脊髓小胶质细胞/星形胶质细胞在运动镇痛中的作用机制

Mechanisms of spinal microglia and astrocytes in exercise-induced analgesia

摘要

运动镇痛(exercise-induced analgesia，EIA)指通过运动训练提高疼痛阈值，降低机体对伤害性刺激的敏感性。运动疗法作为一种非药物治疗方式，对急、慢性疼痛有积极的影响。研究表明痛觉过敏能够通过改变神经胶质细胞活性发挥镇痛作用。脊髓神经胶质细胞通过炎症反应、突触重塑等机制促进疼痛信号的传递，参与病理性疼痛的发生和发展；运动通过差异化调节小胶质细胞/星形胶质细胞的活性，抑制嘌呤能受体P2X4/P2X7、脑源性神经营养因子(brain-derived neurotrophic factor，BDNF)/磷脂酰肌醇-3-激酶(phosphatidylinositol 3-kinase，PI3K)/哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin，mTOR)、白细胞介素(interleukin，IL)-6/Janus激酶(Janus kinase，JAK)2/信号转导及转录激活因子3(signal transducer and activator of transcription 3，STAT3)、p38-丝裂原活化蛋白激酶(mitogen-activated protein kinases，MAPK)、Toll样受体4(Toll-like receptor 4，TLR4)/核因子κB(nuclear factor-kappa B，NF-κB)等多条炎症信号通路，减少促炎性细胞因子释放，降低炎症反应和痛觉敏感性，减轻病理性疼痛的分子机制以及不同运动强度、运动周期及运动频率对神经胶质细胞的影响，为更有效运用运动疗法治疗病理性疼痛提供理论依据。

Abstract

Exercise-induced analgesia (EIA) refers to the elevation of pain thresholds and reduction in sensitivity to noxious stimuli achieved through exercise training. As a non-pharmacological treatment strategy, exercise therapy has demonstrated positive effects on both acute and chronic pain. Increasing evidence indicates that modulation of glial cell activity is an important mechanism underlying analgesia. Spinal glial cells contribute to the development and maintenance of pathological pain by promoting pain signal transmission through inflammatory responses and synaptic remodeling. Exercise can differentially regulate microglia and astrocyte activity, inhibiting multiple inflammatory signaling pathways, such as P2X4/P2X7 purinergic receptors, brain-derived neurotrophic factor (BDNF)/phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR), interleukin (IL)-6/Janus kinase (JAK) 2/signal transducer and activator of transcription 3 (STAT3), p38-mitogen-activated protein kinases (MAPK), and Toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB), thereby reducing the release of pro-inflammatory cytokines, decreasing inflammatory and nociceptive hypersensitivity, and alleviating pathological pain. This review also summarized the effects of different exercise intensities, durations, and frequencies on glial cell responses in order to provide a theoretical foundation for optimizing exercise-based interventions for pathological pain conditions.

Graphical abstract

关键词

运动镇痛 / 病理性疼痛 / 神经胶质细胞 / 炎症信号通路 / 运动模式

Key words

exercise-induced analgesia / pathological pain / glial cells / inflammatory signaling pathways / exercise patterns

运动训练能提高疼痛阈值，降低机体对伤害性刺激的敏感性，此现象称为运动镇痛(exercise-induced analgesia，EIA)^[1]。1979年EIA被首次报道^[2]，此后运动疗法广泛应用于疼痛治疗中。研究^[3]显示健康无疼痛者和疼痛患者通过单次运动即可降低痛觉敏感性，升高疼痛阈值。有氧运动、抗阻运动及柔韧性运动等运动方式均能产生EIA^[4-5]。病理性疼痛以自发痛、触痛和痛觉过敏为主要特点，治疗难度大，给患者和社会带来极大困扰和经济负担^[6]。目前治疗病理性疼痛的药物有非甾体抗炎药(如阿司匹林、布洛芬)、阿片类药物(如曲马多、芬太尼)、抗癫痫药物(如卡马西平、普瑞巴林和加巴喷丁等)及抗抑郁药物，药物治疗虽然具有一定疗效，但均存在不同程度的不良反应，如头晕、恶心呕吐和胃肠道反应等。规律的有氧运动(如打太极、核心稳定训练等)可有效改善纤维肌痛、腰背痛、颈部痛及膝骨关节痛等，同时可以减少镇痛药物的用量^[7-9]。此外，运动不仅对急性疼痛^[10-12]和慢性疼痛^[13]有镇痛作用，还能够抑制慢性疼痛的发生和发展^[14]。

神经胶质细胞的激活在病理性疼痛的产生和维持中起重要作用^[15]。运动可以通过抑制神经胶质细胞活化发挥镇痛作用^[16]。本文旨在总结脊髓神经胶质细胞在病理性疼痛产生中的作用，以及运动疗法通过调控脊髓小胶质细胞/星形胶质细胞功能产生镇痛作用的可能机制，以期为运动疗法作为非药物干预方式治疗病理性疼痛及其慢性化提供可参考的依据。

1 脊髓神经胶质细胞与病理性疼痛的产生 和维持

1.1 小胶质细胞

小胶质细胞活化在神经病理性疼痛的发展中发挥重要作用^[15]。M1型小胶质细胞释放白细胞介素(interleukin，IL)-1β、IL-6和肿瘤坏死因子-α(tumor necrosis factor-alpha，TNF-α)等炎症因子及一氧化氮/活性氧介导促炎；M2型小胶质细胞分泌抗炎与神经营养因子参与脊髓功能的维持和修复^[17]。M1型/M2型小胶质细胞的极化决定促炎与抗炎的平衡。在脊髓背角，嘌呤能受体P2X和P2Y信号介导神经元-小胶质细胞的病理性沟通，是维持痛觉敏化的重要机制之一^[18]。

1.2 星形胶质细胞

星形胶质细胞在慢性疼痛中活化为神经毒性A1型和神经保护性A2型星形胶质细胞^[19]，抑制星形胶质细胞的活化或降低神经胶质细胞原纤维酸性蛋白(glial fibrillary acidic protein，GFAP)的表达可减轻痛觉过敏^[20]。脊髓星形胶质细胞中连接子蛋白43(connexin 43，Cx43)的表达上调参与机械痛觉过敏^[21]。小胶质细胞来源的TNF-α可促使星形胶质细胞释放趋化因子(C-X-C基序)配体1[chemokine (C-X-C motif) ligend 1，CXCL1]，进而通过(C-X-C基序)受体2[chemokine (C-X-C motif) receptor 2，CXCR2]增强兴奋性突触的传递、维持痛觉过敏^[22]。星形胶质细胞通过释放IL-1β、趋化因子配体2[chemokine (C-C motif) ligand 2，CCL2]、CXCL1等介质参与慢性疼痛产生和持续的调控，而小胶质细胞参与疼痛的启动^[23]。

1.3 少突胶质细胞

少突胶质细胞和髓鞘功能改变亦可促进慢性疼痛的发展^[24-25]。神经损伤后，脊髓内少突胶质前体细胞的标志物神经胶质抗原2(neuron-glial antigen 2，NG2)和增殖标志物5-溴-2’-脱氧尿苷(5-bromo-2’- deoxyuridine，BrdU)的表达显著升高^[26]；少突胶质细胞分泌IL-33，通过其受体肿瘤抑制因子2(suppression of tumorigenicity 2，ST2)驱动小胶质细胞/星形胶质细胞发挥促炎作用，并协同磷脂酰肌醇- 3-激酶(phosphatidylinositol 3-kinase，PI3K)/哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin，mTOR)、丝裂原活化蛋白激酶(mitogen-activated protein kinase，MAPK)[包括p38、c-Jun氨基端激酶(c-Jun N-terminal kinase，JNK)和胞外信号调节激酶(extracellular signal-regulated kinase，ERK)1/2]及Toll样受体4(Toll-like receptor 4，TLR4)/核因子κB(nuclear factor-kappa B，NF-κB)信号通路诱发痛觉过敏反应^[27](图1)。

2 脊髓小胶质细胞/星形胶质细胞与EIA

脊髓是EIA的重要调控部位。运动通过差异化调节小胶质细胞/星形胶质细胞的活性缓解疼痛。在神经病理性疼痛条件下，运动可促使小胶质细胞向抗炎的M2型极化。运动训练可通过下调小鼠脊髓背角脑源性神经营养因子(brain-derived neurotrophic factor，BDNF)的表达，逆转小胶质细胞的过度活化；其表型改变表现为促炎标志物CD86降低、抗炎标志物CD206升高。运动还能够减少脊髓背角星形胶质细胞的总数，抑制小胶质细胞/星形胶质细胞释放促炎性细胞因子(如IL-1β、TNF-α和IL-6)，并逆转抗炎因子IL-4和IL-10等的减少^[23]。此外，运动还可以通过抑制脊髓中P2X受体的表达增加来减弱星形胶质细胞诱导的小胶质细胞活化，并通过抑制背角中谷氨酸转运体1(glutamate transporter-1，GLT-1)的降低来减少兴奋性神经递质的传递，从而发挥镇痛作用^[16]。另有研究^[28-33]表明：运动训练能通过调控小胶质细胞/星形胶质细胞的活性抑制多条炎症信号通路[如嘌呤信号P2X4/P2X7等、BDNF/蛋白激酶B(protein kinase B，Akt)/mTOR、p38-MAPK、TLR4/NF-κB等]，减少促炎性细胞因子的释放，进而降低炎症反应和痛觉敏感性。此外，运动亦通过改善情绪和减轻焦虑、抑郁等心理因素，帮助疼痛管理。上述机制均为慢性疼痛的非药物干预提供了科学依据^[34]。

2.1 运动模式对脊髓小胶质细胞/星形胶质细胞的影响

神经胶质细胞在EIA中发挥重要作用，其调控效果依赖于运动强度、运动周期和运动频率。

2.1.1 运动强度

运动强度的“剂量效应”可能通过调节免疫微环境和胶质细胞表型转换而体现：低强度运动在神经病理性疼痛模型中可通过提升抗炎因子(如IL-4)介导镇痛，并促使小胶质细胞向M2型的偏移^[35]。低强度跑台运动能够抑制坐骨神经损伤(spared nerve injury，SNI)模型小鼠星形胶质细胞补体成分3(complement component 3，C3)的表达，并发挥镇痛作用^[36]。中等强度有氧运动能有效抑制脊髓小胶质细胞/星形胶质细胞活化，同时减少促炎性细胞因子(TNF-α、IL-1β等)的释放发挥镇痛作用^[37]。研究表明：高强度游泳运动会使脊髓小胶质细胞/星形胶质细胞活化诱发痛觉过敏^[38]；高强度连续训练可降低自身免疫性神经炎症模型小鼠小胶质细胞的氧化应激水平与促炎反应，呈现神经免疫保护作用^[39]。Yao等^[40]的研究发现高强度间歇训练(high-intensity interval training，HIIT)较中等强度连续训练(moderate-intensity continuous training，MICT)能更有效地改善脑胶质细胞活化、减轻炎症反应。不同的运动类型及强度对慢性压迫损伤(chronic constriction injury，CCI)模型大鼠术后疼痛的影响并无差异，但其未具体提到对胶质细胞的差异性调控^[41]。

运动强度相关的代谢产物(如乳酸)可直接重塑小胶质细胞炎症反应，提示“外周代谢-中枢免疫耦联”可能是运动强度影响胶质细胞活性的关键环节之一^[42]。合理界定运动强度阈值与恢复周期，可能是将运动对胶质细胞良性调控并发挥最佳镇痛效应的关键。目前相关临床前研究不足，且不同运动类型对不同疼痛动物模型的影响也会产生差异^[41]，这均可以作为未来临床前研究关注的方向。

2.1.2 运动周期

短期与长期运动对脊髓胶质细胞的作用可能呈时间依赖性^[43]，通过CCI模型发现：短期跑步训练 (5 d)可显著降低脊髓背角星形胶质细胞标志物GFAP和小胶质细胞CD11b的表达，而长期训练(54 d)反而导致脊髓小胶质细胞/星形胶质细胞持续激活，可以部分抵消短期运动对疼痛的缓解作用；此外，研究人员检测了受损坐骨神经的再生情况，发现与长期运动的小鼠相比，短期运动可加速小鼠受损坐骨神经的再生^[43]，这提示“短而适度”的初期干预更加有利。这也是“短期有效、长期未必优势”的代表性证据之一^[44]。

在可持续性方面，Almeida等^[45]的研究显示：持续5周的游泳运动不仅能正常化CCI模型大鼠脊髓星形胶质细胞的表达，且在停止运动4周后仍能够维持此效应。Sun等^[46]的研究证实：持续3周的跑步训练通过抑制脊髓背角星形胶质细胞增殖，从而缓解SNI模型小鼠的疼痛。这些研究均表明运动周期是影响脊髓胶质细胞活性的关键因素。

运动周期与运动强度、类型等因素共同对胶质细胞活性产生影响。短期中等强度有利于快速抑制胶质活化与缓解疼痛，部分模型中持续中长期训练可维持或巩固镇痛与抗炎效应，但也可能因“负荷-恢复”失衡出现适应性减效。因此，建议未来研究在统一动物模型与时间窗的前提下，系统比较不同“运动周期×运动强度×运动类型”对胶质细胞[GFAP、离子化钙结合适配分子1(ionized calcium-binding adapter molecule 1，IBA-1)、表型标志与转录谱]的连续影响曲线，并纳入停训后的随访窗口以评估EIA的持续性。

2.1.3 运动频率

运动频率同样是影响胶质细胞与镇痛效应的重要因素。Sumizono等^[47]对比高频率(每周5 d)和低频率(每周3 d)跑步训练发现：二者均能抑制CCI模型大鼠脊髓小胶质细胞/星形胶质细胞激活，但高频率运动通过更显著下调BDNF的表达并上调内源性阿片肽，展现出更强的镇痛效果。Sumizono等^[48]进一步研究发现：低频率运动(每周1次，共5周)虽然仍通过C-C趋化因子受体2(C-C motif chemokine receptor 2，CCR2)/肿瘤坏死因子受体相关因子6(tumor necrosis factor receptor-associated factor 6，TRAF6)抑制脊髓胶质细胞活化，降低脊髓IBA-1/GFAP的表达，但与高频率运动(每周5次)相比，低频率运动对缓解CCI大鼠疼痛的效果出现波动，且对脊髓CCR2/TRAF6的表达和脊髓胶质细胞活化的抑制作用不如高频率运动。综上所述，运动干预的强度、周期及频率共同影响胶质细胞的表型与功能，短期、高频率的中等强度或高强度间歇运动可能通过抑制促炎通路、促进神经营养因子平衡，更有效缓解疼痛，而持续的高强度和长期运动需谨慎设计以避免潜在的反向效应^{[23, 37]}。

鉴于频率与强度/周期存在耦合，当前多为单因素对比的动物研究难以给出处方化结论；未来应采用多因素试验明确最佳的“运动频率×周期×强度×类型”组合，并统一/细化运动模式的定义(强度、周期、频率)。同时，建议研究不同运动模式对同一疼痛动物模型或同一运动模式对不同疼痛动物模型的胶质细胞的特异性调控机制；研究设计中应纳入代谢物(如乳酸)、恢复窗口期与性别差异等关键变量，以优化EIA的治疗方案并提升临床转化价值^{[39, 42]}。

2.2 运动对脊髓小胶质细胞/星形胶质细胞炎症通路的抑制作用

2.2.1 运动下调P2X4/P2X7受体的表达

在脊髓背角(lamina Ⅰ~Ⅱ)小胶质细胞膜上的 P2X4/P2X7受体为三磷酸腺苷(adenosine triphosphate，ATP)依赖性离子通道。P2X4受体被激活后可促使p38-MAPK磷酸化水平上升，引发小胶质细胞来源的BDNF释放，其后作用于背角神经元的酪氨酸激酶B(tropomyosin receptor kinase B，TrkB)受体，增强伤害性信息传入并引发疼痛^[49-50]。同时，P2X4/P2X7受体的过度活化使促炎性细胞因子(IL-6、IL-1β、TNF-α)的释放增多，促进星形胶质细胞Janus激酶(Janus kinase，JAK)/信号转导及转录激活因子3(signal transducer and activator of transcription 3，STAT3)与MAPK等通路发挥作用，参与慢性疼痛的维持^[20]。已有研究^[28]提示：运动可通过改变中枢细胞外核苷酸谱与胶质嘌呤能受体表型、降低小胶质细胞中P2X4/P2X7受体的活化水平、减少异常上调的BDNF发挥镇痛作用。Grace等^[51]发现：主动跑轮运动6周可诱导坐骨神经结扎的大鼠脊髓同侧背角神经元兴奋性IL-1β的表达正常化，GLT-1的表达减少，抑制小胶质细胞P2X4受体的表达并缓解大鼠神经病理性疼痛。小胶质细胞表面的P2X4受体的表达降低能够抑制小胶质细胞活性，进而降低组织中IL-1β的表达水平，从而减轻神经炎症^[52]。Castillo等^[53]的研究也指出：P2X4受体的表达水平与小胶质细胞M1型/M2型转变相关，抑制小胶质细胞P2X4受体的表达可以减少M1型小胶质细胞，而增加M2型小胶质细胞，从而产生抗炎及镇痛作用。

P2X7与NOD样受体P3(nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3，NLRP3)/半胱氨酸蛋白酶-1(caspase-1)炎症小体密切相关。研究^{[52, 54]}发现：抗阻运动可以抑制大鼠P2X7受体的表达，降低NLRP3/caspase-1和促炎性细胞因子IL-6、IL-1β和TNF-α水平，缓解神经炎症^{[52, 54]}；抑制P2X7可继发性降低星形胶质活化及其下游环氧合酶-2(cyclooxygenase-2，COX-2)、 β-连环蛋白(β-catenin)水平，伴随内脏痛缓解^[55]。运动可能通过抑制脊髓小胶质细胞/星形胶质细胞P2X4-p38-BDNF轴与P2X7-NLRP3/caspase-1轴，共同降低胶质细胞活化，发挥镇痛作用。

2.2.2 运动抑制BDNF/Akt/mTOR通路

BDNF在神经系统具有双相作用：在生理状态下参与神经可塑与保护^[56]；而当周围神经受损时，除了损伤部位，背根神经节及脊髓背角神经元和胶质细胞中BDNF及神经营养因子的表达也增加^[57]。PI3K是一种磷脂酰肌醇激酶，在神经元分化、再生、突触可塑性等过程中有重要作用，PI3K激活后可以将细胞膜上的磷脂酰肌醇-4,5-二磷酸(phosphatidylinositol-4,5-bisphosphate，PIP2)磷酸化为磷脂酰-3,4,5-三磷脂(phosphatidylinositol-3,4,5-trisphosphate，PIP3)，后与有PIP3结合域的丝氨酸/苏氨酸激酶(磷酸肌醇依赖的蛋白激酶1，PDK1)结合，PDK1将Akt磷酸化激活PI3K/Akt信号通路^[58]。BDNF和Akt与小胶质细胞上的TrkB受体结合后激活Ras和ERK，进而激活下游PI3K/Akt信号通路，参与慢性疼痛的产生与维持。运动能够降低脊髓BDNF，进而抑制PI3K/Akt信号通路缓解疼痛^[59]。mTOR是研究最多的Akt下游底物，Akt能够直接或间接磷酸化激活mTOR，有研究^[60]证实mTOR与慢性疼痛的形成关系密切。运动训练可以通过减少神经炎症模型小鼠神经胶质细胞的激活使中枢神经系统中炎症介质和BDNF的表达正常化^[32]。强度逐渐递增的跑台训练可通过增强神经病理性疼痛大鼠的下行抑制系统发挥镇痛作用，并伴BDNF下调与小胶质细胞增殖抑制^[61]。Kang等^[62]通过对小鼠进行跑步机运动训练发现运动能降低PI3K/Akt/mTOR通路相关因子的表达。此外，运动能够抑制mTOR信号通路，并诱导小胶质细胞向M2型极化、促进炎症消退^[63]。研究^[64]显示：糖尿病神经病理性疼痛模型大鼠通过4~5周的运动可以显著降低mTOR和IL-6的表达水平，并缓解机械性痛觉过敏。Bai等^[32]研究发现：在SNI模型大鼠中，为期2周的跑步机训练可以抑制BDNF/Akt/mTOR通路，诱导小胶质细胞向M2型极化，从而缓解痛觉过敏。总体来看，运动可以通过纠偏“病理性上调”的BDNF-TrkB→PI3K-Akt-mTOR轴，改善从小胶质细胞到神经元的功能，抑制中枢敏化。

2.2.3 运动抑制IL-6/JAK2/STAT3通路

JAK通过激活STAT3而促进大鼠脊髓胶质细胞激活并导致神经病理性疼痛的发生，IL-6/JAK2/STAT3通路在维持脊髓损伤后慢性疼痛及激活小胶质细胞/星形胶质细胞中起重要作用^[65]。研究表明：JAK2/STAT3通路在不同形式的慢性疼痛中异常激活，包括神经病理性疼痛^[65]，炎性痛^[66]和骨癌痛^[67]。JAK2/STAT3的激活发生在神经损伤后，可以由IL-6家族触发。背根神经节中产生的IL-6可经初级传入纤维刺激脊髓小胶质细胞的JAK2/STAT3信号通路影响胶质细 胞-神经元环路并诱导神经病理性疼痛。此外，小胶质细胞和神经元释放更多的激活物质，如前列腺素、活性氧、促炎性细胞因子、一氧化氮和三磷酸腺苷，增强了神经病理性疼痛^[68]。同时，星形胶质细胞的激活也依赖于JAK2/STAT3信号通路的磷酸化状态^[67]；Tang等^[69]通过鞘内给予雷公藤内酯能够改善SNL诱导的机械性痛觉过敏，并证实雷公藤内酯的镇痛作用是通过抑制JAK2/STAT3信号通路，从而减少脊髓星形胶质细胞的激活来实现的。此外，Lee等^[65]发现，在脊髓损伤(spinal cord injury，SCI)模型大鼠中，JAK2/STAT3信号通路在脊髓小胶质细胞/星形胶质细胞中被激活，并参与SCI引起的机械性和热痛觉过敏，通过下调IL-6可以抑制JAK2/STAT3信号通路缓解脊髓损伤引起的痛觉过敏。Wang等^[70]的研究表明：高强度间隙运动能促进骨关节炎(osteoarthritis，OA)大鼠L_3~5脊髓节段小胶质细胞向M2型极化，减少促炎性细胞因子(IL-6、TNF-α)和疼痛相关神经递质的释放，并抑制JAK2/STAT3信号通路从而缓解OA疼痛和炎症。综上，运动能够降低IL-6的水平，进而抑制JAK2/STAT3信号通路的活化，从而减少胶质细胞的活化，是运动干预缓解中枢敏化的路径之一。

2.2.4 运动下调p38-MAPK信号

MAPK家族在细胞信号转导和基因表达中发挥重要作用。研究^[71-73]显示：脊髓小胶质细胞内MAPKs通路参与慢性疼痛的发生和发展；p38、JNK和ERK激活后会进一步调控转录因子c-Jun的活性，促进细胞因子的转录和脊髓伤害感受性神经元的敏化。p38-MAPK是MAPK家族中的重要成员，在细胞应激反应和炎症反应中发挥关键作用，也在疼痛的发生和维持中扮演重要角色。p38-MAPK在小胶质细胞/星形胶质细胞中被激活后，会促进其释放多种促炎介质(如TNF-α、IL-1β和IL-6)。这些介质进一步激活周围的神经元，增加其兴奋性，导致疼痛感受增强。Gong等^[74]发现：2周的跑轮运动抑制了大鼠脊髓背角p38的过度表达，与p38抑制剂SB203580 处理的结果一致，改善了吗啡引起的痛觉过敏和耐受性。研究^[29]发现，在CCI模型大鼠中，SB203580处理后，诱导M1型小胶质细胞向M2型小胶质细胞转化，并降低脊髓背角小胶质细胞激活标志物IBA-1的表达，减轻了神经病理性疼痛；在CCI模型小鼠中，SB203580的处理也可抑制CCI小鼠脊髓星形胶质细胞的激活，改善机械性异常痛觉过敏^[30]。运动通过下调p38-MAPK轴，在多个层面减弱小胶质细胞/星形胶质细胞促炎作用及神经元兴奋性，是其缓解痛觉过敏的重要机制。

2.2.5 运动抑制TLR4/NF-κB 信号通路

TLR4是一种模式识别受体，TLR4在免疫细胞和小胶质细胞/星形胶质细胞中高度表达；NF-κB是一种转录因子，调节多种基因的表达，包括促炎性细胞因子、趋化因子和黏附分子；NLRP3是一种炎症小体的核心成分，负责检测细胞内的应激信号。NLRP3炎症小体的激活可以导致caspase-1的激活，从而促使促炎性细胞因子IL-1β和IL-18的成熟和释放。TLR4在脊髓小胶质细胞/星形胶质细胞中被激活后，通过髓样分化因子88(myeloid differentiation factor 88，MyD88)依赖性途径激活NF-κB，NF-κB进一步上调NLRP3和pro-IL-1β的表达，NLRP3炎症小体的激活导致caspase-1的激活和IL-1β的成熟、释放，进而增强疼痛信号传递。NF-κB是诱导炎症基因表达的关键转录因子，脊髓小胶质细胞/星形胶质细胞中TLR4/NF-κB通路的表达上调会诱导神经病理性疼痛的发生^[20]。Sun等^[31]的研究证实：为期1个月的被动步行训练可以通过抑制脊髓背角胶质细胞的激活抑制TLR4/NF-κB信号通路，降低促炎性细胞因子IL-1β、IL-6、IL-18和TNF-α的表达水平，抑制痛觉过敏反应。目前，关于TLR4/NF-κB信号通路在EIA中作用的相关研究较少，在深入研究EIA的分子机制中值得继续关注(图2)。

3 结语与展望

运动能显著减轻疼痛，其所涉及的机制复杂。近年来，运动疗法通过抑制神经胶质细胞的活化发挥其镇痛作用已愈发得到研究人员的关注。EIA分子机制涉及调控嘌呤能系统、BDNF/Akt/mTOR通路、IL-6/JAK2/STAT3通路、p38-MAPK通路及TLR4/NF-κB通路等的协同调控。尽管运动疗法可以缓解病理性疼痛，但具体的运动方案的选择仍需进一步探索。由此，面向临床的合理思路不应是“一刀切”的通用方案，而应以“疼痛分型×胶质表型”为核心；根据不同疼痛类型的临床特征，结合未来更加系统性的临床前研究，设计更有针对性的运动方案。例如，神经损伤后疼痛，早期多由小胶质细胞活化促炎主导、中后期以星形胶质细胞活动来维持中枢敏化。建议尽早对患者进行运动干预，早期以低强度短期运动抑制小胶质细胞活化。此后根据患者症状-功能来决定训练方案。对于骨关节炎疼痛，其机制包括星形胶质细胞活化，小胶质细胞与星形胶质细胞串扰等。建议采用游泳这一运动方式，避免其他运动方式增加关节的负荷，通过采用高强度间歇运动抑制脊髓小胶质细胞/星形胶质细胞的活化发挥其镇痛作用。

目前，关于运动模式对胶质细胞影响的实验结果不尽相同，不同的运动模式对炎症的影响可能不同，而不同个体对运动疗法的适应性也存在差异。因此，大样本、多中心的临床及临床前研究，并辅以长期随访，可能为探索最佳的运动治疗方案，进一步为明确病理性疼痛的非药物疗法提供有效参考。

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基金资助

国家自然科学基金(82472612)

国家自然科学基金(82074564)

延安大学研究生创新计划项目(YKY2025070┫。This work was supported by the National Natural Science Foundation ┣82472612)

延安大学研究生创新计划项目(82074564)

the Yan’an University Graduate Innovation Program Project(YKY2025070)

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