电针单穴与腧穴配伍对失眠大鼠血清中白介素-1β、脑源性神经生长因子等睡眠-觉醒相关因子含量的影响
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摘要
目的:通过观察电针刺激单穴与腧穴配伍对对氯苯丙氨酸(PCPA)致失眠大鼠血清内源性睡眠-觉醒调节相关因子白介素-1β(IL-1β)、脑源性神经生长因子(BDNF)、前列腺素D2(PGD2)、褪黑激素(MLT)和皮质酮(CORT)含量的影响,探讨电针单穴与腧穴配伍对失眠的调节效应差异及其作用机制。方法:SD大鼠随机分为正常组、模型组、神门组、百会组、三阴交组、神门-百会-三阴交组(配伍组),每组9只。采用连续2d腹腔注射PCPA悬浊液(300 mg/kg)建立失眠大鼠模型,各治疗组分别电针"百会"或双侧"神门""三阴交""神门+百会+三阴交"穴,每次30min,1次/d,连续4d。治疗后比较各组大鼠睡眠潜伏期(SL)和睡眠时间(ST);ELISA法检测血清IL-1β、BDNF、MLT、PGD2和CORT的含量。结果:与正常组相比,模型组SL明显延长(P<0.01),ST显著缩短(P<0.01);与模型组比较,神门组、百会组与配伍组的SL均显著缩短(P<0.05,P<0.01),各单穴组与配伍组ST明显延长(P<0.05,P<0.01);与各单穴组相比,配伍组大鼠的SL明显缩短、ST显著延长(P<0.05)。与正常组相比,模型组血清IL-1β、BDNF、PGD2和MLT的含量显著降低(P<0.05),CORT的含量显著升高(P<0.05);与模型组相比,单穴组和配伍组血清IL-1β、BDNF、PGD2和MLT的含量显著升高(P<0.05),CORT的含量明显降低(P<0.05);配伍组IL-1β、BDNF、PGD2的含量显著高于百会组和三阴交组(P<0.05),MLT的浓度显著高于所有单穴组(P<0.05),CORT的浓度明显低于神门组和三阴交组(P<0.05)。结论:电针单穴"神门""百会"或"三阴交"和腧穴配伍均可改善大鼠的睡眠状况,此效应可能与提高血清中IL-1β等促睡眠因子和下调促觉醒因子CORT的含量有关,并且腧穴配伍应用的调节作用总体上要优于单穴。
Objective To observe the effect of electroacupuncture(EA)stimulation of single and multiple acupoints on sleep and concentrations of interlukin-1β(IL-1β),brain-derived neurotrophic factor(BDNF),prostaglandin D2(PGD2)and melatonin(MLT,sleep-promoting factors)and corticosterone(CORT,awakening-promoting factor)in the serum in insomnia rats,so as to explore its efficacy difference and the mechanism underlying improving sleep.Methods Fifty-four male SD rats were randomly divided into control,model,EA-Baihui(GV 20),EA-Shenmen(HT 7),EA-Sanyinjiao(SP 6)and EA-GV 20+HT 7+SP 6 groups(n=9 rats in each group).The insomnia model was established by intraperitoneal injection of para-chlorophenylalanine(PCPA,300 mg/kg)once daily for 2 days.In the EA-GV 20,EA-HT 7,EA-SP 6 and EA-GV 20+HT 7+SP 6 groups,EA stimulation was administrated for 30 min,once a day for 4 days.The sleep onset latency and sleep duration were measured after intraperitoneal injection of pentobarbital sodium(35 mg/kg).The concentrations of IL-1β,BDNF,MLT,PGD2 and CORT in the serum were detected by ELISA.Results After EA stimulation of GV 20,HT 7,SP 6 and GV 20+HT 7+SP 6,the sleep latency was significantly shortened(P<0.05,P<0.01,except SP 6),and the sleep duration was remarkably prolonged in comparison with the model group(P<0.05,P<0.01),and the therapeutic effects of EA-GV 20+HT 7+SP 6 were significantly superior to those of EA-GV 20,EA-HT 7 and EA-SP 6 in shortening the sleep latency and lengthening the sleep duration(P<0.05).Following modeling,the concentrations of IL-1β,BDNF,PGD2 and MLT were significantly down-regulated,and the CORT level was markedly upregulated in the model group relevant to the control group(P<0.05).Following EA,modeling induced dramatic decrease of serum IL-1β,BDNF,PGD2 and MLT was considerably up-regulated,and the increased CORT level markedly down-regulated in the EA-GV 20,EA-HT 7,EA-SP 6 and EA-GV 20+HT 7+SP 6 groups(P<0.05).The effects of EA-GV 20+HT 7+SP 6 were evidently superior to those of EA-GV 20 and EA-SP 6 in up-regulating serum IL-1β,BDNF and PGD2 levels,and to those of HT 7,GV20 and SP 6 in up-regulating serum MLT level,and significantly superior to those of EA-ST 7 and EA-SP 6 in down-regulating serum CORT(P<0.05).Conclusion EA stimulation of HT 7,GV 20,SP 6 and GV 20+HT 7+ SP 6 can significantly improve the sleep in insomnia rats,which is closely associated with its effects in regulating serum sleep-promoting factors and awakeningpromoting factor.Joint administration of EA of GV 20+HT 7+ SP 6 has a better effect than the single acupoint mentioned above.
Objective To observe the effect of electroacupuncture(EA)stimulation of single and multiple acupoints on sleep and concentrations of interlukin-1β(IL-1β),brain-derived neurotrophic factor(BDNF),prostaglandin D2(PGD2)and melatonin(MLT,sleep-promoting factors)and corticosterone(CORT,awakening-promoting factor)in the serum in insomnia rats,so as to explore its efficacy difference and the mechanism underlying improving sleep.Methods Fifty-four male SD rats were randomly divided into control,model,EA-Baihui(GV 20),EA-Shenmen(HT 7),EA-Sanyinjiao(SP 6)and EA-GV 20+HT 7+SP 6 groups(n=9 rats in each group).The insomnia model was established by intraperitoneal injection of para-chlorophenylalanine(PCPA,300 mg/kg)once daily for 2 days.In the EA-GV 20,EA-HT 7,EA-SP 6 and EA-GV 20+HT 7+SP 6 groups,EA stimulation was administrated for 30 min,once a day for 4 days.The sleep onset latency and sleep duration were measured after intraperitoneal injection of pentobarbital sodium(35 mg/kg).The concentrations of IL-1β,BDNF,MLT,PGD2 and CORT in the serum were detected by ELISA.Results After EA stimulation of GV 20,HT 7,SP 6 and GV 20+HT 7+SP 6,the sleep latency was significantly shortened(P<0.05,P<0.01,except SP 6),and the sleep duration was remarkably prolonged in comparison with the model group(P<0.05,P<0.01),and the therapeutic effects of EA-GV 20+HT 7+SP 6 were significantly superior to those of EA-GV 20,EA-HT 7 and EA-SP 6 in shortening the sleep latency and lengthening the sleep duration(P<0.05).Following modeling,the concentrations of IL-1β,BDNF,PGD2 and MLT were significantly down-regulated,and the CORT level was markedly upregulated in the model group relevant to the control group(P<0.05).Following EA,modeling induced dramatic decrease of serum IL-1β,BDNF,PGD2 and MLT was considerably up-regulated,and the increased CORT level markedly down-regulated in the EA-GV 20,EA-HT 7,EA-SP 6 and EA-GV 20+HT 7+SP 6 groups(P<0.05).The effects of EA-GV 20+HT 7+SP 6 were evidently superior to those of EA-GV 20 and EA-SP 6 in up-regulating serum IL-1β,BDNF and PGD2 levels,and to those of HT 7,GV20 and SP 6 in up-regulating serum MLT level,and significantly superior to those of EA-ST 7 and EA-SP 6 in down-regulating serum CORT(P<0.05).Conclusion EA stimulation of HT 7,GV 20,SP 6 and GV 20+HT 7+ SP 6 can significantly improve the sleep in insomnia rats,which is closely associated with its effects in regulating serum sleep-promoting factors and awakeningpromoting factor.Joint administration of EA of GV 20+HT 7+ SP 6 has a better effect than the single acupoint mentioned above.
引文
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[3]李萍,岳增辉,谢涛,等.针灸治疗失眠的腧穴配伍研究概述[J].山东中医杂志,2015,34(11):887-889.
[4]王艳,李萍,文琪琦,等.针灸治疗原发性失眠症的研究进展[J].上海针灸杂志,2016,35(7):768-772.
[5]文琪琦,刘丽,陈小丽,等.基于现代文献分析腧穴配伍效应的影响因素[J].上海针灸杂志,2016,35(3):253-256.
[6]赵越,王洪峰.基于文献数据挖掘针灸治疗失眠选穴及配伍规律研究[J].世界中西医结合杂志,2018,13(3):315-318.
[7]高巧玲,杨娇娇,王朝辉,等.基于数据挖掘针灸治疗原发性失眠的临床选穴配穴研究概况[J].时珍国医国药,2017,28(9):2296-2298.
[8]HU Y,WANG Y N,ZHANG G Q,et al.Gan-Dan-LiangYi-Tang alleviates p-chlorophenylalanine-induced insomnia through modification of the serotonergic and immune system[J].Exp Ther Med,2016,12(5):3087-3092.
[9]李忠仁.实验针灸学[M].2版,北京:中国中医药出版社,2007:255-257.
[10]魏歆然,魏高文,郑雪娜,等.不同经穴组合针刺对失眠大鼠下丘脑生物钟基因Clock和Bmal 1表达的影响[J].针刺研究,2017,42(5):429-433.
[11]刘艳琴,任玉兰,赵凌,等.基于数据挖掘技术探析针刺治疗失眠症的经穴使用特点[J].中华中医药杂志,2015,30(8):2734-2737.
[12]郭鑫,岳增辉,谢菊英,等.针刺对失眠大鼠血清去甲肾上腺素、多巴胺及5-羟色胺含量的影响[J].中国中医药信息杂志,2018,25(4):46-50.
[13]任毅,陈华德.针灸治疗失眠的研究概况[J].中医临床研究,2011,3(16):52-53.
[14]BUYSSE D J.Insomnia[J].JAMA,2013,309(7):706-716.
[15]付平,贾建平,王葳,等.电针内关和神门穴对脑功能成像不同影响的观察[J].中国针灸,2005,25(1):65-67.
[16]胡吴斌,胡玲,董朝阳,等.电针神门、太渊对正常人事件相关电位P 300影响的比较[J].针刺研究,2013,38(3):186-191.
[17]陈尚杰,刘波,符文彬,等.针刺神门穴和养老穴激活不同脑功能区的功能性磁共振成像研究[J].针刺研究,2008,33(4):267-271.
[18]蒋洁,赵百孝,哈略,等.不同波形电针对PCPA致失眠大鼠下丘脑5-HT和Glu、GABA含量的影响[J].上海针灸杂志,2015,34(7):678-681.
[19]刘振华,王世军.针刺四神聪、百会对失眠大鼠脑组织钟基因及氨基酸类神经递质表达的影响[J].中国老年学杂志,2015,35(21):6067-6069.
[20]王华,梁凤霞.腧穴配伍研究思路和展望[J].中国针灸,2012,32(4):359-362.
[21]张国雪,刘昊,王富春.论腧穴配伍与针灸处方[J].中国针灸,2014,34(10):987-990.
[22]尹红博,王盛春.针刺申脉、照海对原发性失眠多导睡眠图的影响[J].山东中医杂志,2012,31(2):115-116.
[23]KRUEGER J M,WALTER J,DINARELLO C A,et al.Sleep-promoting effects of endogenous pyrogen(interleukin-1)[J].Am J Physiol,1984,246(6Pt 2):R 994-999.
[24]FANG J,WANG Y,KRUEGER J M.Effects of interleukin-1beta on sleep are mediated by the type I receptor[J].Am JPhysiol,1998,274(3Pt 2):R 655-660.
[25]MOLDOFSKY H,LUE F A,EISEN J,et al.The relationship of interleukin-1and immune functions to sleep in humans[J].Psychosom Med,1986,48(5):309-318.
[26]ALAM M N,MCGINTY D,BASHIR T,et al.Interleukin-1beta modulates state-dependent discharge activity of preoptic area and basal forebrain neurons:role in sleep regulation[J].Eur J Neurosci,2004,20(1):207-216.
[27]GIESE M,UNTERNHRER E,HTTIG H,et al.BD-NF:an indicator of insomnia[J].Mol Psychiatry,2014,19(2):151-152.
[28]FARAGUNA U,VYAZOVSKIY V V,NELSON A B,et al.A causal role for brain-derived neurotrophic factor in the homeostatic regulation of sleep[J].J Neurosci,2008,28(15):4088-4095.
[29]SEI H,SAITOH D,YAMAMOTO K,et al.Differential effect of short-term REM sleep deprivation on NGF and BD-NF protein levels in the rat brain[J].Brain Res,2000,877(2):387-390.
[30]SATOH S,MATSUMURA H,NAKAJIMA T,et al.Promotion of sleep by prostaglandin D 2in rats made insomniac by pretreatment with para-chlorophenylalanine[J].Neurosci Res,1994,21(1):41-50.
[31]UENO R,NARUMIYA S,OGOROCHI T,et al.Role of prostaglandin D 2in the hypothermia of rats caused by bacterial lipopolysaccharide[J].Proc Natl Acad Sci U S A,1982,79(19):6093-6097.
[32]BUSCEMI N,VANDERMEER B,HOOTON N,et al.Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction:meta-analysis[J].BMJ,2006,332(7538):385-393.
[33]HAIMOV I,LAUDON M,ZISAPEL N,et al.Sleep disorders and melatonin rhythms in elderly people[J].BMJ,1994,309(6948):167.
[34]刘臻,赵娜,谢晨,等.电针对失眠大鼠睡眠-觉醒昼夜节律及褪黑素节律的影响[J].中华中医药杂志,2016,31(9):3695-3699.
[35]ZHDANOVA I V,WURTMAN R J,LYNCH H J,et al.Sleep-inducing effects of low doses of melatonin ingested in the evening[J].Clin Pharmacol Ther,1995,57(5):552-558.
[36]Melatonin for primary insomnia[J].Drug Ther Bull,2009,47(7):74-77.
[37]ELDER G J,WETHERELL M A,BARCLAY N L,et al.The cortisol awakening response-applications and implications for sleep medicine[J].Sleep Med Rev,2014,18(3):215-224.
[38]SONG H T,SUN X Y,YANG T S,et al.Effects of sleep deprivation on serum cortisol level and mental health in servicemen[J].Int J Psychophysiol,2015,96(3):169-175.
[39]WRIGHT K P J R,DRAKE A L,FREY D J,et al.Influence of sleep deprivation and circadian misalignment on cortisol,inflammatory markers,and cytokine balance[J].Brain Behav Immun,2015,47:24-34.
[40]RODENBECK A,HUETHER G,RUTHER E,et al.Interactions between evening and nocturnal cortisol secretion and sleep parameters in patients with severe chronic primary insomnia[J].Neurosci Lett,2002,324(2):159-163.
[2]白桦,李理,刘法.疏肝汤治疗肝郁化火型失眠症60例临床观察[J].中医药导报,2015,21(12):41-43.
[3]李萍,岳增辉,谢涛,等.针灸治疗失眠的腧穴配伍研究概述[J].山东中医杂志,2015,34(11):887-889.
[4]王艳,李萍,文琪琦,等.针灸治疗原发性失眠症的研究进展[J].上海针灸杂志,2016,35(7):768-772.
[5]文琪琦,刘丽,陈小丽,等.基于现代文献分析腧穴配伍效应的影响因素[J].上海针灸杂志,2016,35(3):253-256.
[6]赵越,王洪峰.基于文献数据挖掘针灸治疗失眠选穴及配伍规律研究[J].世界中西医结合杂志,2018,13(3):315-318.
[7]高巧玲,杨娇娇,王朝辉,等.基于数据挖掘针灸治疗原发性失眠的临床选穴配穴研究概况[J].时珍国医国药,2017,28(9):2296-2298.
[8]HU Y,WANG Y N,ZHANG G Q,et al.Gan-Dan-LiangYi-Tang alleviates p-chlorophenylalanine-induced insomnia through modification of the serotonergic and immune system[J].Exp Ther Med,2016,12(5):3087-3092.
[9]李忠仁.实验针灸学[M].2版,北京:中国中医药出版社,2007:255-257.
[10]魏歆然,魏高文,郑雪娜,等.不同经穴组合针刺对失眠大鼠下丘脑生物钟基因Clock和Bmal 1表达的影响[J].针刺研究,2017,42(5):429-433.
[11]刘艳琴,任玉兰,赵凌,等.基于数据挖掘技术探析针刺治疗失眠症的经穴使用特点[J].中华中医药杂志,2015,30(8):2734-2737.
[12]郭鑫,岳增辉,谢菊英,等.针刺对失眠大鼠血清去甲肾上腺素、多巴胺及5-羟色胺含量的影响[J].中国中医药信息杂志,2018,25(4):46-50.
[13]任毅,陈华德.针灸治疗失眠的研究概况[J].中医临床研究,2011,3(16):52-53.
[14]BUYSSE D J.Insomnia[J].JAMA,2013,309(7):706-716.
[15]付平,贾建平,王葳,等.电针内关和神门穴对脑功能成像不同影响的观察[J].中国针灸,2005,25(1):65-67.
[16]胡吴斌,胡玲,董朝阳,等.电针神门、太渊对正常人事件相关电位P 300影响的比较[J].针刺研究,2013,38(3):186-191.
[17]陈尚杰,刘波,符文彬,等.针刺神门穴和养老穴激活不同脑功能区的功能性磁共振成像研究[J].针刺研究,2008,33(4):267-271.
[18]蒋洁,赵百孝,哈略,等.不同波形电针对PCPA致失眠大鼠下丘脑5-HT和Glu、GABA含量的影响[J].上海针灸杂志,2015,34(7):678-681.
[19]刘振华,王世军.针刺四神聪、百会对失眠大鼠脑组织钟基因及氨基酸类神经递质表达的影响[J].中国老年学杂志,2015,35(21):6067-6069.
[20]王华,梁凤霞.腧穴配伍研究思路和展望[J].中国针灸,2012,32(4):359-362.
[21]张国雪,刘昊,王富春.论腧穴配伍与针灸处方[J].中国针灸,2014,34(10):987-990.
[22]尹红博,王盛春.针刺申脉、照海对原发性失眠多导睡眠图的影响[J].山东中医杂志,2012,31(2):115-116.
[23]KRUEGER J M,WALTER J,DINARELLO C A,et al.Sleep-promoting effects of endogenous pyrogen(interleukin-1)[J].Am J Physiol,1984,246(6Pt 2):R 994-999.
[24]FANG J,WANG Y,KRUEGER J M.Effects of interleukin-1beta on sleep are mediated by the type I receptor[J].Am JPhysiol,1998,274(3Pt 2):R 655-660.
[25]MOLDOFSKY H,LUE F A,EISEN J,et al.The relationship of interleukin-1and immune functions to sleep in humans[J].Psychosom Med,1986,48(5):309-318.
[26]ALAM M N,MCGINTY D,BASHIR T,et al.Interleukin-1beta modulates state-dependent discharge activity of preoptic area and basal forebrain neurons:role in sleep regulation[J].Eur J Neurosci,2004,20(1):207-216.
[27]GIESE M,UNTERNHRER E,HTTIG H,et al.BD-NF:an indicator of insomnia[J].Mol Psychiatry,2014,19(2):151-152.
[28]FARAGUNA U,VYAZOVSKIY V V,NELSON A B,et al.A causal role for brain-derived neurotrophic factor in the homeostatic regulation of sleep[J].J Neurosci,2008,28(15):4088-4095.
[29]SEI H,SAITOH D,YAMAMOTO K,et al.Differential effect of short-term REM sleep deprivation on NGF and BD-NF protein levels in the rat brain[J].Brain Res,2000,877(2):387-390.
[30]SATOH S,MATSUMURA H,NAKAJIMA T,et al.Promotion of sleep by prostaglandin D 2in rats made insomniac by pretreatment with para-chlorophenylalanine[J].Neurosci Res,1994,21(1):41-50.
[31]UENO R,NARUMIYA S,OGOROCHI T,et al.Role of prostaglandin D 2in the hypothermia of rats caused by bacterial lipopolysaccharide[J].Proc Natl Acad Sci U S A,1982,79(19):6093-6097.
[32]BUSCEMI N,VANDERMEER B,HOOTON N,et al.Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction:meta-analysis[J].BMJ,2006,332(7538):385-393.
[33]HAIMOV I,LAUDON M,ZISAPEL N,et al.Sleep disorders and melatonin rhythms in elderly people[J].BMJ,1994,309(6948):167.
[34]刘臻,赵娜,谢晨,等.电针对失眠大鼠睡眠-觉醒昼夜节律及褪黑素节律的影响[J].中华中医药杂志,2016,31(9):3695-3699.
[35]ZHDANOVA I V,WURTMAN R J,LYNCH H J,et al.Sleep-inducing effects of low doses of melatonin ingested in the evening[J].Clin Pharmacol Ther,1995,57(5):552-558.
[36]Melatonin for primary insomnia[J].Drug Ther Bull,2009,47(7):74-77.
[37]ELDER G J,WETHERELL M A,BARCLAY N L,et al.The cortisol awakening response-applications and implications for sleep medicine[J].Sleep Med Rev,2014,18(3):215-224.
[38]SONG H T,SUN X Y,YANG T S,et al.Effects of sleep deprivation on serum cortisol level and mental health in servicemen[J].Int J Psychophysiol,2015,96(3):169-175.
[39]WRIGHT K P J R,DRAKE A L,FREY D J,et al.Influence of sleep deprivation and circadian misalignment on cortisol,inflammatory markers,and cytokine balance[J].Brain Behav Immun,2015,47:24-34.
[40]RODENBECK A,HUETHER G,RUTHER E,et al.Interactions between evening and nocturnal cortisol secretion and sleep parameters in patients with severe chronic primary insomnia[J].Neurosci Lett,2002,324(2):159-163.