脊髓以上多巴胺D2受体介导左旋四氢巴马汀的镇痛作用

目的：研究ＤＡ受体与左旋四氢巴马汀（ｌ－ＲＨＰ）镇痛作用的关系,以阐明ｌＴＨＰ的镇痛机制。方法：腹腔（ＩＰ）与鞘内（ＩＴＨ）给药,以大鼠甩尾反应观测热伤害性致痛阈。结果：ｉｐ ｌ－ＴＨＰ或Ｄ２受体拮抗剂螺哌隆产生剂量依赖性镇痛效应,并能被Ｄ２受体激动剂喹吡罗翻转,蛤不被纳洛酮翻转。而ｉｔｈ ｌＴＨＰ或螺哌隆无镇痛效应,但它们能拮抗ｉｔｈ喹吡罗引起的镇痛效应。结论：激动脊髓Ｄ２受体或阻滞脊髓以上水平     

大鼠多巴胺D_1受体介导二氢埃托啡位置偏爱效应(英文)

目的:研究不同的多巴胺(DA)受体拮抗剂对二氢埃托啡(DHE)奖赏效应的影响,方法:采用条件性位置偏爱模型评价DHE的奖赏效应,DA受体拮抗剂采取外周给药或直接到伏隔核内,结果:DHE(0.05、0.5和5.0μg·kg~(-1),sc)产生位置偏爱效应,氟哌啶醇、Sch-23390 sc或直接注射到伏隔核都能抑制DHE(0.5μg·kg~(-1),sc)的偏爱效应;而l-舒必利和螺哌隆在这两种给药途径下都不影响DHE的偏爱效应,结论:伏隔核中D_1受体(而不是D_2受体)在DHE偏爱效应中起关键作用。     

四氢原小檗碱类对小牛纹状体D_1和D_2多巴胺受体结合的特性(英文)

目的:研究四氢原小檗碱类(THPB)对脑内多巴胺受体D_1和D_2亚型的结合特性,并阐明它们之间的构效关系.方法:放射配位体测定结合双位点模型分析.结果:4个THPB与D_1受体以R_H和R_L双位点结合,它们在C_2和C_9或C_2和C_(10)位有两个羟基,另外11个THPB与D_1受体以单位点结合.对于D_2受体,11个被检测的化合物均以单位点结合,其中,在C_2位有羟基的THPB亲和力最强.结论:在C_2和C_9或C_2和C_(10)位有双羟基的THPB具有D_1受体激动剂的内在活性,其它THPB则无此活性.11个THPB均为D_2受体拮抗剂.     

阿米替林增强左旋四氢巴马汀的镇痛作用

目的　探讨阿米替林增强左旋四氢巴马汀 (L THP)的镇痛作用。方法　采用热板法和化学剌激法进行镇痛实验。结果阿米替林两组剂量 (4 2mg/kg ,8 3mg/kg)均加强了L THP的镇痛作用 ,镇痛作用时间持续 4h。结论　阿米替林可增强L THP的镇痛作用     

下丘脑弓状核参与左旋四氢巴马汀的镇痛作用(英文)

目的:研究弓状核在左旋四氢巴马汀(l-THP)镇痛效应中的作用,以阐明l-THP的镇痛作用机制。方法:应用辣根过氧化物酶(HRP)逆行追踪术追踪纹状体或伏膈核与PAG之间的纤维联系,HRP逆行追踪结合免疫组化观察投射神经元的性质,神经核团损毁和PAG核内注射药物观察对l-THP镇痛作用的影响。结果:纹状体或伏膈核通过弓状核或缰核间接与PAG联系,弓状核投射至PAG的神经元大部分是β内啡肽神经元。损毁弓状核后,l-THP的镇痛作用消失,而损毁缰核对l-THP的镇痛作用无明显影响。PAG核内注射纳洛酮能剂量依赖性翻转l-THP的镇痛作用。结论:弓状核的β内啡肽神经元在l-THP镇痛作用中起重要作用。     

L-四氢巴马汀对离体豚鼠心房的作用

THP和Ver均能对抗CaCl_2所致离体豚鼠右房正性频率作用,非竞争性拮抗CaCl_2左房正性肌力作用以及Iso右房正性频率和左房正性肌力作用。THP和Ver浓度依赖性和频率依赖性地抑制左房收缩中的阶梯现象,使正阶梯翻转为负阶梯。而对休息后加强影响较小。结果提示THP对心房的抑制作用与Ver相似,与拮抗Ca~(2+)有关,可能主要通过抑制心肌细胞外Ca~(2+)内流所致。     

四氢原小檗碱同类物与多巴胺D2受体作用的定量构效关系

四氢原小檗碱同类物是一类新型的脑内多巴胺受体阻滞剂。本文用Ｆｒｅｅ－Ｗｉｌｓｏｎ法研究了一组四氢原小檗碱同类物与多巴胺Ｄ２受体作用的定量构效关系。结果表明：Ｃ－２位上的ＯＨ和Ｃ－１２位上的Ｃｌ使四氢原小檗碱同类物与多巴胺Ｄ２受本的亲和力增强,Ｃ－１１位上的立体位阻可能使亲和力降低,Ｃ－１０位上的取代基可能对亲和力影响不大。     

左旋四氢巴马汀在治疗药物成瘾中的应用研究进展

<正>延胡索乙素,是中药延胡索有效生物碱成分之一[1],化学结构为消旋四氢巴马汀(dl-tetrahydropalmatine,THP)[2],属于四氢原小補碱同类物(tetrahydroprotoberberines,THPBs)[3]。THP经化学分旋后可分为左旋体(l-THP)和右旋体(d-THP)。多年来的研究结果表明,仅l-THP具有中     

左旋四氢巴马汀与左旋千金藤啶碱的单胺受体结合特性与单胺排空作用的关系

本文报道了四氢异喹啉生物碱(TIQ):左旋千金藤啶碱(1—SPD),左旋及消旋四氢巴马汀(THP)及小檗胺(BBM)对大鼠脑内DA_2,5-HT_2及β—肾上腺素受体的结合特性。 所测的四种TIQ对β-肾上腺素受体的亲和力均很低(IC_(50)大于10~(-4)M)。结果表明,THP对单胺能神经递质受体亲和力远小于经典的单胺受体阻断剂,从而提示单胺受体阻断可能并非THP影响单胺能神经传递的主要机制。作者认为THP一类的TIQ,生物碱至少可以通过两种机制发挥作用:单胺受体阻断及利血平样“颗粒效应”。而对于THP,起主要作用的是引起单胺排空的“颗粒效应”。此外,实验中发现1-SPD与DA_2受体结合并不是简单的双分子反应,表现为1-SPD/[~3H]螺环哌啶酮抑制曲线的Hill系数远小于1。这一受体结合特点可能与其在动物行为实验中表现出的部分激动剂性质有关。     

Role of dopamine D-1 and D-2 receptor subtypes in mediating dopamine agonist effects on food consumption in rats

The effects of selective D-2 and D-1 dopamine (DA) receptor agonists on food consumption were investigated in free-feeding rats. A selective D-2 receptor agonist, (+)-4-propyl-9-hydroxynaphthoxazine (PHNO), increased the consumption of standard food pellets in the dose range of 7.5–120 g/kg, while SKF 38393 (5.0 mg/kg), a selective D-1 receptor agonist, decreased food pellet intake. The increase in food pellet intake produced by PHNO was blocked by haloperidol (an antagonist relatively selective for the D-2 receptor at the dose used, 0.05 mg/kg) and SCH 23390 (20 g/kg, a D-1 receptor selective antagonist). Increasing arousal by disturbance associated with repeated food weighting also increased food pellet consumption, but did not diminish PHNO-elecited feeding. However, the same range of doses of PHNO (7.5–120 g/kg) which increased food pellet intake decreased consumption of a liquid diet, and had no overall effect on a highly palatable liquid diet. The increase in consumption of solid food induced by PHNO appears to be secondary to enhancement of chewing behaviors. In contrast, the decrease in food intake induced by SKF 39393 may be due to a direct action of the drug on neural feeding mechanisms.     

Behavioral effects of RO 41-9067: A novel D2 dopamine receptor agonist

The behavioral effects of a novel putative D2 dopamine (DA) receptor agonist, RO 41-9067 (RO), were investigated in the mouse and compared with those of the classic D2 agonist LY 171555 (LY) at equimolar doses. Both RO and LY dose-dependently increased defensive behavior in naive mice interacting with nonaggressive conspecifics at doses higher than 0.2 and 0.16 mg/kg, respectively. Moreover, low and intermediate doses of RO and LY decreased locomotor activity in mice tested individually in an automated apparatus. Finally, coadministration of the D1 selective agonist SKF 38393 and high doses of RO or LY induced the hyperactive response classically induced by high doses of the mixed D1/D2 agonist apomorphine in the mouse while the inhibitory effects of the lowest doses of RO or LY were not affected by coadministration with SKF. These results indicate that RO induces behavioral effects characteristic of a D2 selective agonist when tested in intact mice and suggest that at high doses this compound activates postsynaptic D2 receptors which also cooperate with D1 receptors in the stimulation of DA-induced behaviors, while at low doses it selectively activates DA autoreceptors or inhibitory DA receptors of the D2 type. © 1992 Wiley-Liss, Inc.     

Bromocriptine induces marked locomotor stimulation in dopamine-depleted mice when D-1 dopamine receptors are stimulated with SKF38393

In mice pretreated with reserpine plus alphamethyl-p-tyrosine, neither the D-2 selective agonist bromocriptine, nor the D-1 selective agonist SKF38393, produced any measurable increase in locomotion in mice. However, the combination of the two agonists produced a marked and dose-dependent increase in co-ordinated locomotor activity. In mice with their dopamine stores and dopamine synthesis intact, SKF38393 was inactive by itself, but significantly enhanced the stimulant effect produced by bromocriptine. The data suggest that bromocriptine requires concomitant stimulation of D-1 receptors for the full expression of its behavioural stimulant effects.     

Mechanisms involved in the antinociception induced by systemic administration of guanosine in mice

Background and purpose:

It is well known that adenine-based purines exert multiple effects on pain transmission. However, less attention has been given to the potential effects of guanine-based purines on pain transmission. The aim of this study was to investigate the effects of intraperitoneal (i.p.) and oral (p.o.) administration of guanosine on mice pain models. Additionally, investigation into the mechanisms of action of guanosine, its potential toxicity and cerebrospinal fluid (CSF) purine levels were also assessed.

Experimental approach:

Mice received an i.p. or p.o. administration of vehicle (0.1 mM NaOH) or guanosine (up to 240 mg·kg⁻¹) and were evaluated in several pain models.

Key results:

Guanosine produced dose-dependent antinociceptive effects in the hot-plate, glutamate, capsaicin, formalin and acetic acid models, but it was ineffective in the tail-flick test. Additionally, guanosine produced a significant inhibition of biting behaviour induced by i.t. injection of glutamate, AMPA, kainate and trans-ACPD, but not against NMDA, substance P or capsaicin. The antinociceptive effects of guanosine were prevented by selective and non-selective adenosine receptor antagonists. Systemic administration of guanosine (120 mg·kg⁻¹) induced an approximately sevenfold increase on CSF guanosine levels. Guanosine prevented the increase on spinal cord glutamate uptake induced by intraplantar capsaicin.

Conclusions and implications:

This study provides new evidence on the mechanism of action of the antinociceptive effects after systemic administration of guanosine. These effects seem to be related to the modulation of adenosine A₁ and A_2A receptors and non-NMDA glutamate receptors.     

多巴胺D_2/血管紧张素AT_1嵌合受体:D_2受体第三细胞内环影响受体与配基结合以及与G蛋白偶联的特性(英文)

目的:研究受体第三细胞内环(IL_3)的长度对受体与配基结合及与G蛋白偶联特性的影响.方法:用目前已知的G蛋白偶联受体中IL_3最短的血管紧张素Ⅱ AT_1受体的IL_3替换野生型D_2受体较长的IL_3,组成D_2/AT,嵌合受体.结果:与野生型D_2受体相比,D_2/AT_1嵌合受体与拮抗剂的亲和性均降低,与激动剂的亲和性有的增高,有的降低.嵌合受体失去与G蛋白偶联的能力,也不能产生磷酸肌醇水解.结论:受体的IL_3对受体配基结合位点和空间构象有一定影响;受体与G蛋白的偶联不仅与IL_3有关,而且还受非IL_3区域的影响,而IL_3的长度是决定这两方面影响的因素之一.     

Catalepsy-associated behavior induced by dopamine D1 receptor antagonists and partial dopamine D1 receptor agonists in squirrel monkeys

Observational procedures were used to compare the behavioral effects of dopamine D₁ receptor antagonists and partial dopamine D₁ receptor agonists in squirrel monkeys. The dopamine D₁ receptor antagonists SCH 39166 ((−)-tran-6- 7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-N-methyl-5H-benzo(d)naphtho-(2,1-b)azepine) and BW 737C89 ([S]-6-chloro-1[2,5-dimethoxy-4-propylbenzyl]- hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline) produced dose-related increases in the duration of static and unusual postures, indicative of catalepsy. R-SKF 38393 (R(+)-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-[1H]-3-benzazepine) and SKF 75670 (7,8-dihydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-[1H]-3-benzazepine), which are considered partial dopamine D₁ receptor agonists, also consistently produced dose-related increases in catalepsy-associated behavior and had effects comparable in magnitude to those of dopamine D₁ receptor antagonists. In contrast, the higher efficacy D₁ agonists SKF 81297 (6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-[1H]-3-benzazepine) and SKF 82958 (6-chloro-7,8-dihydroxy-1-phenyl-2,3,4, 5-tetrahydro-3-allylp-[1H]-3-benzazepine) did not produce catalepsy-associated behavior at any dose tested. The results indicate that dopamine D₁ agonists differ with respect to cataleptogenic activity, possibly reflecting differences in intrinsic activity.     

Effects of selective dopamine receptor agonists in rats trained to discriminate apomorphine from saline

Rats (N = 12) were trained to discriminate apomorphine (0.25 mg/kg, IP) from saline in a two-lever, food-reinforced (FR 30) drug discrimination paradigm. When the discrimination was acquired, various doses of apomorphine as well as several other dopamine receptor agonists were injected before test sessions. Apomorphine (0.03-0.25 mg/kg, IP) produced a dose-related increase in the percent of responses that occurred on the drug lever during test sessions. The selective DA2 receptor agonist piribedil (0.25-8.0 mg/kg, IP) produced a dose-related increase in drug lever responding that was similar to that seen with apomorphine. On the other hand, administration of the selective DA1 receptor agonist SKF 38393 (1.0-32 mg/kg, IP) resulted in principally saline lever responding, even at doses that substantially reduced the rate of responding. Administration of dopamine (1.0-8.0 mg/kg, IP), which does not readily cross the blood-brain barrier, also resulted in principally saline lever responding. These results suggest that the discriminative stimulus properties of apomorphine are based on its action at a receptor that is similar to the DA2 receptor that has been characterized in the periphery and that this receptor is centrally located.