和β-catenin, 由于Dvl具有多个结构域, 能够与多个蛋白结合。因此, Dvl和Fzds结合可以启动不同的下游信号[16]。Wnt-Fzd与受体酪氨酸激酶样孤儿受体2 (receptor tyrosine kinase-like orphan receptor 2, Ror2)或受体样酪氨酸激酶(receptor-like tyrosine kinase, Ryk)结合, 导致Dvl募集到Fzd并激活蓬乱蛋白相关形态形成活化因子-1 (dishevelled associated activator morphogenesis-1, Damm1), 进而激活: ①小G蛋白Ras同源基因家族成员A (Ras, homolog gene family, member A, RhoA)及其下游效应器Rho-激酶(Rho associated kinase, ROCK); ②小G蛋白Ras相关的C3肉毒素底物1 (Ras-related C3 botulinum toxin substrate 1, Rac1)及其下游靶点c-Jun氨基末端激酶(c-Jun N-terminal kinase, JNK)[17]。Wnt/PCP信号通路能使活化T细胞核因子(nuclear factor of activated T cells, NFAT)转移至细胞核内从而启动靶基因的转录。
1.3 Wnt/Ca2+信号通路Wnt与Fzd结合并募集Dvl, 从而激活磷脂酶C导致细胞内Ca2+的释放, 继而激活Ca2+敏感组件:蛋白激酶C (protein kinase C, PKC)和钙/钙调素依赖蛋白激酶Ⅱ (calcium/calmodulin-dependentproteinkinase, CaMK Ⅱ)[18]。Wnt/Ca2+信号通路也能使NFAT转移至细胞核内, 从而启动靶基因的转录。
2 Wnt信号通路与神经病理性疼痛的关系Wnts在多种神经痛模型中参与疼痛的发生和维持。Wnt/β-catenin和Wnt/Ryk信号通路的激活通过促进促炎细胞因子的产生、脑源性神经营养因子(brain-derived neurotrophic factor, BDNF)的释放、激活突触蛋白及钙离子依赖的信号通路增强神经元兴奋性, 进而增强突触可塑性, 导致中枢敏化而引起神经痛。
2.1 坐骨神经慢性压迫损伤(chronic constriction injury, CCI)模型CCI模型是研究神经病理性疼痛常用的一种动物模型, 术后动物会出现痛觉过敏、痛觉超敏及自发性疼痛。这种模型模拟了人类由于肿瘤压迫、重金属离子中毒、缺氧等诱发的神经痛症状。神经损伤引起背根神经节(dorsal root ganglion, DRG)神经元和脊髓(spinal cord, SC)的变化对NP的产生至关重要。Zhang等[19]检测了CCI大鼠SC (L4、L5)中19种Wnt配体mRNA表达, 结果显示, Wnt3a、Wnt1、Wnt2、Wnt4、Wnt5b、Wnt8b在术后第1~10天内持续或暂时升高, 其余均略有下降或无显著变化。术后DRG中Wnt3a免疫活性的增加主要分布在大、中、小神经元中[19], 由于神经损伤后, 高敏感的大纤维引发痛觉超敏, 中小纤维引发痛觉过敏, 因此Wnt3a在CCI模型中同时参与了痛觉过敏和痛觉超敏的形成。术后SC中Wnt3a免疫活性的增加主要分布在术侧脊髓背角(spinal dorsal horn, SDH)浅层[19]。以上结果证明, Wnt信号在DRG神经元和SDH神经元的痛觉通路中被广泛激活。此外, Zhao等[20]发现β-catenin、Frizzled 4及谷氨酸受体N-甲基-D-天冬氨酸受体2B亚基(N-methyl-D-aspartate receptor 2B, NR2B)蛋白水平和CaMK Ⅱ、PKC、环磷腺苷效应元件结合蛋白(cAMP-response element binding protein, CREB)、类固醇受体辅助活化因子(steroid receptor coactivator, Src)磷酸化水平在神经损伤后的DRG中显著上升, 鞘内注射Wnt3a抑制剂IWP-2能显著提高CCI大鼠机械痛阈值, 同时降低β-catenin、Frizzled 4及NR2B、p-CaMK Ⅱ、PKC、CREB、Src蛋白表达。已经证明NR2B、CaMK Ⅱ、PKC、CREB和Src与突触可塑性密切相关[21], 并进一步参与中枢敏化形成, 而中枢敏化是造成初始损伤部位以外继发性疼痛的原因[19, 22]。这些结果表明, Wnt3a参与了CCI诱导的神经病理性疼痛的发病机制, Wnt3a与突触后膜的Frizzled 4受体结合引起胞内β-catenin累积并进入细胞核, 然后启动下游靶基因的转录, 使谷氨酸受体NR2B表达和磷酸化CaMK Ⅱ、PKC、CREB、Src蛋白活性增加, 导致突触可塑性及中枢敏化, 最终导致疼痛阈值降低。实验发现, CCI大鼠SC中肿瘤坏死因子-α (tumor necrosis factor-α, TNF-α)、白介素-18 (interleukin-18, IL-18) mRNA和蛋白含量显著增加, 鞘内注射Wnt通路抑制剂IWR-1-endo或Fz-8/Fc可显著降低其含量[19]。ChIP结果表明, 在CCI大鼠SC中, β-catenin抗体与TNF-α和IL-18启动子序列相互作用[19], 说明Wnt/β-catenin可能通过促进促炎因子TNF-α和IL-18的释放参与NP的发生发展。以上结果证明了Wnt/β-catenin信号通路在神经病理性疼痛中发挥着重要作用。
Liu等[22]发现, Ryk (具有细胞内酪氨酸激酶结构域的单跨膜受体)、Wnt5b蛋白在CCI大鼠SC和DRG中表达上调, 鞘内注射Ryk抗体后痛觉过敏和痛觉超敏均减弱, 表明Wnt/Ryk信号通路在神经痛中具有重要作用。Ryk是近年来发现的Wnt信号中的非典型受体[23], 具有Wnt抑制因子1 (Wnt inhibitory factor 1, WIF 1)样细胞外结构域, 使其能够与包括Wnt1在内的不同Wnt配体相互作用[24]。CCI引起的DRG神经元过度兴奋主要表现为动作电位电流阈值(action potential current threshold, APCT)降低及重复放电增加[25], Ryk抗体可逆转APCT下降, 减少细胞内去极化电流诱导的重复放电, 从而抑制神经元的兴奋性。使用Ryk抗体阻断DRG和SC中Ryk可显著抑制传入C纤维和背角神经元之间NR2B激活及细胞内Ca2+和Ca2+依赖的信号蛋白活性, 包括Src、CaMK Ⅱ、PKC、CREB和细胞外调节蛋白激酶(extracellular regulated protein kinases, ERK[22])。中枢敏化是NP发生发展的重要机制, 与长时程增强(long-term potentiation, LTP)密切相关[26]。鞘内注射Ryk抗体可阻断CCI大鼠由两段高频刺激引起的传入C纤维和SDH神经元之间突触的LTP[22]。这些结果提示, 神经损伤后Wnt/Ryk通路可以调节NR2B的激活及细胞内Ca2+和Ca2+依赖的信号蛋白活性, 从而调节痛觉传入C纤维与SDH神经元之间的兴奋性和突触可塑性, 最终导致SC中枢敏化和NP产生。
2.2 腰5脊神经结扎(L5 spinal nerve ligation, SNL)模型SNL模型即脊神经选择结扎模型, 在不损伤DRG和其他神经的情况下切除动物L6横突并紧密结扎L5脊神经, 可诱导动物产生机械性痛觉超敏和热痛觉过敏。研究证明, SNL小鼠SC中Wnt3a和β-catenin蛋白表达增加[27], 鞘内注射Wnt抑制剂XAV939能促进β-catenin磷酸化, 选择性抑制Wnt/β-catenin通路, 有效缓解痛觉超敏[28]。这些结果表明, Wnt/β-catenin通路在SNL诱导的NP发展过程中发挥了重要作用。研究发现小胶质细胞中BDNF能介导NP发展[29-32]。在体外实验中, 给予小胶质细胞Wnt3a刺激, 可激活小胶质细胞并促进BDNF释放。体内实验中, 术侧SDH中BDNF浓度显著升高, 鞘内给予XAV939后, 小胶质细胞的活化被显著抑制[28], 提示Wnt3a上调后可能通过激活Wnt/β-catenin信号通路促进小胶质细胞活化, 进而促进BDNF分泌, 最终导致NP发生。Yang等[23]发现, SC神经结扎后第3~14天, SDH中Ryk的mRNA和蛋白水平以及活化星形胶质细胞中Wnt1 (Ryk配体)蛋白水平明显高于假手术组动物, 而用慢病毒介导的shRNA干扰Ryk可减轻动物炎症反应, 提高机械痛阈值, 表明Wnt1/Ryk与NP密切相关。SNL模型SDH中趋化因子CCL2蛋白水平显著上调, 鞘内注射Ryk抗体后减少了CCL2产生[23], 提示CCL2可能是脊髓Wnt1/Ryk信号传导的下游效应靶点, Wnt1通过Ryk受体调节CCL2的产生和释放来诱导神经性疼痛。
2.3 人类免疫缺陷病毒(human immunodeficiency virus, HIV)相关神经性疼痛病理性疼痛是HIV-1/AIDS患者最常见的神经系统并发症之一[33], 称为HIV相关神经性疼痛, 是神经病理性疼痛的一种。Shi等[12]发现, Wnt5a、Wnt3a、Wnt4、Wnt9b、β-catenin及Axin2在疼痛阳性HIV患者SDH中蛋白表达显著上调, 而在疼痛阴性HIV患者中无明显变化, 表明Wnt通路的激活是HIV诱发神经痛的重要条件。HIV-1 gp120是一种病毒外壳蛋白, 常用于小鼠鞘内注射来模拟疼痛阳性HIV患者。在HIV-1 gp120神经痛模型SDH神经元中, Wnt5a蛋白表达上调, 白介素-1β (interleukin-1β, IL-1β)、白介素-6 (interleukin-6, IL-6)和TNF-α含量增加, 鞘内注射Wnt5a拮抗剂Box5后, IL-1β、IL-6和TNF-α含量与对照组相比显著减少[11, 12]。最近的研究表明, Wnt5a是一种受NMDA调控的蛋白[34], 对兴奋性突触的分化和可塑性至关重要[35, 36]。提示病理性疼痛条件下SDH神经元过度激活刺激了Wnt5a的产生, 从而促进炎症因子IL-1β、IL-6和TNF-α释放, 以及SDH神经元的突触可塑性, 最终诱导人类免疫缺陷病毒相关神经性疼痛。
此外, 研究发现在gp120诱导的小鼠疼痛模型中, SDH神经元Wnt5a蛋白表达上调, CaMKII和JNK蛋白磷酸化水平均显著升高[37], 表明Wnt5a、CaMKII和JNK被gp120激活, 鞘内注射Wnt5a拮抗剂Box5能逆转磷酸化CaMKII和JNK蛋白含量增加[37], 以上结果说明gp120通过激活Wnt5a促进了CaMKII和JNK磷酸化。分别使用抑制剂KN-93和SP600125阻断gp120模型SDH的CaMKII和JNK, 结果显示KN-93抑制了IL-6和IL-1β含量增加, SP600125抑制了IL-6和TNF-α含量增加[37], 表明CaMKII促进IL-6和IL-1β释放, 而JNK促进IL-6和TNF-α释放。这些结果证明, 在gp120神经痛模型中, Wnt5a/CaMKII和Wnt5a/JNK通路被激活从而促进炎症因子释放, 导致NP的发生发展。
2.4 癌性痛(tumor-associated pain)癌症患者常伴有慢性疼痛, 晚期患者的疼痛发生率甚至超过60%[38]。肿瘤细胞植入(tumor cell implantation, TCI)诱导的小鼠骨癌疼痛模型常表现为机械痛觉超敏和热痛觉过敏[19]。研究发现, 术侧SC中Wnt3a、Wnt受体Fz8及β-catenin蛋白表达显著增加[19]。Simonetti等[17]将骨纤维肉瘤细胞植入C3H野生型小鼠的跟骨腔, 模型组注射可溶性卷曲相关蛋白2和3 (soluble Fzd-binding proteins 2 and 3, sFRPs), 这种Wnt拮抗剂呈剂量依赖性地结合与隔离Wnt家族配体[39], 与注射牛血清白蛋白对照组小鼠相比, sFRPs组机械痛阈值显著升高。以上证据表明Wnt信号通路在骨癌痛模型中被激活, 并促进了NP的发展。
2.5 糖尿病性神经痛(diabetic neuropathy pain, DNP)糖尿病是一种常见的代谢性疾病, 并伴有轻度炎症[40]。神经病理性疼痛是糖尿病严重的并发症之一[41], 约有1/3糖尿病患者患有糖尿病性神经痛[42], 通常表现为下肢皮肤烧灼样疼痛、自发性疼痛、痛觉过敏和痛觉超敏。链脲佐菌素(streptozotocin, STZ)是一种针对胰岛细胞的糖尿病化学诱导剂, 可引起氧化和羟基化等毒性, STZ模型被广泛应用于模拟DNP的临床表现。实验发现, STZ诱导的糖尿病大鼠与对照组相比, 其机械痛和热痛阈值显著降低[6, 8], SC中Wnt10a和β-catenin蛋白表达显著升高, 并且促炎细胞因子TNF-α和IL-1β表达也显著升高[6]。这些证据表明, Wnt10a可能通过激活β-catenin信号通路促进TNF-α和IL-1β表达, 从而诱导DNP的发生。
2.6 多发性硬化症(multiple sclerosis, MS)相关神经性疼痛多发性硬化症是一种影响中枢神经系统的自身免疫性疾病, 80%以上多发性硬化症患者会发展为神经病理性疼痛[43]。实验性自身免疫性脑脊髓炎(experimental allergic encephalomyelitis, EAE)小鼠已被广泛用于模拟多发性硬化症相关的神经并发症, 包括中枢神经脱髓鞘、神经炎症和运动障碍等。与MS患者相似, EAE小鼠也会出现神经性疼痛。Yuan等[44]利用免疫组化实验发现Wnt3a、β-catenin、Wnt5a及其受体Ror2在EAE小鼠SDH中显著增加, 鞘内注射Wnt5a拮抗剂Box5和β-catenin抑制剂吲哚美辛(indomethacin, INDO)能够缓解EAE小鼠痛觉超敏(表 1)。这些结果提示, Wnt典型或非典型信号通路异常激活都可能促进EAE相关病理性疼痛的发生。研究证明Wnt5a是促炎细胞因子如IL-1β和TNF-α表达的重要调控因子, 而这些促炎细胞因子是疼痛发生过程中神经炎症的重要介质[45]。因此, Wnt5a信号可能通过刺激促炎细胞因子的表达而参与EAE小鼠病理性疼痛的发病机制。
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Table 1 Main substrates with increased expression in the model. CCI: Chronic constriction injury; SNL: L5 spinal nerve ligation; HIV: Human immunodeficiency virus; DNP: Diabetic neuropathic pain; MS/EAE: Multiple sclerosis/experimental allergic encephalomyelitis; DRG: Dorsal root ganglion; SC: Spinal cord; SDH: Spinal dorsal horn; Ryk: Receptor-like tyrosine kinase; NR2B: N-methyl-D-aspartate receptor 2B; PKC: Protein kinase C; CaMK Ⅱ: Calcium/ calmodulin-dependent protein kinase; CREB: cAMP-response element binding protein; Src:Steroid receptor coactivator; TNF-α: Tumor necrosis factor-α; IL-18: Interleukin-18; IL-1β: Interleukin-1β; IL-6: Interleukin-6; BDNF: Brain-derived neurotrophic factor; JNK: c-Jun N-terminal kinase; Fz8: Frizzled 8; Ror2: Receptor tyrosine kinase-like orphan receptor 2 |
神经病理性疼痛是一个包含多种类型疼痛的综合征, 其发病机制尚未完全阐明[46], 常用镇痛药如阿片类药物和非甾体抗炎药因不良反应而很难长期治疗神经痛, 目前临床一线用药主要为抗抑郁药物, 然而神经痛作为一种慢性疼痛具有长期存在、反复发作及伴有明显情绪反应的特点, 使得完全治愈较为困难。近年来, 多种神经痛模型的建立和完善使机制研究取得了一定进展, 已证明Wnt信号通路与神经痛存在密切联系, 激活Wnt典型和非典型通路均能促进炎症因子的释放、突触可塑性及中枢敏化等来参与神经痛的发生和维持, 而阻断Wnt配体和受体能缓解神经病理性疼痛的症状。然而, 目前Wnt信号通路与NP的临床研究较少, 多数研究内容还停留于动物实验阶段, 尚没有Wnt通路抑制剂作为临床治疗药物。最近, 越来越多的研究关注神经痛所伴随的情绪样疾病, Zhao等[5]研究了选择性神经损伤(spared nerve injury, SNI)模型小鼠腹侧海马神经干细胞(neural stem cells, NSCs)与Wnt/β-catenin信号通路的关系, 研究发现SNI小鼠机械痛和热痛阈值均降低, 腹侧海马NSCs数量减少, 并且NSCs中β-catenin和Axin2蛋白含量降低, 腹腔注射氟西汀(临床上运用最广泛的抗焦虑药)后, 腹侧海马NSCs数量增加, 而且NSCs中β-catenin和Axin2蛋白表达也增加, 然而机械痛和热痛阈值无显著变化, 由此表明, 氟西汀通过Wnt/β-catenin信号通路调节焦虑情绪和痛觉的作用是彼此独立的, 关于Wnt通路与神经痛伴随的情绪反应仍需要进行更深入地研究。microRNA是近年来的研究热点, 也被报道与神经病理性疼痛相关。研究表明, 在SNI大鼠模型中rno-miR-298-5p、rno-miR-1224和rno-miR-488-3p均靶向Wnt9a[47], 但是在神经痛中关于microRNA与Wnt通路的相互作用尚需要更多证明。Wnt信号作为治疗神经痛的潜在靶点具有重大前景, 进一步探究Wnt信号通路的作用机制、寻找新型阻断剂及开发临床用药为患者摆脱神经痛提供巨大帮助。
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