胍丁胺对小鼠和大鼠镇痛及增强吗啡镇痛

AIM: To study the effect of agmatine on pain and morphine analgesia. METHODS: The effect of agmatine on pain was observed in mouse heat radiant tail-flick test, mouse acetic acid writhing test, and rat 4% saline test. Its enhancing effect on analgesia of morphine and clonidine was assessed in rat and mouse heat radiant tail-flick tests. RESULTS: Agmatine did not significantly prolong tail-flick latency of mice, but reduced the number of acetic acid-induced writhing of mice and inhibited writhing responses to saline completely. It potentiated the analgesic effects of morphine and clonidine in dose-dependent manner and decreased the analgesic ED50 of morphine and clonidine by more than 75% in mouse heat radiant tail-flick test. These effects of agmatine were antagonized by idazoxan. CONCLUSION: Agmatine has weak analgesic effects and potentiates morphine and clonidine analgesia by activation of imidazoline receptors.     

胍丁胺及其主要生物学作用

胍丁胺作为咪唑啉受体的内源性配体，能调节某些神经递质的释放，并有多方面的生物学作用如降糖、利尿、对抗阿片类药物所致耐受和依赖、抗炎等，因此胍丁胺很可能是又一个新的神经递质或调质。     

胍丁胺中枢作用的复杂性及多样性

1994年 ,人们发现胍丁胺在牛脑中具有可乐定替代物质的特性。随之的研究表明 ,胍丁胺的作用机制复杂 ,作用靶点多样 ,生物学效应广泛。最近的研究显示 ,胍丁胺是中枢的一种新的神经递质 ,胍丁胺可能是咪唑啉受体的内源性配体     

咪唑克生对吗啡镇痛、耐受和身体依赖的影响

目的:观察咪唑克生对吗啡镇痛及吗啡所致耐受和躯体依赖的影响.方法:采用小鼠醋酸扭体实验和55℃热板实验观察咪唑克生对基础痛阈及吗啡镇痛作用的影响;采用小鼠热辐射甩尾实验和小鼠55℃热板实验观察咪唑克生对吗啡耐受形成过程的影响;采用大鼠、小鼠身体依赖模型观察咪唑克生对吗啡所致身体依赖的影响.结果:咪唑克生(3-9mg/kg)能显著降低小鼠基础痛阈,抑制吗啡镇痛;加重吗啡所致耐受;诱发大、小鼠发生戒断综合征.结论:咪唑啉受体参与痛阈形成;咪唑克生能抑制吗啡镇痛,加重吗啡所致耐受;并诱发吗啡依赖性动物发生戒断综合征.     

胍丁胺抗阿片依赖研究进展

阿片成瘾,又称为阿片依赖,是一种慢性复发性脑疾病,可引起一系列严重的社会、经济和公共卫生问题。由于阿片依赖的神经生物学机制尚未阐明,目前仍缺乏有效的医学干预手段。研究阿片依赖的神经生物学机制、寻找有效的防复吸药物已成为阿片依赖研究领域的热点。胍丁胺是一种新发现的候选神经递质或调质,被认为是咪唑啉受体的内源性配体,本文主要以我们的研究工作为基础,对外源性胍丁胺的抗阿片依赖作用特点及其可能的作用机制加以综述。     

胍丁胺对吗啡长期处理引起的NMDA受体蛋白表达改变的影响

目的:观察胍丁胺对吗啡长期处理引起的NMDA受体蛋白改变的影响。方法:采用吗啡递增给药制备大鼠慢性依赖模型,并观察依赖状态下大鼠海马和伏隔核NMDA受体NR1和NR2B亚基蛋白表达量的变化,以及胍丁胺对吗啡作用的影响。结果:与对照组相比,吗啡慢性处理大鼠在纳洛酮催促下能出现典型的戒断综合征,提示依赖模型建立成功。用免疫印记(Western blotting)技术发现,海马部位的NR2B亚基明显下调,而NR1亚基未见显著性变化;吗啡慢性处理不引起伏隔核NR2B亚基的明显变化,但NR1亚基却显著上调。胍丁胺与吗啡伴随给药能逆转吗啡对两脑区NMDA受体蛋白表达的调节作用。结论:胍丁胺调节阿片依赖可能与其逆转吗啡对NMDA受体亚基数量和构成的调节有关。     

胍丁胺对吗啡所致小鼠耐受和物质依赖的作用

目的 观察胍丁胺对吗啡所致耐受和依赖的作用。方法 分别在小鼠耐受和跳跃实验中观察胍丁胺抑制吗啡所致耐受和物质依赖的作用,结果：胍下胺０．１２５～２．５ｍｇ．ｋｇ＾－１剂量依赖性地阻止小鼠对吗啡耐受,用吗啡预处理小鼠使吗啡镇痛ＥＤ５０（２０．１,１４．４－２８．０ｍｇ．ｋｇ＾－１）与盐水组相比（６．３,５．１－７．８ｍｇ．ｋｇ＾－１）增加３倍以上,用胍丁胺和吗啡共同预处理小鼠则使吗啡丧失引直耐受的能     

胍丁胺对阿片受体环腺苷—磷酸信号转导系统代偿适应的影响

观察胍丁胺对阿片类所致脱敏和物质依赖的作用。方法：分别用放射配体结合实验和放免法测定γ－「３５Ｓ」－三磷鸟苷结合量和环腺苷一磷酸浓度。结果：在陛阿片类药物预处理的ＮＧ１０８－１５细胞实验中,胍丁胺使阿片类药物刺激「＾３５Ｓ」ＧＴＴＰ结合作用的增强３５％;合阿片类药物对ｃＡＭＰ抑制作用增强１１４．３％,使纳洛酮引起的吗啡物质依赖细胞ｃＡＭＰ超射幅度和对照组减小２１４．９％。     

胍丁胺代谢产物腐胺对吗啡镇痛、耐受和依赖的影响

目的观察腐胺对吗啡镇痛、耐受及依赖的影响,探讨腐胺治疗阿片耐受性和依赖性的潜力。方法小鼠醋酸扭体模型和55℃热板法测痛阈;吗啡恒定剂量给药制备耐受模型,55℃热板法测痛阈;吗啡递增剂量给药制备依赖模型,纳洛酮催促观察戒断症状,以胍丁胺(40 mg.kg-1,ig)为阳性对照药,腐胺灌胃给药剂量分别为10,20,40,80 mg.kg-1。结果在小鼠醋酸扭体模型中腐胺具有镇痛作用;而在小鼠55℃热板实验中,腐胺本身无镇痛作用,能较弱地增强吗啡镇痛;腐胺能够减弱吗啡耐受的形成,对已形成的吗啡耐受也有治疗作用;腐胺能够减弱吗啡躯体依赖的形成和表达。结论腐胺和胍丁胺具有相似的生物学活性,具有治疗阿片耐受和依赖的潜力。     

胍丁胺-I1咪唑啉受体对μ阿片受体下调的影响及可能机制

目的:观察胍丁胺通过激活I1咪唑啉受体(I1R)对阿片预处理引起的μ阿片受体(MOR)下调的影响及可能的分子基础。方法:以CHO-μ和CHO-μ/IRAS(imidazoline receptor antisera-selected protein)细胞作为研究对象,用[3H]diprenorphine结合实验方法,确定胍丁胺-I1R作用系统对MOR下调的影响以及可能产生的分子基础。结果:在正常CHO-μ和CHO-μ/IRAS细胞中,DAMGO([D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin,1μmol·L-1)处理两细胞12h后均可出现MOR的下调,胍丁胺(1-100nmol·L-1)浓度依赖性地抑制CHO-μ/IRAS细胞中MOR的下调,而相同浓度胍丁胺在CHO-μ细胞中无此作用。胍丁胺这一作用能被I1R阻断剂依法克生(efaroxan,Efa)所阻断。DAMGO(1μmol·L-1)预处理两细胞30min后,MOR均发生内吞。胍丁胺(1nmol.L-1-1μmol·L-1)和DAMGO共同预处理两细胞30min,胍丁胺能浓度依赖性地抑制由DAMGO预处理引起的CHO-μ/IRAS细胞中MOR的内吞,而相同浓度胍丁胺对CHO-μ细胞中由DAMGO预处理引起的MOR的内吞无显著影响,且这一作用同样能被依法克生所阻断,提示胍丁胺通过激活I1R对DAMGO预处理引起的MOR内吞具有显著的抑制作用,这可能是胍丁胺-I1R作用系统抑制MOR下调的分子基础。结论:胍丁胺通过激活I1R抑制阿片激动剂诱导的MOR的内吞,进而进一步抑制MOR下调。     

精氨酸及精氨酸脱羧酶抗体对痛阈及吗啡镇痛作用的影响(英文)

目的进一步阐明胍丁胺对阿片药理作用的影响。方法采用小鼠醋酸扭体法、小鼠热辐射甩尾法、小鼠热板法评价了精氨酸及精氨酸脱羧酶抗体对痛阈、吗啡镇痛及其耐受作用的影响。结果在小鼠醋酸扭体实验中,脑室注射精氨酸能剂量依赖性地抑制小鼠扭体次数,最大抑制率达84 %。在小鼠热辐射甩尾模型中,精氨酸不影响小鼠的甩尾时间,但能剂量依赖性地增强吗啡的镇痛作用,使吗啡2 .5 mg·kg-1的最大可能镇痛百分率从23 %增加到71 %。此外,在小鼠热辐射甩尾实验中,精氨酸能抑制吗啡100 mg·kg-1所诱导的急性耐受。精氨酸上述作用可被咪唑啉受体拮抗剂咪唑克生(3mg·kg-1,ip)所抑制。在小鼠热辐射甩尾实验和小鼠55℃热板实验中,精氨酸脱羧酶抗体能抑制吗啡镇痛,并能加重吗啡所致的耐受。结论上述结果提示,精氨酸及精氨酸脱羧酶在痛阈、吗啡镇痛及吗啡依赖形成过程中具有重要作用。     

蛛网膜下腔吗啡用于剖宫产术后镇痛效果及对血泌乳素的影响

目的观察蛛网膜下腔吗啡用于剖宫产术后镇痛效果及对血泌乳素的影响。方法 40例剖宫产产妇随机分为蛛网膜下腔吗啡镇痛组（Ⅰ组）及术后疼痛时用哌替啶肌注对照组（Ⅱ组）,每组20例。观察术后6、12、24、48h VAS评分以及术后24、48h血浆泌乳素（PRL）水平,另外观察新生儿的Apgar评分及术后恶心呕吐和皮肤瘙痒发生率。结果Ⅰ组的术后镇痛效果明显优于Ⅱ组（P〈0.01）,术后24、48h的PRL水平亦高于Ⅱ组（P〈0.05）。结论蛛网膜下腔吗啡用于剖宫产术后镇痛可取得非常满意的效果,并可促进术后泌乳素的分泌水平。     

Inhibition of agmatine on psychological dependence induced by morphine and the possible mechanism

Agmatine is the endogenous ligand of imidazoline receptor, it enhanced morphine analgesia, inhibited tolerance to and physical dependence on morphine. In the present study, the effect of agmatine on the psychological dependence on morphine and the possible mechanism was evaluated.     

胍丁胺对新生大鼠海马神经前体细胞增殖的影响

目的探讨胍丁胺对大鼠海马神经前体细胞增殖的影响及可能的作用机制。方法分离新生24 h大鼠的海马组织,制成单细胞悬液后进行无血清条件培养;用CCK-8试剂盒和3H-胸腺嘧啶核苷参入法检测细胞增殖和胍丁胺的作用。结果从新生大鼠海马分离得到的细胞可以持续分裂增殖形成细胞克隆(神经球);胍丁胺1、10μmol.L-1可以显著促进神经前体细胞的增殖,并且这种促增殖作用可以被依法克生所抑制。结论胍丁胺可以促进体外培养的新生大鼠海马神经前体细胞的增殖,其促增殖作用可能与咪唑啉Ⅰ(I1)受体有关。     

Relationships between agmatine anti-abstinence syndrom and its inhibition on down-regulation of hippocampal neurogenesis in morphine-dependent rats

Agmatine derived from arginine is recently considered as a neurotransmitter and/or neuromodulator that potentiates morphine analgesia and inhibits the symptoms of naloxone-precipitated withdrawal in morphine dependent rats.The exact mechanisms of the inhibition of agmatine are not completely known.Recently,more and more results indicate that down-regulation of hippocampal neurogenesis is involved in opioid physical dependence.Therefore,the present study was undertaken to investigate the relationships between agmatine anti-abstinent syndrome and its inhibition on down-regulation of hippocampal neurogenesis in morphine dependent rats,and the possible mechanisms.We found that the chronic pretreatment with morphine induced a classical naloxone-precipitated abstinent syndrome and a decrease in neurogenesis by 23% in the adult rat hippocampal granule cell layer compared with those of saline control.Co-administration of agmatine with morphine was able to inhibit significantly the abstinent syndrome and the decrease in neurogenesis in the adult rat hippocampal granule cell layer at same time.Furthermore,agmatine inhibited the decreased hippocampal expression of brain-derived neurotrophic factor and phosphorylated CREB,in response to chronic pretreatment with morphine.On the other hand,pretreatment with agmatine in vitro significantly increased the proliferation of cultured hippocampal progenitor cells.All these results suggest that agmatine could inhibit morphine-induced physical dependence by up-regulation of the expression of brain-derived neurotrophic factor and cell proliferation in the adult rat hippocampus.Although agmatine is thought to ameliorate morphine dependence in multiple ways,the neurotrophic pathway may be one of the most important routes.     

Agmatine: Biological role and therapeutic potentials in morphine analgesia and dependence

Agmatine is an amine that is formed by decarboxylation of L-arginine by the enzyme arginine decarboxylase (ADC) and hydrolyzed by the enzyme agmatinase to putrescine. Agmatine binds to several target receptors in the brain and has been proposed as a novel neuromodulator. In animal studies, agmatine potentiated morphine analgesia and reduced dependence/withdrawal. While the exact mechanism is not clear, the interactions with N-methyl-D-aspartate (NMDA) receptors, alpha2-adrenergic receptors, and intracellular cyclic adenosine monophosphate (cAMP) signaling have been proposed as possible targets. Like other monoamine transmitter molecules, agmatine is rapidly metabolized in the periphery and has poor penetration into the brain, which limits the use of agmatine itself as a therapeutic agent. However, the development of agmatinase inhibitors will offer a useful method to increase endogenous agmatine in the brain as a possible therapeutic approach to potentiate morphine analgesia and reduce dependence/withdrawal. This review provides a succinct discussion of the biological role/therapeutic potential of agmatine during morphine exposure/pain modulation, with an extensive amount of literature cited for further details.     

罗哌卡因联合吗啡或芬太尼镇痛效果与对肠蠕动影响的临床观察

目的探讨罗哌卡因联合不同镇痛药物对手术后肠蠕动恢复情况的影响。方法对105例普外科择期手术患者,ASAⅠ、Ⅱ级,根据不同的镇痛方案随机等分成3组:(1)吗啡组。0.125%罗哌卡因+0.005%吗啡+0.005%氟哌利多。(2)芬太尼组:0.125%罗哌卡因+0.000 5%芬太尼+0.005%氟哌利多。(3)对照组为不实施患者术后自控镇痛。镇痛治疗后4h、8h、12h、24h、36h进行随访,观察疼痛程度、镇静状态、平均动脉压(MAP)、心率(HR)、呼吸频率(RR)、脉搏氧饱和度(SpO_2),并记录肠蠕动恢复时间。结果吗啡组与芬太尼组均取得较好的镇痛效果,VAS评分显著低于对照组(P<0.01);芬太尼组较吗啡组、对照组肠蠕动恢复时间明显缩短(P<0.05)。结论罗哌卡因联合吗啡、芬太尼组患者术后自控镇痛均能获得良好的效果;罗哌卡因与芬太尼联用可缩短肠蠕动的恢复时间。     

氯诺昔康、右美沙芬与吗啡协同镇痛作用的临床观察

目的:观察小剂量氯诺昔康、右美沙芬复合小剂量吗啡用于上腹部手术后镇痛的效果.方法:择期上腹部手术患者45例,术后使用100mL一次性镇痛泵.所用药物为分别为吗啡50mg(吗啡组,n=14)、吗啡30mg 右美沙芬15mg(右美沙芬组,n=14)、吗啡30mg 氯诺昔康16mg(氯诺昔康组,n=14)和吗啡30mg(对照组,n=6).记录术后3,6,24,48h疼痛视觉模拟评分(VAS)、Ramsay镇静评分、活动后VAS评分和48h内使用吗啡总量并记录可能出现的不良反应.结果:术后6和24h吗啡组、氯诺昔康组VAS明显低于对照组,右美沙芬组6h明显低于对照组.术后6和24h吗啡与氯诺昔康组活动后VAS明显低于对照组,而右美沙芬组与对照组差异无显著性,且在6h显著高于吗啡组.各组术后镇静评分无差异.术后48h吗啡总量吗啡组明显高于其他3组,氯诺昔康与右美沙芬组低于对照组.术后恶心呕吐病例吗啡组明显高于其他3组.右美沙芬组1例眩晕,吗啡组1例皮肤瘙痒,未发现其他不良反应.结论:小剂量非阿片类药物氯诺昔康与右美沙芬与吗啡联合应用可增加吗啡的镇痛效果.