Abstract
临床应用上千年的开窍中药龙脑、麝香、石菖蒲、苏合香、樟脑的主要成分是脂环化合物,可用于治疗神经病理性疼痛。开窍中药的镇痛作用机制包括调控γ-氨基丁酸、 N-甲基- D-天冬氨酸等受体的表达,调节离子通道功能,抑制炎症反应、氧化应激、细胞凋亡,调控神经传递和神经元兴奋性,参与神经保护和神经功能修复等。未来可以从深入探索开窍中药在中枢系统镇痛中的作用机制、高质量快速筛选药物作用靶点、利用开窍中药特性研发靶向制剂等方面进行拓展。本文综述了上述传统开窍中药治疗神经病理性疼痛的机制研究进展,并提出了一些拓展研究的方向。
Abstract
The Chinese herbal medicine for Kaiqiao, such as borneol, musk, grassleaf sweetflag rhizome, storax and camphor, have been prescribed in traditional Chinese medicine for thousands of years and now are widely used for neuropathic pain, the main components of which are annular compounds. Studies have shown that their analgesic mechanisms include regulating the expression of γ-aminobutyric acid, N-methyl- D-aspartic acid and other receptors; regulating ion channel function; inhibiting inflammatory response, oxidative stress and apoptosis; regulating neurotransmission and neuronal excitability; and participating in neuroprotection and neurological repair. It is suggested that the mechanisms of action of Kaiqiao herbs in central nervous system analgesia should be further explored; high-quality rapid screening of drug targets may be used, and the targeted agents using the characteristics of Kaiqiao herbs would be developed. This article reviews the research progress on the effect mechanism of traditional Kaiqiao herbs in the treatment of neuropathic pain to provide further research directions.
Keywords: Kaiqiao herbs, Neuropathic pain, Borneol, Grassleaf sweetflag rhizome, Musk, Storax, Camphor, Review
完全弗氏佐剂(complete freund’s adjuvant,CFA);γ-氨基丁酸(γ-aminobutyric acid,GABA);瞬时受体电位(transient receptor potential,TRP); -甲基- -天冬氨酸( -methyl- -aspartic acid,NMDA) ;NADPH氧化酶(nicotinamide adenine dinucleotide phosphate oxidase,NOX);Janus激酶(Janus kinase,JAK);信号转导和转录激活子(signal transducer and activator of transcription,STAT);寡聚化结构域样受体热蛋白结构域相关蛋白(NOD-like receptor thermal protein domain associated protein,NLRP);瞬时受体电位香草酸受体(transient receptor potential vanilloid subfamily member,TRPV);
慢性疼痛是当今世界最普遍的健康问题之一,数以百万计的人因为头痛、背痛、关节炎等疾病而苦恼。与急性疼痛不同,慢性疼痛在机体损伤修复后仍长期存在,不仅治疗棘手,而且影响患者心理健康。神经病理性疼痛是由躯体感觉神经系统损伤或疾病引起的慢性疼痛,在一般人群中的患病率高达3%~17%,包括疼痛性多发性神经病、带状疱疹后神经痛、三叉神经痛、中风后疼痛,以及部分神经退行性疾病的中枢疼痛 [1] 。神经病理性疼痛的主要特征包括自发性疼痛、痛觉过敏、痛觉超敏,目前其经典一线治疗药物主要是钙通道调节剂、三环类抗抑郁药物 [2] 。然而这些药物通常不能达到精准治疗的目的,且疼痛缓解效果因人而异。此外,这些药物长期使用会产生较多不良反应。因此,神经病理性疼痛的临床治疗仍面临巨大挑战,亟须探索新的镇痛靶点以及开发新型镇痛药。
中药因其毒副作用小、多靶点作用等优势在预防和治疗神经病理性疼痛中越来越受到研究者的关注。中医药治疗疼痛已有几千年的历史,中医学理论对慢性疼痛病因、病机、病位、证候、预后等方面均有较为系统的论述。许多中药具有镇痛作用,如开窍中药多气味辛香,性善走窜,能启闭开窍,引药上行,使邪气蒙闭心窍之神智昏迷得以复苏,适用于各种邪气壅盛、闭证神昏之证,同时具有止痛功效。临床处方中常运用开窍中药治疗带状疱疹后神经痛 [3] 、三叉神经痛 [4] 等,疗效良好。另外,现代医学认为中枢敏化是神经病理性疼痛维持的关键,开窍中药因其独特的作用部位表现出对中枢系统较强的调节作用。现代药理学研究表明,开窍药对中枢神经系统作用较强,能够调节中枢神经系统、镇痛、抗惊厥、保护心肌细胞、保护脑损伤、促进血脑屏障开放,有镇静、催眠、抗癫痫、抗缺氧、抗炎等多种作用。常见的开窍药有龙脑、麝香、石菖蒲、苏合香、樟脑等,其发挥镇痛作用的主要作用成分为脂环化合物 [5] ( 图1),这些有效成分对于不同类型的神经病理性疼痛具有一定的镇痛作用 [ 6- 8] 。本文通过综述龙脑、石菖蒲、麝香、苏合香、樟脑这五种常用开窍中药及其主要成分在神经病理性疼痛治疗中的研究进展及相关机制,为开窍中药治疗神经病理性疼痛的研发提供参考。
图1 .
龙脑(A)、麝香(B)、樟脑(C)、石菖蒲(D)、苏合香(E)主要成分的化学结构
龙脑的镇痛作用
龙脑(又称冰片)首载于《新修本草》 [9] ,沿用至今已1600多年,分为右旋龙脑(梅片)、 左旋龙脑(艾片)和合成龙脑(机制冰片)。本品辛香芳烈,善走窜开窍,性偏寒凉,为“凉开”之品,兼清热止痛之功。从龙脑香科植物龙脑香的树脂和挥发油中提取精制得到的龙脑结晶是较为纯粹的右旋龙脑,因其不良反应少、安全性高常被用于临床治疗。右旋龙脑的树脂和挥发油中含有多种萜类成分,除龙脑外,尚含草烯、β-榄香烯、石竹烯等倍半萜,齐墩果酸、麦珠子酸、积雪草酸、龙脑香醇酮、龙脑香二醇酮、古柯二醇等三萜化合物 [10] 。
现代药理学研究证明,以双环单萜成分为主的龙脑对冰醋酸诱导的扭体疼痛模型、辣椒素和异硫氰酸烯丙酯诱导的疼痛模型均有较好的镇痛作用 [ 11- 13] 。除在急性疼痛模型中表现出良好的镇痛作用外,近年来,龙脑在神经病理性疼痛中的镇痛作用也逐渐被报道。有研究表明,口服和鞘内注射右旋龙脑均以剂量依赖的方式降低由节段性脊神经结扎诱导的神经病理性超敏反应和足底内注射CFA诱导的炎性超敏反应,而GABA A受体拮抗剂可以完全消除右旋龙脑的镇痛作用 [6] 。GABA能抑制作用的丧失是导致中枢敏化的关键,这可能是由于氯离子内流将GABA从抑制作用逆转为兴奋,从而提高了Ⅰ层神经元输出的兴奋 性 [14] 。 而从传统中药中提取的单萜醇和酮(如龙脑、薄荷醇)对GABA受体具有正向调节作用 [15] ,GABA受体激动剂的外源性给药可以逆转脊神经结扎引起的机械异常性疼痛和痛觉过 敏 [16] , 提示龙脑在对抗由神经损伤引起的神经病理性疼痛时可能是通过激活GABA受体起效的。另有研究表示,右旋龙脑在奥沙利铂诱导的神经病理性疼痛小鼠模型中具有显著的抗痛觉过敏作用 [7] 。TRPA1是一种表达于感觉神经元的非选择性阳离子通道,是化疗药物导致周围神经病理性疼痛的关键物质 [ 17- 18] 。不同途径给予TRPA1拮抗剂均可缓解由不同神经损伤或化疗导致的疼痛敏感程 度 [ 19- 20] , 而龙脑可以消除TRPA1受体激动剂肉桂醛导致的异常性疼痛 [7] ,提示龙脑可能通过阻断TRPA1的传递来缓解化疗药物引起的神经病理性疼痛。研究表明,龙脑能够抑制缺血大鼠脑内一氧化氮合酶、肿瘤坏死因子-α、白介素1β等表达,这些分子与神经元的敏化密切相关 [21] 。进一步推测龙脑抑制中枢神经元敏化或许与其抗炎机制也有关系。
此外,含龙脑的中药复方制剂在临床上也常用于治疗神经病理性疼痛。玄白冰散穴位敷贴配合电针治疗不仅可以缓解带状疱疹后的神经痛,还能有效改善抑郁状态 [3] 。当归活血汤联合外敷含龙脑的制剂可以有效缓解三叉神经痛并减少复发 [22] 。杜雅俊 [4] 运用中药吸入法将含龙脑的中药细粉通过鼻腔吸入治疗原发性三叉神经痛,结果显示所有患者的疼痛均有不同程度缓解。
以上研究表明,龙脑及其复方制剂在神经病理性疼痛的临床治疗中发挥重要的作用。龙脑可以通过多种途径在不同的神经病理性疼痛模型中发挥镇痛作用。但目前大部分研究仅停留在初步作用效果阶段,缺乏深入的机制探究以及精准的靶点调控解析。预测龙脑在离子通道中的调控作用或可成为镇痛机制研究的有价值的方向。
石菖蒲的镇痛作用
石菖蒲首载于《神农本草经》 [23] ,沿用至今已近两千年,为天南星科植物石菖蒲的根茎。本品辛香走窜,苦燥温通,有开窍豁痰、醒神益智、化湿开胃之功,为开窍宁神之要药。临床上多用于热闭神昏、心神不宁、脾胃痞满之证,对中枢系统、心血管系统、消化系统、免疫系统、生殖系统等均有作用。石菖蒲的化学成分复杂多样,除主要有效成分挥发油如β-细辛醚、α-细辛醚、甲基异丁香酚、β-石竹烯外,还有有机酸、倍半萜、黄酮类、多糖等 [24] 。
石菖蒲具有镇静、抗惊厥、抗抑郁、改善学习记忆等多种药理作用,能够维持细胞功能形态、影响神经递质的传递、保护神经细胞、促进神经发 生 [ 25- 26] 。 石菖蒲在现代医学中的应用主要集中于治疗神经系统相关性疾病,如阿尔茨海默病、抑郁症、癫痫等 [ 8, 27- 28] 。近年来,很多研究发现,石菖蒲在治疗神经病理性疼痛中也发挥很好的镇痛作用。石菖蒲挥发油的主要成分是α-细辛醚和β-细辛醚。研究表明,α-细辛醚能够抑制慢性缩窄性损伤诱导的内质网应激,以肝脏X受体β依赖的方式缓解痛觉过敏 [29] 。内质网应激会导致小胶质细胞的活化,进而参与神经病理性疼痛 [30] 。α-细辛醚是一种内质网应激抑制剂,可以高效缓解内质网应激和神经炎症 [31] 。以上研究表明,α-细辛醚主要通过其抗炎机制发挥镇痛作用。另有研究指出,口服α-细辛醚可以抑制小鼠热伤害感受和福尔马林诱导的炎性疼痛,而咖啡因和纳洛酮可以逆转这种镇痛作用 [32] ,提示腺苷能和阿片能系统可能参与了α-细辛醚对炎性疼痛的镇痛作用。但也有报道表明,α-细辛醚在CFA诱导慢性炎性疼痛伴抑郁模型中,可以通过调节基底外侧杏仁核中神经传递和神经元兴奋性缓解抑郁样症状,并不影响伤害性感受阈值 [33] 。这可能是由于石菖蒲在CFA诱导的慢性炎性疼痛的治疗前后期介导不同的分子机制所致。
此外,研究发现,石菖蒲挥发油可以减少CFA诱导的大鼠炎性疼痛模型脊髓背角NMDA亚型的表达 [34] ,减少基底外侧杏仁核中星形胶质细胞的表达 [35] 。NMDA是一种离子型谷氨酸受体,可产生兴奋性谷氨酸诱发的电流,介导中枢敏化,参与慢性疼痛的发生和发展 [36] 。小胶质细胞及初级传入的炎性信号会诱发星形胶质细胞激活 [37] ,活化的星形胶质细胞会引起炎症反应;另外,星形胶质细胞的光遗传学激活可以诱导小鼠的疼痛超敏反应 [38] 。研究表明,药物激活星形胶质细胞的自噬可以改善慢性缩窄性损伤引起的神经病理性疼 痛 [39] 。 星形胶质细胞可以通过释放NMDA受体共激动剂来调节NMDA受体激活 [40] ,抑制星形胶质细胞上Sigma-1受体(可增加NMDA受体磷酸化),减轻坐骨神经损伤引发的疼痛 [41] 。提示石菖蒲挥发油可能通过调控星形胶质细胞和NMDA受体的表达,影响神经元的兴奋性,从而发挥神经保护作用,具体机制有待进一步研究。
在临床中,含有石菖蒲的中药复方制剂常用于治疗颈部以上的神经病理性疼痛,如针灸联合头痛圣愈方用于治疗偏头痛 [42] ;李永宸教授针对痰瘀阻络的病机,运用加味温胆汤治疗三叉神经痛 [43] ;张允岭教授认为远志汤以石菖蒲配伍远志可以在改善睡眠记忆的同时缓解头痛 [44] 。石菖蒲及其复方制剂在临床镇痛运用中效果显著,其镇痛机制主要与其抗炎特性相关,但因涉及范围较广,靶向性差 [ 45- 47] 。石菖蒲及其复方制剂具有较好的神经保护和调节神经元兴奋性的作用 [ 48- 49] 。下一步可以考虑从神经环路调控着手,解析石菖蒲对中枢系统的作用机制,以期实现精准靶向性镇痛。
麝香的镇痛作用
麝香首载于《神农本草经》 [23] ,为鹿科动物林麝、马麝或原麝成熟雄体香囊中的干燥分泌物。本品辛温气香、行善走窜,有开窍醒神、活血通经、消肿止痛之功,为“温开”之品,临床应用于神经系统、心血管系统、呼吸系统、消化系统等。除了主要有效成分麝香酮之外,国内外学者还从麝香中提取出了其他有效成分,主要包括甾体类、大环酮类和多肽蛋白质类化合物等 [50] 。
麝香具有保护脑损伤、保护心肌细胞、抗炎等药理作用,其机制包括抑制细胞凋亡和炎症,减少钙内流和氧化应激,通过激活血管内皮生长因子的表达促进血管生成等 [ 51- 54] 。麝香酮可以延长醋酸引起的小鼠疼痛反应的潜伏期 [55] ;单独使用麝香酮对热伤害感受无影响,但可以降低氯胺酮对小鼠的镇痛催眠作用 [56] 。麝香酮通过抑制NOX4/JAK2-STAT3通路以及NLRP3炎性小体的产生抑制小胶质细胞激活所介导的炎症反应,从而缓解CFA诱导的炎症性疼痛 [57] 。上述研究提示,麝香酮可能只对部分伤害感受具有缓解作用,与其抗炎机制相关。尽管麝香对于神经病理性疼痛的作用机制目前研究较少,但临床研究证实,其复方制剂在治疗神经病理性疼痛方面发挥着重要作用。元麝止痛液外用擦涂可以缓解不同癌性疼 痛 [58] ; 麝香止痛酊、前列地尔联合六神丸均可以有效缓解带状疱疹后的神经痛 [ 59- 60] 。有待进一步阐明麝香及其复方制剂的镇痛机制,从而为扩大麝香的临床应用范围提供有力的理论依据。
苏合香的镇痛作用
苏合香首载于《新修本草》 [9] ,沿用至今已有一千多年,为金缕梅科植物苏合香树的树干渗出的香树脂经加工精制而成。本品性温气香,作用似龙脑而力稍逊,善治寒闭,能温散寒凝气滞,止痛效果佳。苏合香的主要成分包括萜类、黄酮类、酚酸类、苯丙素类、挥发油类等,其中苯甲酸、苯甲酸苄酯、肉桂酸苄酯、肉桂酸肉桂酯的含量较高,其主要有效成分为肉桂酸 [61] 。
研究表明,苏合香对醋酸所致小鼠扭体反应有一定的镇痛作用 [62] 。另外,苏合香对中枢神经系统具有镇静和抗惊厥的作用,通过抑制GABA转氨酶的活性抑制中枢神经系统,从而发挥抗惊厥的作用 [63] 。维持中枢神经系统GABA与谷氨酸的平衡对于治疗神经病理性疼痛也是极为重要的环节。此外,体外实验表明,苏合香通过抑制核因子κB活化保护原发性星形胶质细胞 [64] ,早期干预可促进脑缺血大鼠的神经功能修复 [65] ,对四氯化碳诱导的氧化应激有预防和保护作用 [66] 。抗氧化应激和神经保护作用在慢性疾病的预防和治疗中具有重要意义,这为苏合香应用于神经病理性疼痛提供新的治疗思路。近年发现,苏合香丸可以缓解巅顶头痛 [67] ,含苏合香的中药配方可用于治疗三叉神经痛 [ 68- 69] 。长久以来,苏合香用于治疗心脑血管疾病,新的临床应用和药理学研究表明,苏合香在神经病理性疼痛的治疗中也具有“老药新用”的巨大潜能。
樟脑的镇痛作用
樟脑首载于《集验方》 [70] ,沿用至今已有八百多年,为樟科植物樟的枝、叶及根部经精炼制得的颗粒状结晶。本品味苦辛、性温热、气芳香,具有通关窍、利滞气、杀虫止痒、消肿止痛的功效。樟脑的主要成分为右旋樟脑,一种萜类化合物,是世界上最早应用的天然有机化学药物之一 [71] 。
研究表明,樟脑的药理作用广泛,内服具有兴奋中枢系统兼强心之功,外用可以消炎、镇痛、驱虫 [ 72- 73] 。目前认为,樟脑的镇痛作用主要与TRP离子通道蛋白有关。TRPA1与伤害性感受有显著的相关性 [74] ,樟脑可以完全抑制TRPA1介导的基础电流 [75] ,减轻肉桂醛诱导的伤害性反应 [76] 。同时研究发现,樟脑通过抵抗非选择性TRP拮抗剂钌红来抑制青蛙坐骨神经干复合动作电位,抑制神经传导,但其抑制的功效不如龙脑 [77] 。虽然樟脑对TRPV1的激活效果较辣椒素差,但可使TRPV1更快、更彻底地脱敏,且在浓度足够的情况下可以产生显著的镇痛作用 [75] 。此外,反复使用樟脑可以抑制热伤害感受,这可能与对温度敏感的TRPV1~4受体相关 [78] 。
樟脑是现代临床常用的成分,可通过肌肉注射缓解乳房肿胀引起的疼痛 [79] 。临床上常见的伤湿止痛膏、活血止痛散等也都含有樟脑的成分 [80] 。此外,二乌膏贴于患处可用于治疗坐骨神经痛 [81] ;含有樟脑的复方贴剂敷贴于患处可治疗三叉神经痛 [82] ;樟脑酒精可用于神经痛、肌肉痛、关节痛的治疗 [83] 。可见樟脑的镇痛作用在临床应用广泛。
目前认为,樟脑的镇痛作用主要与TRP通道的调节相关,涉及外周及中枢神经系统,但镇痛机制的研究大多停留在分子层面,无法做到精准止痛。今后可以考虑从更多类型的神经病理性疼痛模型入手,探究樟脑镇痛的环路甚至基因层面的机制。
应用于神经病理性疼痛的开窍中药研发思考
基于上述研究,开窍药镇痛的主要作用机制与其抗炎、神经保护、抗氧化应激、免疫调节有关,同时也包括腺苷能、阿片能系统的参与,见 图2。这些机制研究为开窍药研发提供了一定的理论依据,未来需要结合先进的技术手段深入探究药物镇痛机制、高质量筛选药物作用靶点,以期为开窍中药的研发提供新颖、科学的指导。
图2 .
常用开窍药在神经病理性疼痛治疗中的作用机制
开窍中药可通过抑制脑内一氧化氮合酶(NOS)、一氧化氮、肿瘤坏死因子(TNF)-α、白介素(IL)1β的表达或减少炎性小体、内质网应激、由超氧阴离子和羟自由基等引起的氧化应激,进而抑制小胶质细胞的活化以及星形胶质细胞活化引起的炎症反应,从而抑制中枢敏化,发挥镇痛作用. 开窍中药可通过直接或间接抑制 N-甲基- D-天冬氨酸(NMDA)受体的表达,调节神经元兴奋性,进而调控中枢参与镇痛. 开窍中药可通过调控瞬时受体电位(TRP)通道中的TRP香草酸受体(TRPV)1和TRPA1的表达,抑制神经传导. 氯离子内流可以引导γ-氨基丁酸(GABA)从抑制转为兴奋,开窍中药还通过激活GABA受体的抑制作用进而调节神经元兴奋性.
深入探索开窍药在中枢系统镇痛中的作用机制
目前,开窍药在神经病理性疼痛中的作用机制研究相对分散,缺乏研究深度,且部分药物在典籍记载及临床应用中具有止痛功效,但机制尚未阐明,临床应用受限。通过光遗传学、药理遗传学等调控手段对神经环路或神经元类型进行解析,可以进一步阐释开窍药在中枢系统镇痛中的作用机制,从而揭示开窍药“启闭开窍”的中医学理论。另外,焦虑、抑郁等不良情绪在神经病理性疼痛中普遍存在 [84] ,且随疼痛的发展进程产生变 化 [85] 。 研究发现,龙脑可以缓解小鼠的恐惧和焦虑情绪 [86] ,麝香酮可以抑制炎症反应而产生抗抑郁作用 [87] 。开窍药对中枢系统的调节作用使其有益于情绪障碍的改善。利用选择性调控、行为学分析手段深入解析疼痛伴焦虑、疼痛伴抑郁等疼痛共患病的发病机制,有望拓展开窍药在神经病理性疼痛中的治疗前景。
高质量快速筛选药物作用靶点
开窍药以多成分、多靶点、多途径的特点在疾病预防和治疗中发挥作用,涉及多种受体、细胞因子和通路。如何高质量、快速地筛选药物作用靶点是亟待解决的问题。网络药理学将网络生物学与多重药理学相结 合 [88] , 可以预测疾病治疗的潜在靶点和作用机制 [ 89- 90] 。将网络药理学和计算机辅助药物设计技术相结合,通过计算机模拟对接方法对中药的靶点进行预测和识别,运用蛋白质组学和生物芯片技术在实验水平上对已识别的候选靶点进行直观验证,从而实现镇痛作用靶点的高效筛选。
结语
综上所述,开窍药以其独特的“开窍”特性,在缓解神经病理性疼痛中发挥着重要的作用。深入研究开窍中药的镇痛机制可以为临床用药提供更科学的指导。随着现代科学研究技术的更新和开窍中药机制研究的深入,开窍药与新型制剂的结合可以实现精准靶向给药。运用多种给药方式及联合治疗,如芳香疗法、汤贴联合,发挥开窍药“辛香走窜”“启闭开窍”的优势,通瘀通阻,引药上行,解决服药难、吸收难的问题,可使开窍药在临床神经病理性疼痛中发挥更好的治疗作用。
除了用于治疗疼痛,利用开窍中药特性还可以开发更多应用。开窍药的脂溶性结构是其顺利通过血脑屏障的基础,可以考虑将开窍药与其他难以透过血脑屏障的镇痛药物联合应用,引药上行,促进药物入脑,在减少药物剂量的同时发挥更好的疗效。另外,开窍中药如龙脑是较好的脑靶向递送系统增强剂,可以增强药物的渗透和转运并调节紧密连接相关蛋白的表达 [ 91- 92] 。以开窍药物的构型作为材料外包结构,包载其他镇痛药入脑,亦能达到增效减毒、精准治疗的目的。
COMPETING INTERESTS
所有作者均声明不存在利益冲突
Funding Statement
浙江省自然科学基金(LD22H310003); 浙江中医药大学基本科研能力提升项目(2021JKJNTZ010B)
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