王玲燕;夏桂阳;夏欢;王亚男;卫晓红;田贵华;林生;
WANG Ling-yan;XIA Gui-yang;XIA Huan;WANG Ya-nan;WEI Xiao-hong;TIAN Gui-hua;LIN Sheng;State Key Laboratory of Bioactive Substance and Function of Natural Medicines,Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College;Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing,Dongzhimen Hospital,Beijing University of Chinese Medicine;

• 1:中国医学科学院北京协和医学院药物研究所天然药物活性物质与功能国家重点实验室
• 2:北京中医药大学东直门医院中医内科学教育部和北京市重点实验室

摘要(Abstract)：

疼痛是机体对有害刺激的一种保护性防御反应,长期疼痛不仅严重影响患者的躯体,给病人带来极大的痛苦,也给病人家庭和社会带来巨大的经济负担,已成为当今困扰人类健康最严重的问题之一。目前临床常用止痛药为阿片类和非甾体抗炎药(NSAIDs)等,但易造成多种不良反应或存在成瘾性的风险。寻找和开发更安全更有效的新型镇痛药物,已成为医学领域研究的热点及难点。生物碱是广泛存在于动、植物及微生物中的一类天然活性成分,多种生物碱已经明确具有较好的镇痛作用,如以吗啡为代表的阿片类镇痛药物,以及延胡索、附子等传统镇痛中药主要镇痛活性成分均为生物碱类成分。该文综述了已发现的具有镇痛活性的天然生物碱类成分的研究进展,以期为基于天然产物的镇痛药物的研发提供参考和借鉴。
Pain is a protective defense response of the body to harmful stimuli. Long-term pain not only seriously affects the body of the patient and brings great pain to the patient, but also brings huge economic burden to the patient′s family and society. It has become one of the most serious problems affecting human health. At present, opioids and non-steroidal anti-inflammatory drugs(NSAIDs) are commonly used as painkillers, but they tend to cause a variety of adverse reactions or risk of addiction. To find and develop new analgesic drugs, which are safer and more effective, has become the hot spot and difficulty in medical research. A variety of alkaloids derived from terrestrial plants, microorganisms, marine organisms and fungi have been an important source of clinical analgesic medicines. Various alkaloids have been proved to have good analgesic effects, such as morphine and the related to opioids, the main analgesic active components from Corydalis Rhizoma and Aconiti Lateralis Radix Praeparata. Here we summarized the research progress of natural alkaloids with analgesic activity, in order to provide reference for the research and development of analgesic drugs based on natural products.

关键词(KeyWords)： 天然产物;生物碱;镇痛
natural products;alkaloids;analgesic

Abstract:

Keywords:

基金项目(Foundation): 北京市自然科学基金项目(JQ18026);; 国家自然科学基金项目(81773589,81522050,82073978)

作者(Author): 王玲燕;夏桂阳;夏欢;王亚男;卫晓红;田贵华;林生;
WANG Ling-yan;XIA Gui-yang;XIA Huan;WANG Ya-nan;WEI Xiao-hong;TIAN Gui-hua;LIN Sheng;State Key Laboratory of Bioactive Substance and Function of Natural Medicines,Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College;Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing,Dongzhimen Hospital,Beijing University of Chinese Medicine;

Email:

DOI: 10.19540/j.cnki.cjcmm.20200909.201

参考文献(References)：

• [1] COHEN M,QUINTNER J,VAN RYSEWYK S.Reconsidering the international association for the study of pain definition of pain [J].Pain Rep,2018,3(2):e634.
• [2] VOLKOW N D,MCLELLAN A T.Opioid abuse in chronic pain--misconceptions and mitigation strategies[J].New Engl J Med,2016,374:1253.
• [3] CROFFORD L J.Chronic pain:where the body meets the brain [J].Trans Am Clin Climatol Assoc,2015,126:167.
• [4] DUBIN A E,PATAPOUTIAN A.Nociceptors:the sensors of the pain pathway [J].J Clin Invest,2010,120(11):3760.
• [5] MERBOTH M K,BARNASON S.Managing pain:the fifth vital sign[J].Nurs Clin North Am,2000,35(2):375.
• [6] GOLDBERG D S,MCGEE S J.Pain as a global public health priority [J].BMC Public Health,2011,11:770.
• [7] 刘瀛瀛,王宁,罗非.慢性疼痛预测指标的研究进展[J].中国疼痛医学杂志,2014,20(8):580.
• [8] 李谦,过立农,郑健,等.乌头属药用植物的研究进展[J].药物分析杂志,2016,36(7):1129.
• [9] ZHU H Q,XU J,SHEN K F,et al.Bulleyaconitine A depresses neuropathic pain and potentiation at C-fiber synapses in spinal dorsal horn induced by paclitaxel in rats [J].Exp Neurol,2015,273:263.
• [10] SONG D,LU M,LI H,et al.Experimental study on antiinflammatory mechanism of deoxyaconitine [J].Eur J Pharm,1990,183(6):2267.
• [11] AMERI A.The effects of Aconitum alkaloids on the central nervous system [J].Prog Neurobiol,1998,56(2):211.
• [12] NESTEROVA Y V,POVET′YEVA T N,SUSLOV N I,et al.Analgesic activity of diterpene alkaloids from Aconitum baikalensis [J].Bull Exp Biol Med,2014,157(4):488.
• [13] WANG D P,LOU H Y,HUANG L,et al.A novel franchetine type norditerpenoid isolated from the roots of Aconitum carmichaeli Debx.with potential analgesic activity and less toxicity [J].Bioorg Med Chem Lett,2012,22(13):4444.
• [14] GUO Q,XIA H,MENG X,et al.C19-Diterpenoid alkaloid arabinosides from an aqueous extract of the lateral root of Aconitum carmichaelii and their analgesic activities [J].Acta Pharm Sin B,2018,8(3):409.
• [15] ZHAO D K,AI H L,ZI S H,et al.Four new C18-diterpenoid alkaloids with analgesic activity from Aconitum weixiense [J].Fitoterapia,2013,91:280.
• [16] GUO Q,XIA H,SHI G,et al.Aconicarmisulfonine A,a sulfo-nated C20-diterpenoid alkaloid from the lateral roots of Aconitum carmichaelii [J].Org Lett,2018,20(3):816.
• [17] WANG C,WANG S,FAN G,et al.Screening of antinociceptive components in Corydalis yanhusuo W.T.Wang by comprehensive two-dimensional liquid chromatography/tandem mass spectrometry [J].Anal Bioanal Chem,2010,396(5):1731.
• [18] CHU H,JIN G,FRIEDMAN E,et al.Recent development in studies of tetrahydroprotoberberines:mechanism in antinociception and drug addiction [J].Cell Mol Neurobiol,2008,28(4):491.
• [19] LIU Y Y,WANG T X,ZHOU J C,et al.Dopamine D1 and D2 receptors mediate analgesic and hypnotic effects of l-tetrahydropalmatine in a mouse neuropathic pain model [J].Psychopharmacology (Berl),2019,236(11):3169.
• [20] ZHANG Y,WANG C,WANG L,et al.A novel analgesic isolated from a traditional Chinese medicine [J].Curr Biol,2014,24(2):117.
• [21] INGRAM S L.Pain:novel analgesics from traditional Chinese medicines [J].Curr Biol,2014,24(3):R114.
• [22] KüPELI E,KO?AR M,YE?ILADA E,et al.A comparative study on the anti-inflammatory,antinociceptive and antipyretic effects of isoquinoline alkaloids from the roots of Turkish Berberis species [J].Life Sci,2002,72(6):645.
• [23] LIU X,HU Z,SHI Q,et al.Anti-inflammatory and anti-nociceptive activities of compounds from Tinospora sagittata (Oliv.) Gagnep [J].Arch Pharm Res,2010,33(7):981.
• [24] HU J,ZHANG W D,LIU R H,et al.Benzophenanthridine alkaloids from Zanthoxylum nitidum (Roxb.) DC,and their analgesic and anti-inflammatory activities [J].Chem Biodivers,2006,3(9):990.
• [25] 何志敏,佟继铭,宫凤春.白屈菜碱镇痛作用研究[J].中草药,2003,34(9):837.
• [26] 邹翔,王雨蒙,王嘉琪,等.白屈菜碱的药理作用研究进展[J].现代药物与临床,2014,29(11):1326.
• [27] GRYNKIEWICZ G.Synthesis and biological activity of O-acyl and O-alkyl chelidonine derivatives [J].Eur J Med Chem,2001,36(11/12):951.
• [28] SCHIFF J P L.Opium and its alkaloids [J].Am J Pharm Educ,2002,66(2):186.
• [29] 吴世星,吕晓强,杨丽.苦参有效成分镇痛作用的研究进展[J].辽宁中医杂志,2015,42(3):653.
• [30] 王海燕,刘红艳,顿玲露,等.苦参碱对神经病理性疼痛小鼠疼痛行为的干预[J].中国药理学与毒理学杂志,2012,26(3):441.
• [31] 严继贵,杨宇清,王雅洁,等.槐定碱抗骨癌痛作用及其机制研究[J].中国中药杂志,2013,38(23):4134.
• [32] 唐敏,伍冠一,朱婵,等.马钱子碱镇痛研究进展[J].中草药,2014,45(12):1791.
• [33] YU G,QIAN L,YU J,et al.Brucine alleviates neuropathic pain in mice via reducing the current of the sodium channel [J].J Ethnopharmacol,2019,233:56.
• [34] IDOWU T O,IWALEWA E O,ADEROGBA M A,et al.Anti-nociceptive,anti-inflammatory and antioxidant activities of eleagnine:an alkaloid isolated from Chrysophyllum albidum seed cotyledons [J].J Biol Sci,2006,6(6):1029.
• [35] FAZAL-UR-REHMAN,KHAN M F,KHAN I,et al.Analgesic activity of carbazole alkaloid from Murraya paniculata Linn.(Rutaceae) [J].J Agric Environ Sci,2014,14(3):240.
• [36] KUMATIA E K,ANNAN K,DICKSON R A,et al.Anti-inflammatory and analgesic effects in rodent models of ethanol extract of Clausena anisata roots and their chemical constituents [J].Nat Prod Commun,2017,12(1):67.
• [37] RATNAYAKE W,SURESH T S,ABEYSEKERA A M,et al.Acute anti-inflammatory and anti-nociceptive activities of crude extracts,alkaloid fraction and evolitrine from Acronychia pedunculata leaves [J].J Ethnopharmacol,2019,238:111827.
• [38] BANBURY L K,SHOU Q,RENSHAW D E,et al.Compounds from Geijera parviflora with prostaglandin E2 inhibitory activity may explain its traditional use for pain relief [J].J Ethnopharmacol,2015,163:251.
• [39] HIRANITA T,LEON F,FELIX J S,et al.The effects of mitra-gynine and morphine on schedule-controlled responding and antinociception in rats [J].Psychopharmacology,2019,236(9):2725.
• [40] RAFFA R B,BECKETT J R,BRAHMBHATT V N,et al.Orally active opioid compounds from a non-poppy source [J].J Med Chem,2013,56(12):4840.
• [41] STEVEN C.Use of huperzine for neuropathic pain:US8193212B2 [P].2012-06-05.
• [42] KNOTKOVA H,PAPPAGALLO M,SZALLASI A.Capsaicin (TRPV1 agonist) therapy for pain relief:farewell or revival?[J].Clin J Pain,2008,24(2):142.
• [43] MASON L,MOORE R A,DERRY S,et al.Systematic review of topical capsaicin for the treatment of chronic pain [J].Br Med J,2004,328:991.
• [44] LONG Z,ZHANG Y,GUO Z,et al.Amide alkaloids from Scopolia tangutica [J].Planta Med,2014,80(13):1124.
• [45] HELYES Z,NéMETH J,THáN M,et al.Inhibitory effect of anandamide on resiniferatoxin-induced sensory neuropeptide release in vivo and neuropathic hyperalgesia in the rat [J].Life Sci,2003,73(18):2345.
• [46] RE G,BARBERO R,MIOLO A,et al.Palmitoylethanolamide,endocannabinoids and related cannabimimetic compounds in protection against tissue inflammation and pain:potential use in companion animals [J].Vet J,2007,173(1):21.
• [47] PETROSINO S,DI MARZO V.The pharmacology of palmitoylethanolamide and first data on the therapeutic efficacy of some of its new formulations [J].Br J Pharmacol,2017,174(11):1349.
• [48] TASLEEM F,AZHAR I,ALI S N,et al.Analgesic and anti-inflammatory activities of Piper nigrum L.[J].Asian Pac J Trop Med,2014,7:S461.
• [49] TREVISAN G,MALDANER G,VELLOSO N A,et al.Antinociceptive effects of 14-membered cyclopeptide alkaloids [J].J Nat Prod,2009,72(4):608.
• [50] KALEEM W A,MUHAMMAD N,QAYUM M,et al.Antinociceptive activity of cyclopeptide alkaloids isolated from Ziziphus oxyphylla Edgew (Rhamnaceae) [J].Fitoterapia,2013,91:154.
• [51] WANG Y,YANG X,ZHENG X,et al.Theacrine,a purine alkaloid with anti-inflammatory and analgesic activities [J].Fitoterapia,2010,81(6):627.
• [52] SANTOS A R S,MIGUEL O G,YUNES R A,et al.Antinociceptive properties of the new alkaloid,cis-8,10-di-N-propyllobelidiol hydrochloride dihydrate isolated from Siphocampylus verticillatus evidence for the mechanism of action [J].J Pharm Exp Ther,1999,289(1):417.
• [53] NAKAMURA M,CHI Y M,YAN W M,et al.Strong antinociceptive effect of incarvillateine,a novel monoterpene alkaloid from Incarvillea sinensis [J].J Nat Prod,1999,62(9):1293.
• [54] KIM J,BOGDAN D M,ELMES M W,et al.Incarvillateine produces antinociceptive and motor suppressive effects via adenosine receptor activation [J].PLoS ONE,2019,14(6):e0218619.