四氢原小檗碱同系物的合成

为探索四氢巴马汀与千金藤啶碱类化合物的构效关系,将四氢原小檗碱的C环扩展为七元环,合成环上带有不同取代基的同系化合物。7-苄氧基-1-(3′-羟基-4′-甲氧基)苯乙基-6-甲氧基-1,2,3,4-四氢异喹啉与甲醛在乙醇中共热,进行酚环化;或在盐酸存在下与甲醛进行Mannich反应,分别获得带有不同取代的目标化合物。合成的化合物进行了对多巴胺神经受体的亲和力试验。     

四氢原小檗碱同类物对α1肾上腺素受体的拮抗作用

用放射配体结合实验与离体血管收缩功能实验相结合的方法,研究了4种四氢原小檗碱(tetrahydroproberberine,THPB)同类物对α₁-肾上腺素受体(α₁-AR)的作用。结果显示左旋四氢巴马汀(l-THP),左旋千金藤立陡碱(l-SPD),四氢原小檗碱-18(THPB-18)和四氢小檗碱(THB)¹²⁵IBE2254¹²⁵I-2-β(4-hydroxyphenyl)-ethyaminomethyl-tetralone,¹²⁵IBE)与大鼠脑皮质α₁-AR的结合呈竞争性拮抗作用,pK_I值分别为5.54±0.36,5.56±0.47,5.75±0.56和6.01±0.60,Hill系数接近于1.0。并拮抗苯肾上腺素(phenylephrine,PE)介导大鼠主动脉的收缩,pA₂值分别为5.48±0.58,5.66±0.54,5.64±0.34和5.45±0.76,斜率与1.0无显著性差别。结果提示,4种四氢原小檗碱同类物对α₁-AR均有非亚型选择性拮抗效应,且亲和性相同。     

左旋四氢巴马汀及其同类物的心血管药理作用

<正> 左旋四氢巴马汀(L-tetrahydropalmatjne.L—THP)又称颅痛定.为中药延胡索的主要有效成分—延胡索乙素(dl—THP)的左旋物,已作为镇痛药广泛用于临床。1—THP与左旋千金藤立定(1—stepholi—dine.l—SPD)、四氢小檗碱(tetrahydroberberine,THB)同属四氢原小檗碱类(THPB).有相同的化学结构母核(附图)早年发现THPB类化合物具有多种相似的中枢药理作用.如镇痛、镇静、安定、催眠等。近来研究证明它们还有多种相近的心血管效应。本文拟从以下几方面对其作用及其临床研究作一综述。     

左旋四氢巴马汀和左旋千金藤啶碱对吗啡处理

目的：研究慢性吗啡处理大鼠相关脑区神经胶质纤维酸性蛋白(GFAP)的改变，以及左旋四氢巴马汀和左旋千金藤啶碱的干预作用。方法：以剂量递增给药方式建立吗啡慢性依赖模型后分别给予左旋四氢巴马汀、左旋千金藤啶碱和等体积蒸馏水(作为自然戒断组)治疗30 d。制备相关脑区的冰冻切片，进行GFAP的免疫组织化学染色，测定阳性细胞的平均吸收度。结果：自然戒断组大鼠前额叶皮质、伏隔核壳区、海马CA1区、黑质、杏仁核的GFAP表达与正常对照组无显著差异，但中脑腹侧背盖区(VTA）GFAP表达较正常对照组显著升高。左旋四氢巴马汀及左旋千金藤啶碱组大鼠脑VTA区GFAP表达较自然戒断组均显著降低，且可达到正常水平。结论：GFAP表达持续升高反映吗啡处理对VTA区的损伤，左旋四氢巴马汀及左旋千金藤啶碱可以使GFAP表达恢复正常，可能是它们对成瘾药物的精神依赖性有干预作用的机制之一。     

左旋四氢巴马汀（1-THP）的镇痛和抗毒品复吸（relapse）的作用机制

左旋四氢巴马汀（1-tetrahydropalmatine，1-THP）是著名的镇痛中药延胡索（Corydalisyanhusuo．W,T,Wang）的有效旋光体。后来从千金藤属植物（Stephenoa rotunda）中发现1-THP，故其药名为罗通定（Rotundine）。     

左旋四氢巴马汀对门静脉压的影响及其机制

为探讨左旋四氢巴马汀（ｌ－ｔｅｔｒａｈｙｄｒｏｐａｌｍａｔｉｎｅ，ｌ－ＴＨＰ）对门静脉压的影响及可能机理，观察ｌ－ＴＨＰ对正常大鼠和利血平化大鼠门静脉压的作用，并与哌唑嗪比较。结明表明：ｌ－ＴＨＰ使正常大鼠门静脉压下降２９．７９±９．７８％（Ｐ＜０．０１），并拮抗苯肾上腺素升高门静脉压的作用。大鼠利血平化后，哌唑嗪不再降低门静脉压，而ｌ－ＴＨＰ仍使门静脉压下降１５．９８±５．１７％（Ｐ＜０．０５）。提示α１受体阻断作用是ｌ－ＴＨＰ降低门静脉压的主要机理之一，α１受体以外降门静脉压机理亦共同参与作用。     

左旋四氢巴马汀和左旋千金藤啶碱对吗啡处理大鼠相关脑区神经胶质纤维酸性蛋白的影响

目的：研究慢性吗啡处理大鼠相关脑区神经胶质纤维酸性蛋白（GFAP）的改变，以及左旋四氢巴马汀和左旋千金藤啶碱的干预作用。方法：以剂量递增给药方式建立吗啡慢性依赖模型后分别给予左旋四氢巴马汀、左旋千金藤啶碱和等体积蒸馏水（作为自然戒断组）治疗30d。制备相关脑区的冰冻切片，进行GFAP的免疫组织化学染色，测定阳性细胞的平均吸收度。结果：自然戒断组大鼠前额叶皮质、伏隔核壳区、海马CA．区、黑质、杏仁核的GFAP表达与正常对照组无显著差异，但中脑腹侧背盖区（VTA）GFAP表达较正常对照组显著升高。左旋四氢巴马汀及左旋千金藤啶碱组大鼠脑VTA区GFAP表达较自然戒断组均显著降低，且可达到正常水平。结论：GFAP表达持续升高反映吗啡处理对VTA区的损伤，左旋四氢巴马汀及左旋千金藤啶碱可以使GFAP表达恢复正常，可能是它们对成瘾药物的精神依赖性有干预作用的机制之一。     

Effects of four dopamine agonists on l-tetrahydropalmatine-induced analgesia and electroacupuncture analgesia in rabbits

The effects of icv 4 dopamine (DA) agonists on analgesia caused by iv l-tetrahydropalmatine (THP) 8 mg/kg or by electro-acupuncture (EA) were studied by using the potassium iontophoretic dolorimetry in rabbits. The results showed that both THP-induced analgesia and EA analgesia were markedly attenuated by icv of DA or apomorphine (Apo), 2 mixed D1/D2 agonists. Similar results were obtained when SKF-38393, a selective D1 agonist, was applied. On the contrary, quinpirole hydrochloride (Qui), a selective D2 agonist, was found to enhance the analgesic action of THP or EA. However, DA, Apo, SKF-38393 or Qui per se did not influence the baseline pain threshold. All these observations indicate that functional alterations in DA receptor activities may be involved in THP-induced analgesia and EA analgesia, in which D1 and D2 subtype receptors exert different roles.     

Potentiation of morphine analgesia by muscimol

The injection of 0.15 to 0.2 mg/kg of muscimol intravenously, lowered the ED₅₀ dose of morphine in mice and rats. Maximal tolerated doses of muscimol failed to cause alangesia when injected alone     

Potentiation of morphine analgesia by d-amphetamine

Rats were trained to escape from aversive electrical brain stimulation delivered to the mesencephalic reticular formation (MRF). The threshold for this escape behavior was determined by a modification of the classic psychophysical method of limits. Escape thresholds were determined after the administration of morphine alone, d-amphetamine alone, and the combination of d-amphetamine and an ineffective dose of morphine. Morphine alone caused a dose-dependent raising of the escape threshold (1.0–16.0 mg/kg IP) while d-amphetamine alone (0.06–2.0 mg/kg IP) had no effect or caused a slight lowering of threshold. For each animal, a dose of morphine that produced no change in escape threshold was then selected to be administered concomitantly with various doses of d-amphetamine. The co-administration of morphine and d-amphetamine resulted in a significant, dose-dependent increase in the escape threshold, which was not seen with d-amphetamine alone and was as great or greater in magnitude than the increase seen with the highest dose of morphine tested. The results of this study clearly demonstrate that opiate analgesia is potentiated by concomitant d-amphetamine administration. The mechanisms involved in this potentiation warrant further investigation for the clinical management of pain.     

Potentiation of morphine analgesia by caffeine.

Significant potentiation of morphine (5 mg kg-1 s.c. or 1 mg kg-1 i.v.) analgesia (tail-withdrawal reflex at 55 degrees C) was observed in caffeine-treated (100 mg kg-1 i.p.) rats as compared to the control group and lower doses of caffeine (2mg kg-1 i.p.) did not show this effect. Potentiated analgesia was reversed by naloxone. Pharmacokinetic or dispositional factors appear to be involved in part in this potentiation.     

Potentiation of cold-water swim analgesia and hypothermia by clonidine

The analgesia induced by acute exposure to cold-water swims (CWS) covaries with levels of brain norepinephrine and is reduced by lesions placed in the locus coeruleus. In assessing whether alpha-noradrenergic receptor mechanisms mediated CWS analgesia, the first experiment found that clonidine pretreatment (500, 1000 micrograms/kg) elevated jump thresholds 60 min following injection. While clonidine (1000 micrograms/kg) paired with a 2 degrees C CWS potentiated CWS analgesia in a synergistic manner, additivity of analgesic effects was observed following pairing of clonidine (500 micrograms/kg) with a 2 degrees C CWS and pairing of clonidine (500 and 1000 micrograms/kg) with a 15 degrees C CWS. The second experiment showed that clonidine (500 micrograms/kg) paired with a 2 degrees C CWS enhanced CWS enhanced CWS analgesia on the tail-flick test. The third experiment indicated that while clonidine (500 and 1000 micrograms/kg) or CWS (2 degrees C) each produced hypothermia, pairing of these clonidine doses with CWS enhanced CWS hypothermia. These data are discussed in terms of the possible modulatory role that norepinephrine, and particularly its alpha-noradrenergic receptor subclass, plays in the full expression of CWS analgesia and hypothermia.     

Neuropharmacological analysis of electroacupuncture analgesia

It was established in experiments on conscious rats using concurrent recording of pain sensitivity and evoked potentials that the leading part in electroacupuncture analgesia is played by endogenous opioid peptides. However, numerous pharmacological substances can alter the level of electroacupuncture analgesis suggesting the participation in its genesis of different mediator cerebral systems. In the animals resistant to acupuncture, administration of morphine did not produce marked analgetic effect.     

Potentiation of morphine analgesia by subanesthetic doses of pentobarbital

Pentobarbital pretreatment reportedly either inhibits, enhances or has no effect on morphine analgesia. The effect of subanesthetic doses of sodium pentobarbital (8-12 mg kg-1, SC) delivered via a delivery system on analgesia of morphine (5 mg kg-1, SC or 1 mg kg-1, IV) acutely administered 45 min after the sodium pentobarbital pellet implantation was assessed using the warm water (55 degrees C)-induced tail-withdrawal reflex in male Wistar rats. Significant potentiation of morphine analgesia was observed in sodium pentobarbital as compared to the placebo-pelleted animals. Pharmacokinetic or dispositional factors were not involved in this potentiation, which was possibly due to the activation of the descending inhibitory control pathways of nociceptive spinal tail-withdrawal reflex by a combined interaction of two drugs at spinal and supraspinal sites of action, that mediate opiate antinociception.