纳曲酮与纳洛酮对吗啡,依托尼秦及羟甲芬太尼的拮抗作用…

在整体和受体水平对阿片受体拮抗剂的纳曲酮和纳洛酮对吗啡，依托尼秦和「＾３Ｈ」羟甲芬太尼的拮抗作用进行了比较。研究表明，在整体水平，纳曲酮在很小剂量下就能对抗吗啡在小鼠的镇痛作用，小鼠吗啡急性中毒以及依托尼秦致大鼠翻正反射消失。     

Human μ-opioid receptor overexpressed in baculovirus system and its pharmacological characterizations

目的：高效表达具有类似哺乳动物特性的人μ阿片受体．方法：人μ阿片受体表达在重组杆状病毒感染的Ｓｆ９昆虫细胞中，用受体结合分析和ｃＡＭＰ分析研究表达产物的药理学特征．结果：［３Ｈ］二丙诺啡及［３Ｈ］羟甲芬太尼（Ｏｈｍ）的最大结合能力分别是９．１±０．７，６５２±０．２３ｎｍｏｌ／ｇ蛋白．μ选择性激动剂对［３Ｈ］二丙诺啡或［３Ｈ］Ｏｈｍ与表达受体的结合均有很强的抑制作用，而δ及κ激动剂则均无抑制作用．μ选择性激动剂有效抑制ｆｏｒｓｋｏｌｉｎ刺激的ｃＡＭＰ聚集，这种作用能被拮抗剂纳洛酮阻断．结论：在Ｓｆ９昆虫细胞中高效表达的人μ阿片受体保持着野生型人μ阿片受体的特征     

新的高强度高选择性阿片μ受体激动剂［~11C］－羟甲芬太尼的合成

羟甲芬太尼（Ｉ）是一个新的高强度高选择性阿片μ受体激动剂。本文用ｃｉｓ－Ａ－Ｎ－［１－（２－羟基－２－苯乙基）－３－甲基－４－哌啶基］－苯胺（ＩＩ）或ｃｉｓ－Ｎ－［１－（苯甲酰甲基）－３－甲基－４－哌啶基］－苯胺（ＩＩＩ）作为前体合成了［１１Ｃ］－羟甲芬太尼，以便用正电子发射断层扫描（ＰＥＴ）来观察μ受体。通过水解ｃｉｓ－Ａ－羟甲芬太尼（Ｉ）和ｃｉｓ－Ｎ－［１－（苯甲酰甲基）－３－甲基－４－哌啶］－Ｎ－苯基丙酰胺（ｃｉｓ－ＩＶ）的４－Ｎ－丙酰基分别获得ＩＩ和ＩＩＩ。溴乙烷的格氏试剂与回旋加速器产生的［１１Ｃ］－二氧化碳反应后继而直接加入邻苯二甲酸二酰氯和２，６－二叔丁基吡啶生成同位素标记中间体［１１Ｃ］－丙酰氯。［１１Ｃ］－丙酰氯与ＯＨ－前体（ＩＩ）反应后再经ＨＰＬＣ分离纯化直接得［１１Ｃ］－羟甲芬太尼；［１１Ｃ］－丙酰氯与酮－前体（ＩＩＩ）反应后，再用硼氢化钠甲醇溶液处理，然后进行ＨＰＬＣ分离纯化得［１１Ｃ］－羟甲芬太尼。两种方法均可获得ｌｌ．１～１４．８ＧＢｑ／μｍｏｌ的特异性放射化学纯［１１Ｃ］－羟甲芬太尼。总共耗时为４０～５０ｍｉｎ（ＥＯＢ）。     

三种国产阿片受体拮抗剂催促活性的比较研究

用大鼠和小鼠对三种国产阿片受体拮抗剂-纳络酮、环丙羟丙吗啡、烯丙吗啡的催促作用强度进行了比较，研究结果表明：1．使用剂量逐步递增方式给药，可在短期内使大鼠和小鼠对吗啡、芬太尼、噻芬太尼和强痛定产生快速耐受和身体依赖性；2．三种国产阿片受体拮抗剂的催促作用强度从强到弱依次为：环丙羟丙吗啡，纳络酮，烯丙吗啡，与国外从拮抗镇痛强度方面所报道结果相一致；3．国产环丙羟丙吗啡与纳络酮的催促活性基本相近。     

纳曲酮国产品与进口品的药效和药物代谢动力学比较

纳曲酮国产品与进口品的药效和药物代谢动力学比较王小铁李桦秦伯益（军事医学科学院毒物药物研究所，北京１００８５０）纳曲酮是继纳洛酮之后研制成功的又一阿片受体拮抗剂．与纳洛酮相比，纳曲酮具有强效，长效，口服有效的特点．在小鼠，我们比较了纳曲酮国产品与进口...     

［~3H］二氢埃托啡与大鼠脑膜阿片受体的结合

目的：观察二氢埃托啡（ＤＨＥ）与阿片受体的结合情况．方法：采用放射配体受体结合实验，观察了［３Ｈ］ＤＨＥ与大鼠脑膜阿片受体的结合．结果：饱和实验显示［３Ｈ］ＤＨＥ的结合呈高亲和力单一位点，Ｋｄ＝０１９±００５ｎｍｏｌ·Ｌ－１，Ｂｍａｘ＝１１５±２１ｐｍｏｌ／ｇｐｒｏｔｅｉｎ．动力学实验表明［３Ｈ］ＤＨＥ与阿片受体结合极快，解离很慢．ＮａＣｌ１００ｍｍｏｌ·Ｌ－１＋鸟苷三磷酸（ＧＴＰ）５０μｍｏｌ·Ｌ－１可使［３Ｈ］ＤＨＥ的Ｋｄ值提高为７８７ｎｍｏｌ·Ｌ－１，Ｂｍａｘ值不变．激动剂和拮抗剂的竞争抑制实验均表明［３Ｈ］ＤＨＥ与μ阿片受体的亲和力大于δ和κ受体．结论：ＤＨＥ对μ阿片受体具有一定选择性．     

抗羟甲芬太尼单克隆抗体

采用细胞融合和单克隆技术，获得抗羟甲芬太尼单克隆抗体ＭＡｂ－Ｄ２和ＭＡｂ－Ｆ４．ＭＡｂ－Ｄ２和ＭＡｂ－Ｆ４与Ｏｈｍ－ＢＳＡ结合亲和力高、专一性强。ＭＡｂ－Ｄ２和ＭＡｂ－Ｆ４还能抑制［３Ｈ］Ｏｈｍ与大鼠脑匀浆膜蛋白上的阿片受体的结合，并能对抗浆膜蛋白上的阿片受体的结合，并能对抗Ｏｈｍ的抑制电场刺激引起豚鼠回肠收缩的作用。以上结果表明ＭＡｂ－Ｄ２和ＭＡｂ－Ｆ４是特异性的抗Ｏｈｍ单克隆抗体，作为Ｏｈｍ的     

兔小脑μ阿片受体的特性及其分布

应用放射配体结合试验和放射自显影研究了［＾３Ｈ］羟甲芬太尼（［＾３Ｈ］ＯＭＦ），［＾３Ｈ］埃托啡（［＾３Ｈ］Ｅｔｏ），［＾３Ｈ］Ｕ６９５９３和［＾３Ｈ］ＤＰＤＰＥ与兔小脑的结合特性。［＾３］ＯＭＦ和［＾３Ｈ］Ｅｔｏ与兔小脑有一呈饱和性的单位点的结合，它们的Ｋｄ分别为２．２±１．３和１．０±０．４ｎｍｏｌ·Ｌ＾－１，Ｂｍａｘ分别为６９±１３和１６±６ｆｍｏｌ／ｍｇ蛋白。［＾３Ｈ］Ｕ６９５９３和［＾３     

脑室注射ACTH对抗羟甲芬太尼引起的镇痛

通常中枢注射促肾上腺皮质激素（ＡＣＴＨ）能够拮抗阿片的镇痛作用，然而其机制尚未阐明。本实验用辐射热─甩尾法测定痛阈，ｓｃｍｕ型阿片受体高选择性激动剂──羟甲芬太尼（０．８μｇ·ｋｇ－１），引起明显的镇痛效应，然后ｉｃｖＡＣＴＨ。发现小剂量的ＡＣＴＨ（１５．６～２５０ｎｇ）即可剂量依赖性抑制羟甲芬太尼的镇痛效应，其最大抑制率为７７．３％，半数有效量为１０７ｎｇ。单独注射ＡＣＴＨ２５０ｎｇ对基础病阈无影响。结果提示，ＡＣＴＨ在ｍｕ型阿片受体介导的镇痛中起重要作用。     

6β-纳曲醇与纳曲酮拮抗吗啡镇痛作用的比较

目的　比较 6 β 纳曲醇 ( 6 β naltrexol,6 β NOL)与纳曲酮 (naltrexone ,NTX)拮抗吗啡的镇痛作用。 方法　用小鼠热板法和小鼠热辐射甩尾法 ,sc和ig两种途径研究 6 β NOL和NTX拮抗吗啡镇痛作用的强度和有效时间。用放射配体结合实验研究 6 β NOL和NTX对阿片受体的亲和力。 结果　小鼠热板法和甩尾法显示 ,6 β NOL的抗吗啡镇痛作用强度和有效时间分别约为NTX的 ( 6 1± 1 7) %和 3～ 4倍 ;po拮抗吗啡镇痛作用强度约为sc的 30 % ,与NTX相近。在受体水平 ,6 β NOL对阿片 mu受体的亲和力约为NTX的 12 5 % ,这与它们在整体水平拮抗吗啡镇痛作用的强度相近。结论　 6 β NOL抗吗啡镇痛作用比NTX弱 ,但作用时间长     

Effects of ohmefentanyl on rat respiration

The respiratory depression in rats induced by sc ohmefentanyl showed a ceiling effect, but a linear relation with log dose when applied into the dorsal medulla. It elicited, however, a marked excitation on respiration when applied to dorsal pons. This excitatory effect of ohmefentanyl was antagonized by naloxone, and it antagonized to some extent the respiratory depressant effect induced by ohmefentanyl itself applied on dorsal medulla. It was postulated that the respiratory excitatory effect of sc ohmefentanyl on dorsal pons may have a bearing on the ceiling effect of its respiratory depression.     

Analgesic activity and opioid receptor selectivity of stereoisomers of ohmefentanyl isothiocyanate.

Ohmefentanyl is a very potent and highly selective agonist for mu-opioid receptors. We now study analgesia, in vitro activity and opioid receptor affinity of the stereoisomers of ohmefentanyl isothiocyanate. We found that some isomers of ohmefentanyl isothiocyanate had a potent analgesic effect and that all isomers except (3R,4S,2'S)-ohmefentanyl isothiocyanate had a more potent inhibitory action on the electrically evoked contractions of mouse vas deferens than of guinea pig ileum. The inhibitory actions could be antagonized by naloxone. However, compared with the activity of the corresponding stereoisomers of ohmefentanyl, these ohmefentanyl isothiocyanates had significantly reduced analgesia and in vitro activity. They also inhibited the binding of [3H]DPDPE ([D-Pen(2),D-Pen(5)]enkephalin) and [3H]DAGO ([D-Ala(2),Mephe(4),Gly-ol(5)]enkephalin) to opioid receptors in mouse brain membranes. The inhibitory effect of stereoisomers of ohmefentanyl isothiocyanate at mu-opioid receptors was markedly lower than that of their parent compounds. The affinity of stereoisomers of ohmefentanyl isothiocyanate for delta-opioid receptors was, however, greater than or equal to that of their corresponding stereoisomers of ohmefentanyl. The results showed that the introduction of an isothiocyanato group into the phenyl ring in position-1 of ohmefentanyl reduced bioactivity and affinity to mu-opioid receptors but that the selectivity of these compounds for delta-opioid receptors was enhanced. Isomer (3R,4S,2'R)-ohmefentanyl isothiocyanate showed highest selectivity for delta-opioid receptors (K(i)(mu)/K(i)(delta)=13.6) and potent analgesic activity (ED(50)=0.25 mg/kg).     

The discriminative stimulus effects of naloxone and naltrexone in morphine-treated rhesus monkeys: comparison of oral and subcutaneous administration

  Rationale: Opioid antagonists are used to reverse the toxic effects of opioids, to diagnose opioid dependence and to treat opioid and other (alcohol) drug abuse. Objectives: This study compared the discriminative stimulus effects of two opioid antagonists (naloxone and naltrexone), after parenteral and oral administration. Methods: The discriminative stimulus effects of naloxone and naltrexone were evaluated every 15 min over a 2-h period in four morphine-treated (3.2 mg/kg per day) rhesus monkeys discriminating between subcutaneous (SC) injections of naltrexone (0.01 or 0.032 mg/kg) and saline, while responding under a fixed-ratio 5 schedule of stimulus shock termination. Results: Within 15 min of SC administration, naloxone and naltrexone produced greater than 90% drug-appropriate responding at doses of 0.032 and 0.01 mg/kg, respectively. The largest dose of naloxone (3.2 mg/kg) administered orally produced 82% drug-appropriate responding within 90 min; the same dose of naltrexone administered orally produced greater than 90% drug-appropriate responding within 30 min. Although both drugs were at least 100-fold more potent when administered SC, as compared to orally, there was little difference (3-fold) between the potency of naloxone and naltrexone by either route. Conclusions: These results fail to support the view that naloxone has reduced bioavailability after oral administration, as compared to naltrexone, or that its pharmacokinetic profile is particularly advantageous for some therapeutic settings (e.g. Talwin Nx). Received: 15 July 1998 / Final version: 21 December 1998     

Role of endogenous opioids on ventilation and chemical control of breathing in pentobarbitone-anesthetized rats

To investigate the role of endogenous opioids on ventilatory control in pentobarbitone-anesthetized rats, the opioid antagonists naloxone and naltrexone were studied for their effects on ventilation, arterial blood gases and on ventilatory responses to hypoxia and carbon dioxide. In animals breathing room air, intravenous administration of naloxone and naltrexone (4 and 10 mg/kg) caused a dose-related increase in tidal volume, respiratory rate and minute volume. These ventilatory responses were rapid in onset and were associated with a decrease in arterial PaCO2, an increase in arterial pH and an increase in arterial PaO2. Intravenous naloxone (4 mg/kg) antagonized the increase in PaCO2 and decrease in arterial pH induced by the administration of morphine (3 mg/kg, i.v.). In animals breathing 100% O2, intravenous administration of naloxone and naltrexone (4 and 10 mg/kg) did not stimulate ventilation. Furthermore, intracerebroventricular administration of naloxone (15 and 150 micrograms) had no measurable effect on ventilation. Ventilatory responses to both hypoxia and carbon dioxide were not augmented by intravenous naloxone (4 mg/kg) and naltrexone (4 and 10 mg/kg). In fact, the increase in respiratory rate due to hypoxia was significantly (p less than 0.05) reduced by naltrexone (10 mg/kg, i.v.). In conclusion, our results demonstrate that naloxone and naltrexone caused hyperventilation in pentobarbitone-anesthetized rats. This effect was probably triggered by stimulation of the peripheral arterial chemoreceptors and did not involve mechanisms directly associated with the central nervous system. However, endogenous opioids were not involved in the chemical control of breathing in pentobarbitone-anesthetized rats since ventilatory responses to hypoxia and carbon dioxide were not changed by administration of these opioid antagonists.     

Naloxone pretreatment blocks acute morphine-induced sensitization to naltrexone

The present experiment was designed to examine whether the acute sensitization to naltrexone that is induced by a single dose of morphine could be blocked by pretreatment with naloxone. Food-deprived male Sprague-Dawley rats were trained to respond for food on a multiple-trial fixed interval 3-min schedule. Reinforcement was contingent upon a response within a 10-s limited hold period following a fixed interval of 3 min. A trial consisted of three fixed intervals separated by a 10-min timeout period during which responses were not reinforced. The rate decreasing effects of the opioid antagonist naltrexone were determined by cumulative dosing. Pretreatment with morphine (3.0 mg/kg, SC) resulted in a 70-fold increase in sensitivity to the response rate decreasing effect of naltrexone compared with saline pretreatment. The increased sensitivity was dose-dependently blocked by naloxone administration 10 min before morphine. The blockade by naloxone was overcome by increasing the pretreatment dose of morphine to 10 mg/kg. The results provide further evidence that acute agonist-induced sensitization to the rate-reducing effects of naltrexone is mediated by opioid receptors.     

Effects of naloxone and naltrexone on memory consolidation in CD1 mice: involvement of GABAergic mechanisms

The involvement of GABAergic mechanisms in the effects exerted by the opioid antagonists naloxone and naltrexone on memory consolidation was investigated in CD1 mice tested in a one-trial inhibitory avoidance task. In a first group of experiments posttraining administration of naloxone (2.0 and 4.0 but not 1.0 mg/kg) and naltrexone (0.5 and 1.0 but not 0.25 mg/kg), as well as those of the GABA-antagonists picrotoxin (0.5 and 1.0 but not 0.25 mg/kg) and bicuculline (0.25 and 0.5 but not 0.1 mg/kg) enhanced, whereas those of the GABA-agonist muscimol (1.0 and 2.0 but not 0.5 mg/kg) impaired retention on a 24-hr test. In a second group of experiments, picrotoxin, or bicuculline, administration enhanced, while muscimol treatment attenuated the effects of naloxone and naltrexone on retention. The results suggest that naloxone and naltrexone may influence memory consolidation in CD1 mice by interacting with the GABAergic system.     

Interactions between narcotic agonists,partial agonists and antagonists evaluated by punished and unpunished behavior in the rat

The effects of morphine, ketocyclazocine, cyclazocine, and SKF-10,047 were tested alone and in conjunction with naltrexone or naloxone, in rats responding under a multiple fixed-interval 3-min schedule of food presentation. Under this paradigm, electric shock was delivered on a fixed-ratio schedule for responses occurring during alternate schedule components. All of the drugs (except naltrexone and naloxone) decreased average rates of responding maintained by the unpunished component in a dose-dependent manner. The rate-decreasing effects of morphine and ketocyclazocine were antagonized by naltrexone. The rate-decreasing effects of cyclazocine were only slightly reversed by the antagonists, while those effects of SKF-10,047 were not affected by naltrexone. In some animals, certain doses of SKF-10,047 increased unpunished responding. This rate-increasing effect was antagonized by naltrexone. Morphine, ketocyclazocine, cyclazocine, and SKF-10,047 increased responding that was suppressed by electric shock, and these increases were antagonized by naltrexone and naloxone. Thus, the antagonism of opiate effects by narcotic antagonists depends in part on the behavior being evaluated.In partial fulfillment of the degree of Master of Arts in Clinical Psychology     

Effects of naloxone and naltrexone on locomotor activity in C57BL/6 and DBA/2 mice

Administration of naloxone or naltrexone in DBA/2 (DBA) mice was followed by dose related depressant effects. The locomotor activity of the C57BL/6 (C57) mice injected with naltrexone was also depressed. Low doses of naloxone induced a decrease in activity in the C57 strain. This effect gradually disappeared at intermediate doses and recurred again at higher doses. The results are discussed in terms of differences in type number and/or distribution of the receptors influenced by naloxone and naltrexone in the two strains of mice tested.     

Opioid modulation of thermal dehydration-induced thirst in rats.

Male Sprague-Dawley rats were utilized to study the effects of the opioid receptor antagonists, naloxone and naltrexone, on thirst induced by thermal dehydration. In an initial experiment, the depressant effect of naloxone (1.0 mg/kg, IP) on the water intake of rats deprived of water for 24 h was confirmed. In subsequent experiments, rats were thermally dehydrated by exposing them without water to a 40 degrees C environment for 1-4 h. Following heat exposure, rats were injected with either naloxone or naltrexone either IP or ICV. Fifteen minutes later, rats were provided with water and water intake was measured for 2 h. Both naloxone and naltrexone had dose (0.1-5.0 mg/kg, IP)-dependent effects of reducing water intake of rats thermally dehydrated for 3 h. Water intake of rats thermally dehydrated for 2 or 4 h was also attenuated by pretreatment with naloxone. Rats thermally dehydrated for 3 h exhibited decreases in water intake following ICV injection of either naloxone or naltrexone at a dose of 50 micrograms. Neither naloxone nor naltrexone had an effect on urine output in any experiment. The water intake data support the hypothesis that thirst induced by thermal dehydration in rats is modulated by an opioid mechanism.     

The involvement of histamine receptors in morphine-induced increased naloxone potency in mice

In the present study, the effect of histamine agonists and antagonists on morphine antinociception and naloxone antagonism were studied. The antinociceptive effect of morphine and the antagonistic effect of naloxone were measured by the acetic acid-induced abdominal constriction test in mice. It was found that pretreatment with 2-methylhistamine, a histamine H1-receptor agonist, altered neither the antinociceptive effect of morphine nor the antagonistic effect of naloxone. When 2-methylhistamine was given together with morphine as pretreatment, the naloxone potency was enhanced compared with pretreatment by morphine alone. Pretreatment with 2-pyridylethylamine, another histamine H1-receptor agonist, alone or in combination with morphine, altered neither the antinociceptive activity of morphine nor the antagonistic potency of naloxone. Pretreatment with 4-methylhistamine, a histamine H2-receptor agonist, did not alter the antinociceptive activity of morphine or the antagonistic effect of naloxone. However, when given together with morphine as the pretreatment, the antinociceptive effect of morphine as well as the antagonistic activity of naloxone were enhanced. Similar effects were observed with dimaprit, another histamine H2-receptor agonist. Pretreatment with diphenhydramine, a histamine H1-receptor antagonist, alone or in combination with morphine, altered neither the antinociceptive effect of morphine nor the antagonistic activity of naloxone. Pretreatment with cimetidine, a histamine H2-receptor antagonist, did not affect the antinociceptive effect of morphine and the antagonistic potency of naloxone. However, when given together with morphine as pretreatment, it suppressed the ability of morphine in inducing an increase in naloxone potency. Similar effects were observed with ranitidine, another histamine H2-receptor blocker.(ABSTRACT TRUNCATED AT 250 WORDS)