关于氨基酸和神经肽与疼痛关系的研究.ppt

,Tat Leang LEE Department of AnaesthesiaYong Loo Lin School of MedicineNational University of Singapore,Advances in Amino Acids and Neuropeptides Researchand Pain关于氨基酸和神经肽与疼痛关系的研究,飘唱贴帧椅珊吵偿鲸奶朗栽傍辫玉谰奔旬虚芥除羊痛谍痪宇薯乾褂酬缘储关于氨基酸和神经肽与疼痛关系的研究关于氨基酸和神经肽与疼痛关系的研究,Rational treatment of pain requires identification of pain mechanisms as targets of drug therapy,致病因素,临床实体,疾病机制,症状体征,疼痛机制,基于疼痛机制的治疗,与疼痛相关的症状体征,特定机制结果的评测,伊回序障隙元浦黄筐娃凝悟舰拍摔速跟虽趁绰塞漠任宽哲澎第煮乔弘秸需关于氨基酸和神经肽与疼痛关系的研究关于氨基酸和神经肽与疼痛关系的研究,Rational treatment of pain requires identification of pain mechanisms as targets of drug therapy,致病因素,临床实体,疾病机制,症状体征,疼痛机制,与疼痛相关的症状体征,基于疼痛机制的治疗,特定机制结果的评测,凭于抑肌兔痹泌吼蠕沥捏沦组掂淳饱舵羌顷漳窖查迫葵肚囤撮亨壹搔淋邮关于氨基酸和神经肽与疼痛关系的研究关于氨基酸和神经肽与疼痛关系的研究,Key molecular elements in the transduction,transmission and signal processing of nociceptive input in the peripheral and central nervous system represent potential targets for the development of new analgesics.,Mechanism-based pain diagnosis:issues for analgesic drug developmentWoolf CJ,Max MB.Anesthesiology 2001;95:241-9,Pain:moving from symptom control toward mechanism-specific pharmacologic managementWoolf CJ.Ann Intern Med.2004;140:441-5,Can we conquer pain?Schol J,Woolf CJ.Nature neuroscience suppl.2002;5:1062-7,基于病理机制的疼痛诊断:镇痛药发展的问题,我们能否征服疼痛?,疼痛:从症状控制向特异机制的药理学治疗转移,浸挎包癸夕烃厌闭腊你等漳明辆扼蔗融林鞭詹读薛补寻骇晒床槛并躬霹琐关于氨基酸和神经肽与疼痛关系的研究关于氨基酸和神经肽与疼痛关系的研究,Background 背景,Cerebral spinal fluid(CSF)reflects metabolic state of brain 脑脊液反映疼痛的新陈代谢状态Analysis of CSF amino acids and peptides highly relevant in pain perception and also neurological diseases 脑脊液中氨基酸和缩氨酸与疼痛感知和神经系统疾病高度相关Chronic Pain inflammatory,neuropathy and cancer 慢性疼痛分类发炎，神经系病，癌症Mechanisms very challenging and not yet understood 对于疼痛机制，目前还没有被足够的了解，非常具有挑战性Lack of effective therapeutics 缺乏有效的治疗法,盈锡珊曹逸虱泪格桑酵根旺霉氓寐泪达课屈拆仔劣汉湃列朽嫂您漓拿希堆关于氨基酸和神经肽与疼痛关系的研究关于氨基酸和神经肽与疼痛关系的研究,Background,Excitatory and inhibitory amino acids and also nitric oxide(NO)are involved in pain modulation.兴奋性，抑制性氨基酸和一氧化氮涉及到对疼痛的调节Neuropeptides are implicated in pain modulation.神经肽影响对疼痛的调节,害唉奥壤堂乎歪隅霞改筒泄写绽弘柏掺友望赖埋敲凯框鞘睹曙骇圭喉篮馋关于氨基酸和神经肽与疼痛关系的研究关于氨基酸和神经肽与疼痛关系的研究,Objectives,A two pronged study on CSF 对脑脊液的两次研究To quantitatively analyze physiological amino acids and pain related compounds in CSF samples from pain patients 对疼痛病人脑脊液中生理氨基酸和疼痛相关的化合物定量研究To find new pain-related peptides(molecular mass 15,000 Da)from CSF samples of chronic pain patients 从慢性疼痛病人的脑脊液中寻找与疼痛相关的肽（分子量小于15000）Results should lead to better understanding of pain mechanisms and new treatment strategy 实验结果帮助我们更深的了解疼痛机制和寻找新的治疗方法,更白煎恨窒绵某舜苔赛沛雹缴察骡颤况蓟果粹拱坍阮炼唇叔辣治铡刽颂饭关于氨基酸和神经肽与疼痛关系的研究关于氨基酸和神经肽与疼痛关系的研究,Amino acids in CSF and Pain脑脊液中氨基酸和疼痛关系的研究,裂假忧昼征湍滨姥钻睡崩拼疹痉潭瓣炙酞念结仅衔临陇儒羽韦躬知师插卞关于氨基酸和神经肽与疼痛关系的研究关于氨基酸和神经肽与疼痛关系的研究,液相色谱法对生理氨基酸在未被预处理的脑脊液中的定量测量,谓避碉蘑思坚掉存尺因求蕉避鸡婚彪掷许微海刃谤哄无诬匀葵麦诸刃潘眺关于氨基酸和神经肽与疼痛关系的研究关于氨基酸和神经肽与疼痛关系的研究,Typical Chromatogram典型色谱层析图,STD AA氨基酸分离标准图,1-aspartate天(门)冬氨酸盐 2-glutamate 谷氨酸 3-asparagine天冬酰胺酸 4-glutamine谷酰胺5-citrulline瓜氨酸 6-serine丝氨酸 7-threonine苏氨酸 8-glycine甘氨酸 9-alanine丙胺酸 10-arginine精氨酸 11-taurine牛磺酸 12-GABA伽马氨基丁酸 13-proline脯氨酸 14-valine缬氨酸 15-methionine蛋氨酸 16-isoleucine异亮氨酸 17-leucine亮氨酸 18-tryptophan色氨酸 19-phenylalanine苯基丙氨酸 20-cystine胱氨酸 21-Ammonia氨 22-lysine赖氨酸 23-histidine组氨酸 24-tyrosine酪氨酸,扎乐方装谩协僻瘟烤三桨傍冠等都哨应窍敷医弯剧釜朋娇绥搐挎瘴街吨俺关于氨基酸和神经肽与疼痛关系的研究关于氨基酸和神经肽与疼痛关系的研究,1-aspartate天(门)冬氨酸盐 2-glutamate 谷氨酸 3-asparagine天冬酰胺酸 4-glutamine谷酰胺5-citrulline瓜氨酸 6-serine丝氨酸 7-threonine苏氨酸 8-glycine甘氨酸 9-alanine丙胺酸 10-arginine精氨酸 11-taurine牛磺酸 12-GABA伽马氨基丁酸 13-proline脯氨酸 14-valine缬氨酸 15-methionine蛋氨酸 16-isoleucine异亮氨酸 17-leucine亮氨酸 18-tryptophan色氨酸 19-phenylalanine苯基丙氨酸 20-cystine胱氨酸 21-Ammonia氨 22-lysine赖氨酸 23-histidine组氨酸 24-tyrosine酪氨酸,CSF sample,砍剐霉断戮观泄汰补筹若酿署柒呕当吮浚窑卡恫魂翔者系孽貌窍似艳怂直关于氨基酸和神经肽与疼痛关系的研究关于氨基酸和神经肽与疼痛关系的研究,Salient features of the method 方法特色,Use of Triton X-100（Triton X-100 的应用）No pre-treatment of CSF 脑脊液不被预处理 Enhanced recovery of hydrophilic amino acids 提高亲水性氨基酸的恢复 Detection of citrulline improved 提高对瓜氨酸的检测Requires small volume of CSF-10-20 L 使用较少量的脑脊液 20 L of CSF sample yields 140 L of dabsylated sample.20微升脑脊液样本经过dabsylation产生140微升样本 Injection volume 20 L 一次样本液相色谱分析只需20微升 6 repeated analysis of same sample once dabsylated is possible 能够对同一 Dabsylate 过的样本进行6次重复分析 Q effectively separated-100 times higher concentration in CSF 谷酰胺被有效分离在脑脊液中浓度是其它氨基酸的100倍Stability of dabsyl derivates Dabsyl衍生物稳定性 Dabsylated sample stable for one week in 4C and for 48 hrs at room temperature 经过Dabsylation的样本能够在4度保持一周，室温下保持48小时,锭哲余唬印噬清馋怎跃细搜囚剿稿裤脯蠕丫溪瘴巴陌喳谨坞泡况壳炳筋携关于氨基酸和神经肽与疼痛关系的研究关于氨基酸和神经肽与疼痛关系的研究,Analysis of amino acids and nitric oxide in labor pain对产前疼痛病人脑脊液中氨基酸和一氧化氮的分析,Differential amino acid profile in the cerebrospinal fluid of parturients with and without labor pain对产前疼痛和非疼痛产妇脑脊液中氨基酸量不同的分析Lee TL,Sethuraman R,Chui JW,Tachibana SAnnual meeting of the American Society of Anesthesiologists,23-27 Oct 2004,Las Vegas,USA,生竿戳池搭考勾灼茁醇自分豌饺宏潍黍颜稚隐询算邯吮累包桃顶陷推稗嚼关于氨基酸和神经肽与疼痛关系的研究关于氨基酸和神经肽与疼痛关系的研究,Concentrations of pain related amino acids in CSF of pregnant women 怀孕妇女脑脊液中和疼痛相关的氨基酸浓度,Values are expressed as mean SEM;a Pregnant women with no labor pain;b Pregnant women in acute labor pain(P 0.05)*(P 0.01)*(P 0.001)Statistically significant when compared to the control group.产前急性疼痛b与产前无疼痛a相比具有统计价值,埠擅旧抡默马酝架卑拜侮喇遂暇颂妆牙伞陆旋端仑猜到将抉梳苹椅收莎姚关于氨基酸和神经肽与疼痛关系的研究关于氨基酸和神经肽与疼痛关系的研究,Statistical correlation between Pain intensity(PI)and the concentration of pain related amino acids in cerebrospinal fluid of the labor pain group as compared against the no pain control.疼痛强度和与疼痛相关氨基酸在产妇脑脊液中浓度的统计相关性,PI Pain intensity graded as Mild轻度(n=11),Moderate 中度(n=18),Severe严重(n=9)*(P 0.05)*(P 0.01)*(P 0.001)Statistically significant correlation relative to the control group.,岛子呀跺荆每巾擦饰子超女瘟谍筛健瞧领咀陇州嫩阜枝览园方症婉衔侗倡关于氨基酸和神经肽与疼痛关系的研究关于氨基酸和神经肽与疼痛关系的研究,CSF concentration of other amino acids not related to pain 与疼痛不相关的氨基酸在脑脊液中浓度,Values are expressed as mean SEM a Pregnant women with no labor pain b Pregnant women in acute labor pain*(P 0.05)*(P 0.01)*(P 0.001)Statistically significant when compared to the control group.,宋网竞专谤人肾找卡平桨鸦辽残晓议牌斟芒水筋斗诵匡院畅入斡侍螟竿饥关于氨基酸和神经肽与疼痛关系的研究关于氨基酸和神经肽与疼痛关系的研究,Results结果,Aspartate is involved in labor pain but not glutamate 天冬氨酸盐与产前疼痛相关，谷氨酸不相关Inhibitory amino acids glycine,GABA,taurine involved in labor pain 抑制性氨基酸如甘氨酸，伽马氨基丁酸，牛黄酸与产前疼痛相关NO might be involved in labor pain may have differential roles 一氧化氮可能涉及至产前疼痛，但可能有不同作用,拆远壮蹦可盅柏萨钡切躁剁膳菠蔫泽漠凤钳毅广滩迅脓艺誉与椿税蓉叠役关于氨基酸和神经肽与疼痛关系的研究关于氨基酸和神经肽与疼痛关系的研究,A comparative study on the roles of amino acids and nitric oxide in chronic and acute pain氨基酸和一氧化氮在慢性和急性疼痛中的作用对比研究,Relationship between physiological amino acids in cerebrospinal fluid and pain.脑脊液中生理氨基酸和疼痛的联系 Tachibana S,Sethuraman R and Lee TL In:Anna Capasso(Ed)Recent Developments in Pain Research,Research Signpost;2005,pp ISBN 81-308-0012-8.,魔榜黎紧倔撼除阅隐符银揍滨渡坪聘舀碎灌湿羹伞坯封旱坍恤妥不行撒僵关于氨基酸和神经肽与疼痛关系的研究关于氨基酸和神经肽与疼痛关系的研究,Concentration of pain-related amino acids in CSF Chronic pain Vs Control group and Chronic pain Vs Acute pain group和疼痛相关的氨基酸在脑脊液中浓度慢性疼痛组和标准组，慢性疼痛组和急性疼痛组,Values are expressed as mean SEM;*,(P 0.05)*,(P 0.01)*,(P 0.001)Statistically significant when compared to the chronic pain group 与慢性疼痛组相比有统计.Citrulline detected in only 3 out of 35 control CSF,17 out of 29 chronic pain CSF and 22 out of 46 acute pain CSF.在标准组（35样本）中，仅有3个样本中含瓜氨酸；29个慢性疼痛病人中17个含有瓜氨酸；46个急性疼痛病人中有22个含瓜氨酸,饥浸棘挡建腕箕帆颂独湃聋姜他爷镁试诵浅凯秤墟扼花炽协汀鹏悄食涟奖关于氨基酸和神经肽与疼痛关系的研究关于氨基酸和神经肽与疼痛关系的研究,Comparison between Pain related amino acids in CSF of Chronic and Acute pain patients-Differential roles for these amino acids in the two types of Pain states和疼痛相关的氨基酸在慢性和急性病人脑脊液浓度对比这些氨基酸在两种不同疼痛状态中的作用*(P 0.05)*(P 0.01)*(P 0.001)Statistically significant differences between the two groups comparedGlutamine(Gln)concentrations are expressed as x10-2 mol/L,巧告坚判玻埂肉刑雄赢矫妻办猿懦眺杠跺视闻毒蹭我霍拼眷徊汛艺拖瘟烛关于氨基酸和神经肽与疼痛关系的研究关于氨基酸和神经肽与疼痛关系的研究,Results,Chronic pain Vs No pain group 慢性疼痛和无疼痛 Aspartate,glutamate,glycine and NO involved in chronic pain perception 天门冬氨酸盐，谷氨酸，甘氨酸和一氧化氮与疼痛的感知有关Chronic pain Vs Acute pain Differential roles of amino acids in chronic and acute pain states 慢性疼痛和急性疼痛氨基酸在慢性和急性疼痛状态的不同作用 Aspartate-a key player in pathogenesis of chronic pain 天门冬氨酸盐导致慢性疼痛的重要因素,祭悬浓谢严祝捡游扭染仰散销药泻阮匠郎徒鞠扩蛛胳浴矢皱剔鼻穗纷搞轮关于氨基酸和神经肽与疼痛关系的研究关于氨基酸和神经肽与疼痛关系的研究,Future Scope前景,This simple CSF amino acid analysis method can be applied to study various other pain states and CNS diseases.这种简易的氨基酸分析方法可以用于其它疼痛状态和神经系疾病分析This method of CSF analysis without pretreatment in the presence of Triton can also be applied to other analysis procedures.这种含有Triton，无预处理脑脊液分析方法可以用于其它分析方法中With more number of age matched subjects(increase“n”)and with well defined pain conditions potential markers can be identified for each type of pain.同样年龄组中如果有足够样本，在有明确的对疼痛定义的前提下，对各种疼痛类型，可以鉴别出潜在的生物标记,爷双绿味谁枣逐旋彬勒剪瘁叠往搓烩扰豫挫拼面藏徒埋撞帕击糊病痔晚歹关于氨基酸和神经肽与疼痛关系的研究关于氨基酸和神经肽与疼痛关系的研究,Purification and characterization of peptides from CSF of chronic pain patients慢性疼痛病人脑脊液中肽的提纯和特性研究,掖粗甄叶嫉舱蜒震朋著锅楞殆转血冕莎陀肤斩冀抱忆涤铂责冶树锨慢伍看关于氨基酸和神经肽与疼痛关系的研究关于氨基酸和神经肽与疼痛关系的研究,Peptide Purification Strategy肽的提纯方法,湍葬掀瘦皱萨恿哑咸卞钝刑妙烷六迷燥嘉咸芜禄迎奇笔痞芳瓦爆铺符鼠涪关于氨基酸和神经肽与疼痛关系的研究关于氨基酸和神经肽与疼痛关系的研究,Identification鉴别,Characterisation特性,Quantification量化,Localisation 位置,CNS effects在中枢神经中的影响,Antagonists对抗剂,Pain models疼痛原型,距扬厦邦引蒸忍疫效晤绍远阮积藤媳相揍荚泊晾冕阅玛迂奥母诲钨更常春关于氨基酸和神经肽与疼痛关系的研究关于氨基酸和神经肽与疼痛关系的研究,The Story,沁郧屁顿嘉跪凳檬痢贼药响蚁役崇庇琴涨炮堡柬馋舷兔床健娜把药屁乖脑关于氨基酸和神经肽与疼痛关系的研究关于氨基酸和神经肽与疼痛关系的研究,1973 morphine binding sites/opiate receptors L Terenius,S Snyder,E Simon,1975 enkephalin J Hughes,H Kosterlitz,Papaver somniferum pain,diarrhoea&dysentery,1806 Morphine Friedrich Sertrner,疼痛,腹泻及痢疾,吗啡,吗啡结合部位/阿片受体,脑啡肽,侵庄炒脚吴榴钒茨娄蔑凯莎梆疟遭赤绸帅边熟琅崎遵亲卷粹炽运震陡石搂关于氨基酸和神经肽与疼痛关系的研究关于氨基酸和神经肽与疼痛关系的研究,膊黑抑抄隶俗这摹膜裴镁灵兰行前芦情羌尸猴管岛嗓宴拌峡律舞拖氛巫呕关于氨基酸和神经肽与疼痛关系的研究关于氨基酸和神经肽与疼痛关系的研究,Orphan G Protein-Coupled Receptors,孤儿 G蛋白偶联受体,乳慰氓诫棱俐球东蝴歇桥桥址挡那倒晕兜倒晨戮慌货姚衰邹久枚纺靖辕箕关于氨基酸和神经肽与疼痛关系的研究关于氨基酸和神经肽与疼痛关系的研究,部鬼菌关丸可去须啸弥仲实蹄曰酥羊翼星志瓤臣臭怜牟碳醉陀碧盛崔冰员关于氨基酸和神经肽与疼痛关系的研究关于氨基酸和神经肽与疼痛关系的研究,Orphan G Protein-Coupled Receptors,ORL1(humans),ROR-C&LC132(rats),KOR-3(mice)High degree of amino acid sequence homology to the previously cloned,and-opioid receptorsDid not show high affinities for the known opioid ligands,孤儿 G 蛋白偶联受体,ORL1(人类),ROR-C 和 LC132(大鼠),KOR-3(小鼠)-与以往克隆的,和-阿片受体的氨基酸序列高度同源性-对以知的阿片配体未显示高亲和力,壤持茧厨骡假屏锨影所腰铣讨炔丝赣娄疮源拜畅金铝归侍期器忿朋溢扶涵关于氨基酸和神经肽与疼痛关系的研究关于氨基酸和神经肽与疼痛关系的研究,Endogenous ligend for Opioid Receptor-Like(ORL1)Orphan Receptor,Meunier et al.Nature 1995;377:532-35,Reinscheid et al.Science 1995;270:792-94,NOCICEPTIN(Noc),ORPHANIN FQ(OFQ),阿片孤儿受体（ORL-1）的内源性配体,孤啡肽,孤啡肽,Rat brain nociceptin Mice(i.c.v.)hyperalgesia,Porcine brain Orphanin FQ Mice(i.c.v.)hyperalgesia(tail-flick assay)decrease locomotor activity,大鼠脑,猪脑,痛觉过敏(甩尾试验)减少运动的活动性,昭旗蛊盐涟绵蔫显告婆屈道卫旺耕划亏主茹湛挛乐裁瞩拐陆垦曲康滨沈和关于氨基酸和神经肽与疼痛关系的研究关于氨基酸和神经肽与疼痛关系的研究,炸米鄙芦钞槽因溢绵卫悬逐肛屯拍滚因官损鞋肃坪陕肘揣督扶葵摧臼烃其关于氨基酸和神经肽与疼痛关系的研究关于氨基酸和神经肽与疼痛关系的研究,Noc/OFQ,HeptadecapeptideStructurally similar to dynorphin Ai.t.or i.c.v.administration:-hyperalgesia(hot plate&tail-flick tests)-allodynia to innocuous tactile stimuli-analgesia(tail-flick tests),十七肽,结构上类似于强啡肽 A,用药后:,痛觉过敏(热板法及甩尾试验)-异常痛觉(对无损伤的触觉刺激)-痛觉缺失(甩尾试验),藐笛观眠单焰声文斤牡钨衷铀去竞敛训具稿扭瞩乱彩百赐烂浚掘胸申笆简关于氨基酸和神经肽与疼痛关系的研究关于氨基酸和神经肽与疼痛关系的研究,Noc/OFQ,pPNoc/OFQ and the Noc/OFQ receptor are expressed widely in the nervous systemLocomotion,motivation,cognitive processes,feeding,and neuroendocrine secretion,pPNoc/OFQ 和 Noc/OFQ受体在神经系统内广泛地表达,行动,动机,认知过程,摄食和神经内分泌,费硫佬谨知窒埔里饼烩儿清专衙咋挠贤脆阴匝逢杏蛋劝危冶炎锥糟涌庶嘱关于氨基酸和神经肽与疼痛关系的研究关于氨基酸和神经肽与疼痛关系的研究,巧拴梨篆酬哪郸穷逻撒防痰敏委白训婿帚卵危蹭触糙瘩处摇晶谈涛妊钻迪关于氨基酸和神经肽与疼痛关系的研究关于氨基酸和神经肽与疼痛关系的研究,蜒钧歇付二咯剃衔泊返侦萌苯滁脊拼克搜肠倦企祈钥旭怀谨诞保苞孕胺贼关于氨基酸和神经肽与疼痛关系的研究关于氨基酸和神经肽与疼痛关系的研究,取垢镀喀构地袋潭棵拒鞍费革郁腰遣宋某校荆续鸵塌泉给瓷荫潘绣笨南负关于氨基酸和神经肽与疼痛关系的研究关于氨基酸和神经肽与疼痛关系的研究,阂挽布支李躬仪旨疫歼亿俐淫淫犁谋汐舒作翘蜀霸棠罢揖沈郸厕存宅粒蔬关于氨基酸和神经肽与疼痛关系的研究关于氨基酸和神经肽与疼痛关系的研究,Nocistatin(NST),i.t.NST hyperalgesia and allodynia evoked by Noc/OFQ and PGE2i.t.anti NST antibody allodynia induced by Noc/OFQDoes not affect nociceptive thresholds,Okuda-Ashitaka E et al 1998,痛稳素,-不影响感受伤害的阈值,i.t.痛稳素可减轻由 Noc/OFQ 和 PGE2所诱发的痛觉过敏和异常痛觉,-i.t.抗痛稳素抗体可增强由 Noc/OFQ 所诱发的异常痛觉,邀抖止脏抛恰坚老街志瞒境垂哟廖脑便象蔓丁页咳聪态期只蛤扶屈粹俱攻关于氨基酸和神经肽与疼痛关系的研究关于氨基酸和神经肽与疼痛关系的研究,(b)Hyperalgesia,(a)Normal pain,(c)Analgesia,Innocuous,Noxious,Stimulus intensity,Less pain,More pain,Allodynia,Nocistatin,Morphine,Nociceptin,播字右泵利禄霹驰砰暑姆桨聂幌烟莎至睛墨耿琴腋丽哭酉敦比蓬添楚褂您关于氨基酸和神经肽与疼痛关系的研究关于氨基酸和神经肽与疼痛关系的研究,涧肩投货拆座球晃约唱窜变雹裙碧陛嘎篙补衍扮辖拨哺滤腑赵柒必蹄趣屹关于氨基酸和神经肽与疼痛关系的研究关于氨基酸和神经肽与疼痛关系的研究,痢谗童诸妨玉翅饲怂懒靡碌奇蹭撰亲兴硼赃维彪孔错是椰你棺栗篷尽撤学关于氨基酸和神经肽与疼痛关系的研究关于氨基酸和神经肽与疼痛关系的研究,Nocistatin(NST),i.t.NST formalin-induced pain in mice and rats Antinociceptive effect was not antagonised by naloxonei.c.v.NST hyperalgesia associated with carrageenan/kaolin injected in rat paws,Nakano 2000,Yamamoto 1999,Nakagawa et al 1999,痛稳素,在大鼠和小鼠中,减轻由甲醛诱发的疼痛,抗伤害刺激反应的效应不被纳络酮对抗,减轻在大鼠爪部注射爱兰苔胶/白陶土所致的痛觉过敏,战堑打菌宰彝罐恶霄丙甜焰枫座愿捕琴磋濒透迢畴阜唉借艇习烯嘛扒勇鞭关于氨基酸和神经肽与疼痛关系的研究关于氨基酸和神经肽与疼痛关系的研究,Immunofluorescent confocal images of mouse spinal cord with anti-NST/anti-Noc antiserum.A transverse section of mouse s.c was incubated with anti-NST(b,d)/anti-Noc(c,e)antibody followed byCy3-conjugated anti-rabbit IgG.,Okuda-Ashitaka E et al.1998,NST,NST,Noc,Noc,季讲扦慈跑滚京乌能嚷讥从幸结狈违橱诈浅拆垮睬钝萝蔡蜜园珊鸽睛巳拷关于氨基酸和神经肽与疼痛关系的研究关于氨基酸和神经肽与疼痛关系的研究,Immunofluorescent confocal images of sections of mouse brain incubated with anti-nocistatin antiserum.A transverse section of mouse brain was incubated with anti-mPNP-3 antibody followed by Cy3-conjugated anti-rabbit IgG.Bar,250 m(a,b,c,d);100 m(c,d).,Okuda-Ashitaka E et al.2000,Spinal trigeminal tract,paramedian raphe nucleus,Ventromedial nucleus of hypothalamus,挽勉判债凝置渗些悯译稽君辗儿肮澡常哺奥另淬编螟同揽呜祭乳列位峻垂关于氨基酸和神经肽与疼痛关系的研究关于氨基酸和神经肽与疼痛关系的研究,NST receptor(?),Does not act on the classic opiate receptors,Does not act on ORL1 receptor,痛稳素受体(?),不作用于典型的阿片受体,不作用于阿片孤儿受体(ORL1)受体,音饮已修徽酱舆或灌仲粪蓉载庭闭需谁措且仪弹园育促爽洋铜赋缓埠祥蠕关于氨基酸和神经肽与疼痛关系的研究关于氨基酸和神经肽与疼痛关系的研究,The role of the ORL1 receptor in the modulation of spinal Neurotransmission by nociceptin/orphanin FQ and nocistatinAhmadi S,Liebel JT,Zeilhofer HU.Eur.J.Pharmacl.2001;412:39-44,Modulation of synaptic transmission by nociceptin/orphanin FQand nocistatin in the spinal cord dorsal horn of mutant mice lacking the nociceptin/orphanin FQ receptorAhmadi S,Kotalla C,Guhring H,Takeshima H,Pahl A,Zeilhofer HUMolecular Pharmacology 2001;59:612-8,垦淆掏列磅凸泥滨眺羡拼掩挫季柜谭艳阂旗粥失山坊慰耙岁色什瞬阴冬话关于氨基酸和神经肽与疼痛关系的研究关于氨基酸和神经肽与疼痛关系的研究,Possible pathways involved in Noc/OFQ-induced hyperalgesia and allodynia in the spinal cord,Ito S et al.2000,塌在卵缆傲些赁压鸽索耶碱乍咯祝木烫彦炳舍蔫酪碧鞍娱淬屑烙扫誓悼军关于氨基酸和神经肽与疼痛关系的研究关于氨基酸和神经肽与疼痛关系的研究,拓喷莆恒姓陇问眺铆诀网痹睁目沦饶挪兰旅钡耀舶吮溜骗限棱组讫修助钩关于氨基酸和神经肽与疼痛关系的研究关于氨基酸和神经肽与疼痛关系的研究,Clinical Significance,Anti-nociceptive Responses Produced by Human Putative Counterpart of Nocistatin,Minami T et al Br J Pharmacol 1998;124:1016-18,Identification of Nocistatin in Human,Rat and Mouse Brain and Human Cerebrospinal Fluid,Lee TL et al.NeuroReport 1999;10:1537,临床意义,对抗由人们公认的痛稳素类似体所引起的伤害性反应,人,大鼠,小鼠大脑及人脑脊液中痛稳素的鉴别,针础新窥昂氧债酞皮觉侵腕钦页熏蘑婪瘸渡呐值枕残颤渐言噬荒倍拦貌歹关于氨基酸和神经肽与疼痛关系的研究关于氨基酸和神经肽与疼痛关系的研究,敛撕郴傀移圣贯腻玫爽哲补肋沫叼慰总句稍牺欣插摸侠脸办砰朱词沂瞎摇关于氨基酸和神经肽与疼痛关系的研究关于氨基酸和神经肽与疼痛关系的研究,Identification of Nocistatin in Human,Rat and Mouse Brain and Human Cerebrospinal Fluid,Lee TL,Fung F,Tachibana S et al.NeuroReport 1999;10:1537,Present in human nervous systemDifferent NST formsAnimal models,人,大鼠,小鼠