氟哌利多加强针刺镇痛时大鼠脑内μ受体结合位点增加:放射自显影研究(英文)

目的:观察μ受体在氟哌利多加强针刺镇痛过程中的变化.方法:运用放射自显影技术,以μ受体的高选择性配基羟甲芬太尼在大鼠脑片上作放射受体结合分析.结果:针刺使~3H-羟甲芬太尼与mu受体的结合在大鼠脑内许多核团明显增加;当氟哌利多增强针刺镇痛时,这一结合进一步增加.增加程度较大的核团有尾核,伏核,视前区,中脑导水管周围灰质(P<0.01);中等程度的增加可见于丘脑,下丘脑外侧区,脊髓背角等(P<0.01或0.01);增加程度较小者有隔核,视前区,黑质(P<0.05).结论:μ受体介导了氟哌利多对针刺镇痛的加强作用.     

CCK-8及其受体拮抗剂对吗啡戒断大鼠额叶皮质、尾壳核、海马μ阿片受体的影响

目的通过观察CCK-8及其受体拮抗剂对吗啡戒断大鼠额叶皮质、尾壳核、海马μ阿片受体的影响,初步探讨CCK-8对吗啡戒断症状的影响及其受体机制。方法建立大鼠吗啡慢性依赖及纳络酮催促戒断模型,观察CCK-8及CCK1受体拮抗剂L-364,718、CCK2受体拮抗剂LY-288,513慢性干预对戒断症状的影响,并采用放射配基结合法测定额叶皮质、尾壳核、海马μ阿片受体的结合活性,即受体数量(Bmax)及结合力(Kd)。结果①给予吗啡前腹腔注射CCK-8及CCK受体拮抗剂慢性干预均可减轻吗啡戒断症状;②慢性吗啡作用后,额叶皮质和海马μ阿片受体数量及结合力下降,而尾壳核μ阿片受体数量无变化,仅结合力降低;戒断后,额叶皮质、尾壳核μ阿片受体数量及结合力升高,而海马μ阿片受体数量无变化,仅结合力升高;③CCK-8及其受体拮抗剂慢性干预后,使吗啡戒断大鼠尾壳核μ阿片受体结合力降低、海马μ阿片受体数量增加,但是对额叶皮质μ阿片受体的结合活性无影响。结论 CCK-8及其受体拮抗剂可通过调节μ阿片受体减轻吗啡戒断症状,并具有脑区特异性。     

氟哌利多结合电针使大鼠脑内前脑啡肽原mRNA的表达进一步增加(英文)

目的:观察氟哌利多与电针(EA)合用后前脑啡肽原(PPE)mRNA的表达.方法:氟哌利多与电针合用后取大鼠脑切片,以非放射性的原位杂交组织化学技术观察PPE mRNA.结果:电针10 h之后,PPE mRNA的表达增强了;而EA与氟哌利多合用后,PPE mRNA的表达在许多与痛觉调制有关的核团被进一步增强.如尾壳核,伏核,隔核,斜角带核,杏仁核,下丘脑,中脑导水管周围灰质,脚间核,黑质,脊髓背角.结论:氟哌利多促进电针对PPE mRNA表达的作用,与其加强针刺镇痛的机制有关.     

去甲肾上腺素对吗啡依赖大鼠中枢痛觉的调制

目的研究去甲肾上腺素(NE)和酚妥拉明对吗啡依赖大鼠伏核(NAc)内痛兴奋神经元(PENs)和痛抑制神经元(PINs)生物电活动的影响。方法采用NAc内给药的方法,以电脉冲刺激右侧的坐骨神经作为伤害性刺激,用玻璃微电极记录吗啡依赖大鼠NAc内PENs或PINs的电变化。结果 NAc内微量注入NE(4 g.L-1,0.5μl)可使吗啡依赖大鼠NAc中PEN对伤害性刺激反应的痛诱发放电频率减少,潜伏期延长,但PIN痛诱发放电频率增加,抑制时程(ID)缩短,呈现出NE的镇痛效应。NAc内注入酚妥拉明(4g.L-1,0.5μl)产生相反反应,表明酚妥拉明可阻断内源性NE的作用。结论 NE和α-肾上腺素能受体均参与吗啡依赖大鼠NAc内伤害性信息的调控。NAc是调制吗啡依赖大鼠中枢痛觉的重要核团之一。     

神经肽Urocortin2对吗啡成瘾大鼠VTA神经元放电及DA能神经传递的影响

目的明确神经肽urocortin2(UCN2)在吗啡成瘾中抑制丘脑腹侧背盖区(ventral tegmental area,VTA)神经活动的机制。方法建立吗啡成瘾大鼠模型,采用七管微电泳方法,电泳UCN2对吗啡成瘾大鼠VTA神经元自发放电的改变,及UCN2对多巴胺(dopamine,DA)能神经元簇发放电模式的影响,明确UCN2在VTA神经元中与DA存在汇聚作用。另外,给予促皮质激素释放因子(coticortropin-releasing factor,CRF)受体阻断剂及蛋白激酶A(protein kinase A,PKA)抑制剂,明确UCN抑制吗啡成瘾中发挥关键作用。结果UCN2使82%(31/38)吗啡成瘾大鼠VTA神经元放电频率减慢,平均放电频率由微电泳前的(20.89±2.86)Hz减少到(13.66±3.93)Hz,给药前后放电频率降低具有显著性(P<0.01),UCN2抑制作用可被PKA抑制剂H89及CRF-2R阻断剂AST-2B取消。另外,微电泳UCN2可抑制吗啡成瘾大鼠VTA中DA神经元的爆发放电,AST-2B可增强DA的兴奋效应。结论 UCN2与CRF-2R结合后,通过PKA信号途径,抑制VTA内DA神经元异常放电,在吗啡类药物成瘾中发挥抑制作用,为其用于临床治疗阿片类药物成瘾提供理论依据。     

氟哌利多致椎体外系反应2例

氟哌利多(又名:氟哌啶)具有强效镇静,镇吐作用,其主要是阻断多巴胺受体和a-肾上腺腺能受体起作用,常用围麻醉期利用其强效镇静作用作为麻醉前用药、全麻诱导药或神经组滞的辅助药,术后镇痛的P A C液中加入氟哌利多可预防吗啡所致的恶心,呕吐,剂应用较大时,偶尔可发生椎体外系症     

三氟拉嗪的抗伤害作用及其作用机理

应用小鼠热板法和醋酸扭体法伤害实验 ,评价三氟拉嗪的抗伤害作用 ,并对其作用机理进行探讨 .结果表明 :在热板法伤害实验中 ,三氟拉嗪 (2～ 2 0mg·kg- 1)剂量依赖性地延长热板伤害反应的潜伏期 ,三氟拉嗪 (2mg·kg- 1)和吗啡 (1,3和 6mg·kg- 1)合并使用 ,增加吗啡抗伤害的作用和效率(2 9.4 %～ 5 4 .4 % ) ;在醋酸扭体法伤害实验中 ,三氟拉嗪 (0 .1～ 3mg·kg- 1)非常显著地抑制醋酸伤害刺激所致小鼠扭体反应的次数 ,增加扭体反应的潜伏期 ,呈剂量依赖性 .进一步研究结果表明 :μ受体拮抗剂纳洛酮 (1～ 9mg·kg- 1)和多巴胺 1(DA1) /多巴胺 2 (DA2 )受体激动剂阿扑吗啡 (1～ 9mg·kg- 1)对三氟拉嗪的抗伤害作用无翻转作用 .这些结果提示 :三氟拉嗪具有一定的抗伤害刺激的药理作用 ,但是中枢神经系统中的 μ受体和DA2 受体不参与三氟拉嗪的抗伤害作用     

不同频率电刺激VTA对吗啡成瘾大鼠ACbSh的放电活动的影响

目的:观察电刺激大鼠腹侧被盖区(VTA)对吗啡成瘾大鼠伏隔核壳部(ACbSh)神经元的影响,为应用脑深部电刺激技术治疗阿片类药物成瘾提供实验依据。方法:采用单管玻璃微电极细胞外记录法,观察不同频率电刺激VTA对吗啡成瘾大鼠ACbSh神经元放电的影响。结果:低频(50Hz)电刺激VTA,吗啡组ACbSh神经元主要表现为无反应(47.83%);高频(135Hz)电刺激VTA,吗啡组多数ACbSh神经元表现为抑制性作用(50.00%)。结论:高频电刺激VTA有可能作为新方法用于治疗阿片类药物成瘾。     

氟哌利多对大鼠脑缺血海马CA1区锥体细胞持续钠通道电流的影响

目的 :研究氟哌利多对大鼠脑缺血海马CA1区锥体细胞持续钠通道电流的影响。方法 :酶消化法急性分离SD大鼠 (10～ 14d)海马CA1区锥体细胞 ,通过低氧和无糖法制备神经元缺血模型 ,全细胞膜片钳技术记录氟哌利多对脑缺血时锥体细胞持续性钠通道电流的影响。结果 :在钳制电压 (Vh) 10 5mV ,刺激电压 (Vt) 30mV条件下 ,神经元缺血 3min和 5min后持续钠电流显著增强。 3、10和 30μmol·L-1氟哌利多能明显抑制缺血引起的持续钠电流增强 (P <0 .0 1,n =7) ,不同浓度氟哌利多的作用间无显著差别。结论 :临床麻醉浓度的氟哌利多能够抑制体外脑缺血时海马神经元持续钠电流增强 ,对缺血神经元有保护作用。     

多巴胺诱导大鼠海马脑片Ca~(2 )-钙调素依赖性蛋白激酶Ⅱ活性的抑制作用(英文)

目的:研究多巴胺(DA)对大鼠海马脑片Ca~(2 )-钙调素依赖性蛋白激酶Ⅱ(CCDPK Ⅱ)活性的影响。方法:采用大鼠海马脑片体外培养模型,以~(32)P-掺入法测定CCDPK Ⅱ的活性。结果:外源性DA可显著降低大鼠海马脑片CCDPK Ⅱ活性,并有一定的浓度依赖性和时间依赖性。去除胞外的Ca~(2 )对不同浓度DA诱导的CCDPK Ⅱ活性抑制有部分或完全保护作用。阿扑吗啡(非特异性DA受体激动剂)、SKF38393(特异性D_1样DA受体激动剂)和喹吡罗(特异性D_2样DA受体激动剂)均可显著降低CCDPK Ⅱ的活性。Sch-23390(特异性D_1样DA受体拮抗剂)和多潘立酮(特异性D_2样DA受体拮抗剂)均可拮抗DA所诱导的酶活性抑制。结论:DA抑制海马CCDPK Ⅱ的活性,其作用机制与D_1样和D_2样受体以及胞外Ca~(2 )的内流有关。     

三氟拉嗪抑制吗啡依赖大、小鼠纳洛酮催促的戒断症状

目的　研究三氟拉嗪对吗啡依赖大、小鼠纳洛酮催促戒断症状的影响 ,并探讨其机制。方法　吗啡依赖大、小鼠纳洛酮催促实验。结果　三氟拉嗪 (2～ 2 0mg·kg-1)呈剂量依赖性抑制吗啡依赖小鼠纳洛酮催促所致的跳跃、湿狗样抖动、前爪震颤和体重下降。三氟拉嗪 5～ 2 0mg·kg-1ip ,对吗啡依赖大鼠大部分纳洛酮催促的阳性戒断症状均具有明显的抑制作用 ,其中包括跳跃、湿狗样抖动、排泄物、体重下降、咬牙、流涎、腹泻、上睑下垂、激惹。作为DA1/DA2 受体激动剂 ,阿朴吗啡 (2～ 8mg·kg-1)对三氟拉嗪抑制吗啡依赖小鼠纳洛酮催促戒断症状无明显影响 ,而钙通道阻滞剂硝苯吡啶 (5～ 2 0mg·kg-1)则呈剂量依赖性加强三氟拉嗪对吗啡依赖小鼠纳洛酮催促戒断症状的抑制作用。结论　三氟拉嗪对吗啡依赖大、小鼠纳洛酮催促的戒断症状具有明显的抑制作用。对受体后钙调素生物活性的抑制作用可能是三氟拉嗪抗吗啡依赖大、小鼠躯体戒断症状主要机制 ,而中枢神经系统DA2 受体可能不参与三氟拉嗪对吗啡躯体戒断症状的抑制作用     

虎门合剂对吗啡依赖大鼠海马中学习记忆相关中枢神经递质的影响

目的:探讨吗啡依赖对学习记忆功能的影响,以及中药验方虎门合剂对该影响的调节作用。方法:应用经典的大鼠学习记忆行为学检测手段,对成瘾及用药组大鼠学习记忆功能改变进行观察。在此基础上对相应组别学习记忆相关神经递质AChE、DA、NE、5-HT、β-end、Glu进行检测。结果:与正常组比较,模型组海马AChE、DA、NE、5-HT、Glu均明显升高,β-end明显降低。而中药组与模型组比较,前者海马AChE、DA、NE、5-HT、Glu均明显降低,β-end明显升高。结论:虎门合剂对吗啡依赖所致的记忆损伤具有良性调节作用。     

Co-release of noradrenaline and dopamine in the prefrontal cortex after acute morphine and during morphine withdrawal

RATIONALE: Acute morphine and abstinence from chronic morphine have been shown to increase and to decrease extracellular dopamine (DA) in the nucleus accumbens, respectively. In contrast, extracellular DA in the prefrontal cortex (PFC) is not modified by acute morphine and is markedly increased during abstinence syndrome. OBJECTIVES: We investigated whether the peculiar behaviour of PFC DA might depend on the fact that extracellular DA originates not only from DA but, mainly, noradrenaline (NA) terminals. Accordingly, we studied if the effect of acute morphine and morphine-abstinence was modified by the inhibition of DA or NA neurons. METHODS: Extracellular DA and noradrenaline (NA) concentrations were determined by microdialysis in the PFC (densely innervated by DA) and in the parietal cortex (lacking DA afferents) both after acute morphine and in morphine-dependent rats during naloxone-precipitated abstinence syndrome. Dialysate catecholamine levels were evaluated by high performance liquid chromatography (HPLC) with electrochemical detection. RESULTS: Acute morphine (5 mg/kg IP) reduced extracellular NA (by 30%) and failed to modify extracellular DA level in the PFC, but reduced both amines by 40% in the parietal cortex. The co-administration of morphine and the D(2) agonist quinpirole (0.5 mg/kg IP) decreased both extracellular DA and NA by 40% in the PFC. In morphine dependent rats the administration of naloxone (1.0 mg/kg, SC) precipitated a typical abstinence syndrome associated with a concomitant dramatic increase in extracellular DA and NA by about 200 and 100%, respectively, in the PFC. The alpha(2)-adrenoceptor agonist clonidine (0.15 mg/kg IP) suppressed naloxone precipitated abstinence symptoms and brought both NA and DA output in the PFC to <50% baseline values. In contrast, quinpirole was totally ineffective. CONCLUSIONS: The results suggest that: a) morphine-stimulated DA release from DA terminals is compensated by reduced DA release from NA terminals; b) morphine abstinence-induced inhibition of DA release from DA terminals is overshadowed by a marked increase in DA released from NA terminals. Thus, the paradoxical response of PFC DA to morphine and morphine abstinence may be explained by the fact that extracellular DA in the PFC mainly represents the amine co-released from NA terminals.     

Simultaneous electric activities of pain-excitation and pain-inhibition neurons in nucleus parafascicularis of thalamus in rats during acute morphine tolerance

When acute morphine-tolerated rat was administered by ip morphine (10 mg/kg) which was effective before the acute tolerance to morphine, both the inhibitory effect of morphine on the electric discharges of pain-excitation neurons (PEN) in nucleus parafascicularis (PF) and the excitatory effect of morphine on the electric activities of pain-inhibition neurons (PIN) were simultaneously weakened, or even vanished. If a large dose of morphine (20 mg) was given ip, the modulating action of morphine on simultaneous electric discharges of PEN and PIN reappeared. It is obvious that the phenomenon of acute morphine tolerance and the antagonism to morphine tolerance can be explicitly expressed on the level of central neurons.     

Evidence for a peripheral mechanism in cardiac opioid withdrawal

Studies involving heart catecholaminergic systems in morphine-dependent rats have not established whether the adaptive changes observed in the heart during morphine withdrawal are mediated peripherally or centrally. In this study, naloxone (Nx), naloxone methiodide (NxM) and N-methyl levallorphan (NML), quaternary derivatives of Nx and levallorphan, respectively, that do not cross the blood-brain barrier, were administered to morphine-dependent rats and catecholamines and their metabolites determined in the right ventricle. Rats were made dependent on morphine by implantation of morphine pellets for 7 days. On day 8 animals received s.c. injections of saline, Nx (1 mg/kg), NxM (5 mg/kg) or NML (5 mg/kg) and were decapitated 30 min later. Noradrenaline (NA) and its metabolites normetanephrine (NMN) and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) and dopamine (DA) and its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) were determined by high-performance liquid chromatography with electrochemical detection. After NxM or NML administration to morphine-dependent rats there was a pronounced increase in NMN and DOPAC levels, as well as in NA and DA turnovers (as estimated by NMN/NA and DOPAC/DA ratios, respectively) in the right ventricle. Similarly, giving Nx to morphine-dependent rats increased NMN and DOPAC levels and NA and DA turnovers. In addition, in the paraventricular nucleus of the hypothalamus (PVN) NA and DA turnover, measured as the MHPG/NA or DOPAC/DA ratios, increased after Nx administration but not after NxM or NML These results suggest that the changes in cardiac sympathetic activity observed during morphine withdrawal are due to intrinsic mechanisms outside the central nervous system. These data may be important for understanding the adaptive changes induced in the heart in subjects dependent on opioids.     

5-HT_(1A)受体激动剂乌拉地尔对吗啡依赖大鼠前列腺组织的病理学影响

目的··:观察5-HT1A 受体激动剂乌拉地尔对吗啡依赖大鼠前列腺的组织学影响。方法··:皮下注射(sc)5d吗啡 ,建立吗啡依赖大鼠模型 ;实验组分别进行侧脑室注射 (icv)乌拉地尔和继续sc吗啡。实验后将前列腺组织作HE染色后在光镜下观察。结果··:吗啡依赖大鼠的前列腺组织有轻度萎缩 ,吗啡依赖大鼠自然戒断后前列腺有明显增生 ,icv乌拉地尔可抑制吗啡戒断大鼠的前列腺组织增生。结论··:乌拉地尔可抑制吗啡戒断大鼠前列腺组织的增生     

达尔康对吗啡依赖大鼠戒断症状的影响

目的 :观察中药达尔康对吗啡依赖大鼠戒断症状的抑制作用。方法 :采用剂量递增法皮下注射吗啡 14d和3 0d ,分别建立大鼠吗啡依赖模型 ,观察达尔康大、中、小 3个剂量对吗啡依赖大鼠纳洛酮催促和自然戒断的戒断症状及体重的影响。结果 :达尔康能显著减轻吗啡依赖大鼠ip纳洛酮引起的催促戒断症状 (P <0 .0 5 )和体重下降(P <0 .0 1) ,能抑制自然戒断大鼠体重下降 (P <0 .0 1和P <0 .0 5 )。结论 :达尔康对吗啡依赖大鼠戒断反应有明显的抑制作用     

Retardation of cerebral dopamine turnover after morphine withdrawal and its enhanced acceleration by acute morphine administration in rats

Summary To clarify the effects of withdrawal from chronic morphine treatment on cerebral dopamine (DA) turnover, we have measured the -methyl-p-tyrosine (MT)-induced depletion of DA in five brain areas of male Wistar rats given morphine twice daily for 40 or 60 days. After the last morphine dose (50 or 70 mg/kg) the rats were withdrawn for 1, 2 or 4 days. In order to study the development of tolerance some of the rats were challenged with 10 mg/kg of morphine.Withdrawal of morphine retarded the MT-induced DA depletion in the limbic forebrain and after long enough chronic treatment in the striatum, too. The challenge dose of morphine accelerated the cerebral DA depletion slightly less in rats withdrawn for 1 day from 60-day chronic morphine treatment than in rats treated chronically with saline, but it enhanced the DA depletion more in rats withdrawn from morphine for 2 and 4 days than in chronic saline rats. This enhancement was clearest in rats withdrawn for 4 days from 60-day treatment. Thus withdrawal from morphine seems to sensitize the rats to the DA depletion accelerating effect of morphine.Our results show that repeated administration of morphine creates no marked tolerance to the DA depletion accelerating effect of morphine. In contrast, the dopaminergic neurones of the chronically treated rats seem to depend on continuous morphine administration for their normal functioning. Furthermore, the retarded DA turnover after discontinuation of morphine treatment seems to sensitize the dopaminergic neurones to the DA depletion accelerating effect of morphine. The limbic dopaminergic neurones are more easily affected by both acute and chronic morphine treatment than the striatal ones.     

长波紫外线照射对吗啡戒断大鼠血液中去甲肾上腺素及多巴胺含量的影响

吗啡成瘾大鼠的血液在体外经长波紫外线照射后回输其体内，对纳络酮诱导的戒断症状有明显抑制作用。这种作用被认为与血液中单胺类递质水平的改变有关。以吗啡成瘾大鼠模型，利用高压液相色谱－电化学检测法，发现成瘾大鼠血液中去甲肾上腺素和多巴胺含量较正常大鼠有明显增加；而经长波紫外线照射的血液中上述两种递质含量显著下降；若血液在接受照射的同时吹入氧气流，则含量下降更为显著。     

吗啡依赖大鼠脊髓和脑干一氧化氮含量和合酶活力分析

本文检测了吗啡依赖大鼠脊髓和脑干一氧化氮合酶（ＮＯｓ）活力,一氧化氮（ＮＯ）以及ｃＧＭＰ含量。结果显示吗啡依赖大鼠脊髓ＮＯｓ活力,ＮＯ和ｃＧＭＰ含量较正常对照组降低,脑干中ＮＯｓ活力轻度降低,而ＮＯ和ｃＧＭＰ含量降低。纳洛酮激发戒断症状后大鼠脊髓和脑干ＮＯｓ活力,ＮＯ以及ｃＧＭＰ含量急剧升高。ＮＯｓ抑制剂Ｌ－Ｎ－硝基精氨酸甲酯（Ｌ－ＮＡＭＥ）处理可以抑制大鼠吗啡戒断反应,同时减少脊髓和脑干ＮＯ含量。结果表明吗啡戒断反应与脊髓和脑干的ＮＯ－ｃＧＭＰ途径的兴奋有关。