酮咯酸,一种具有强力镇痛作用的非甾体类抗炎药

酮咯酸是一种新型非甾体类抗炎药,为一强效前列腺素合成酶抑制剂,其镇痛作用强度类似或强于吗啡、哌替啶,且不抑制呼吸也无成瘾的危险。口服和注射均有效,无局部刺激性。主要用途为减轻术后疼痛,可作为麻醉性镇痛药的代用品。     

不同分型钙通道阻滞剂在吗啡成瘾中的作用

长期应用吗啡可产生成瘾,Ca2+参与镇痛和成瘾过程的形成。近年来研究发现不同分型钙通道阻滞剂对吗啡的镇痛、耐受和依赖等药理作用具有不同的影响,为进一步阐明吗啡成瘾机制和戒毒药物的研究提供了新的启示。     

吗啡的抗炎免疫作用

<正> 吗啡具有多种作用,如镇痛、呼吸抑制、镇静等。这些作用多是由于中枢神经系统的受体介导的。一般认为,吗啡脊髓水平以上的镇痛作用、欣快症、呼吸抑制及机体的依赖性主要是与μ受体结合的结果;κ受体主要与脊髓水平的镇痛作用、缩瞳及镇静作用有关;δ受体则主要与焦虑、致幻作用及心脏刺激作用有关。 一、吗啡的外周镇痛作用 近年来,吗啡的外周镇痛作用受到了     

14-羟基吗啡酮的镇痛作用

本文直接比较了14-羟基吗啡酮和吗啡的镇痛作用,研究了纳络酮对14-羟基吗啡酮镇痛作用的拮抗作用,观察了14-羟基吗啡酮的毒副反应。改装幻灯机为辐射热刺激装置,用于镇痛实验。     

胍丁胺对炎性疼痛的镇痛作用及对吗啡镇痛作用的影响

目的观察胍丁胺对炎性疼痛的镇痛作用及其对吗啡镇痛作用的影响,研究胍丁胺的镇痛作用是否与激动咪唑啉受体或影响受体前谷氨酸和γ-氨基丁酸(gamma-aminobutyr-icacid,GABA)释放有关。方法应用福尔马林致大鼠炎性疼痛模型,观察胍丁胺镇痛和增强吗啡镇痛的作用。应用高效液相色谱技术测定胍丁胺对脊髓切片孵育液中谷氨酸和GABA基础释放量及对高钾诱发神经元去极化引起神经递质释放的影响。结果单侧足底注射5%福尔马林使大鼠出现明显的双相伤害性行为反应。胍丁胺抑制福尔马林引起的第二相疼痛行为反应及痛觉过敏,并增强吗啡对第二相疼痛的镇痛作用,但在第一相疼痛过程中,无明显镇痛和增强吗啡镇痛的作用。咪唑啉受体拮抗剂咪唑克生不能拮抗胍丁胺镇痛及增强吗啡镇痛的作用。1~1000μmol.L-1胍丁胺对脊髓谷氨酸和GABA的基础释放量和高钾诱发谷氨酸和GABA释放量的升高均没有影响。结论胍丁胺对炎性疼痛具有明确的镇痛作用,并明显增强吗啡的镇痛效果,其镇痛机制可能与咪唑啉受体无关,也不是通过在受体前水平抑制谷氨酸或促进GABA释放来实现的。     

纳洛酮临床应用的研究进展——神经精神、内分泌、代谢和心血管系统方面

1960年Fishman 首先合成了纳洛酮(N-Allylynorexy Morphone;Naloxone 缩写N_x)。其结构虽似吗啡,但不成瘾,故不属麻醉药物禁限范围。N_x与具有双向激动-拮抗作用的药物如烯丙甲吗啡(Nalorphin);丙烯左吗喃(Levallorphan)和镇痛新(Pentazocine)等不同,N_x只具有拮抗中枢性麻醉药的作用。它极易通过血脑屏障,能较快地与内源性μ、K和σ三种阿片受体起竞争性拮抗作用,其中与μ受体亲合力最强。1961年Blumberg 报导N_x对镇痛有拮抗作用。近年来由于镇痛原理的研     

合成镇痛剂及拮抗剂的新进展

吗啡是阿片的主要成分,其镇痛作用确切,效果良好,但也有许多不良的副作用如呼吸抑制,便秘、昏睡、呕吐等,但最大的问题是容易成瘾及产生耐药性,因而受到麻醉品条例的严格控制。为了寻找不成瘾的镇痛剂,并减少吗啡的其它副作用,进行了大量的合成筛选及作用原理的研究工作,早期的工作大多围绕着用半合成方法改变吗啡结构。自从1939年度冷丁被合成并肯定其镇痛作用以来,特别是近廿年来,新镇痛剂研究的数量和质量都取得显著进展,但寻找不成瘾镇痛剂的任务还远未解决,随着新化合物的不断出现和新的药理作用的不断     

6β-纳曲醇与纳曲酮拮抗吗啡镇痛作用的比较6β-纳曲醇与纳曲酮拮抗吗啡镇痛作用的比较

目的比较6β-纳曲醇(6β-naltrexol,6β-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6β-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6β-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,6β-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,6β-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6β-NOL抗吗啡镇痛作用比NTX弱,但作用时间长。     

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     

视上核催产素神经元在吗啡依赖中的作用

吗啡是一种疗效显著的麻醉性镇痛药,但长期以来吗啡的成瘾性一直困扰着人类,为了克服吗啡成瘾问题,人们做了大量的研究工作。目前,对吗啡依赖机制还没有完全认识,根治吗啡成瘾,尤其是解除吗啡的精神依赖性,仍是一大难题。催产素是一种垂体神经肽,它参与痛觉调制和加强阿片类物质的镇痛作用,并可影响药物成瘾性和学习记忆过程。近年的研究结果表明,催产素与吗啡依赖存在着密切联系,催产素可抑制吗啡耐受的形成过程,而吗啡及其类似物可抑制催产素释放。那么催产素神经元与吗啡依赖之间可能存在着怎样的联系呢？催产素神经元主要集中分布在下丘…     

Influence of thyrotropin releasing hormone (TRH) on drug-induced narcosis and hypothermia in rabbits

Thyrotropin releasing homone (TRH) administered via the intracerebroventricular (icv) route in doses ranging between 0.1 and 100 g decreased the duration of pentobarbital-induced narcosis in rabbits. Antagonism of narcosis occurred whether TRH was administered before or after the barbiturate. TRH doses above 10 g produced, in addition, behavioral excitation and hyperthermia. The antagonism of phenobarbital-induced narcosis was not as profound; animals were aroused only for a short period of time, after which the narcotized state returned. However, TRH exerted a prolonged antagonism or reversal of the phenobarbital-induced hypothermia. The central nervous system depression and analgesia produced by morphine were unaffected by TRH, but hypothermia and respiratory depression were reversed. TRH may represent an arousal factor in mammalian brain.     

Naloxone as a GABA antagonist: evidence from iontophoretic, receptor binding and convulsant studies

TRH and a new TRH analog (all L-pyro-2-aminoadipyl-histidyl-thiazolidine-4-carboxamide, MK-771) have been compared with several other peptides for their "analeptic" activity and their ability to enhance the excitatory actions of microiontophoretically applied acetylcholine (ACh) on cerebral cortical neurons of rats. TRH and MK-771 offset the narcosis induced by pentobarbital in mice, whereas the C-terminal free acid derived from TRH, melanostatin, somatostatin and pyroglutamyl-histidineamide have been found inactive. Similarly, of these peptides only TRH and MK-771 induced a tremor of the forepaws in pentobarbital-anesthetized mice. Employing comparable ejection currents and durations, only TRH and MK-771, applied by microiontophoresis, enhanced the excitatory actions of ACh on spontaneously active cortical neurons in anesthetized rats. Based on these findings and other recent data, it is suggested that the interactions of TRH and MK-771 with cholinergic mechanisms may underlie some of the actions, including their anti-anesthetic effects, of these peptides.     

Comparative effects of thyrotropin releasing hormone,MK-771 and DN-1417 on morphine abstinence syndrome

The effect of thyrotropin releasing hormone (TRH) were compared with two of its analogs, l-N-(2-oxopiperidin-6-yl-carbonyl)-l-histidyl-l-thiazolidine-4-carboxamide (MK-771) and -butyrolactone-4-carboxyl-histidylprolineamide (DN-1417) on the abrupt and naloxone-precipitated abstinence symptoms in morphine-dependent male Swiss-Wester mice. Mice were made physically dependent on morphine by subcutaneous implantation for 3 days of a pellet containing 75 mg morphine free base. Control mice were implanted with placebo pellets. Intracerebral administration of TRH (10 ng-10 g per mouse) immediately after removal of placebo pellets had no effect on the basal temperature of mice. Mice implanted with morphine pellets exhibited a characteristic hypothermic response following the removal of the pellets. TRH at all doses employed prevented the hypothermia observed during abrupt withdrawal of morphine (pellet removal). DN-1417 and MK-771 (10 ng-10 g per mouse) on the other hand produced a short lived hyperthermic response in mice from which placebo pellets had been removed. However, both TRH analogs produced long-lasting antagonism of withdrawal hypothermia in mice from which morphine pellets had been removed. TRH and its analogs had no effect on the body weight loss observed during abrupt withdrawal of morphine. Intracerebral administration of 10 g TRH and its analogs inhibited the naloxone-induced jumping response as evidenced by increases in naloxone ED₅₀ values to elicit this response. It is concluded that TRH and its analogs may be useful in combating some of the withdrawal symptoms in opiate-dependent subjects.     

Stimulus properties of thyrotropin-releasing hormone

Male Sprague-Dawley rats were trained in a two-lever operant discrimination task using 20 mg/kg thyrotropin-releasing hormone (TRH) and saline as cues. Following completion of 40 daily training sessions, 22 of 25 subjects demonstrated a high level of discriminative responding based on the TRH and saline cues. An evaluation of the time course of TRH indicated that the stimulus properties peak between 5 and 15 min and dissipate substantially by 55–65 min. During additional testing, rats showed dose-dependent generalization between the training treatments (20 mg/kg TRH and saline) and novel doses of TRH (1, 5, 10, and 40 mg/kg). However, animals failed to show generalization between the training drug (20 mg/kg TRH) and d-amphetamine sulfate (0.8, 1.6, or 2.4 mg/kg); likewise, animals trained to discriminate d-amphetamine (0.8 or 1.6 mg/kg) from saline failed to show generalization between d-amphetamine and TRH (10, 20, or 30 mg/kg). Microgram quantities of TRH (2.5–25 g) administered into either the lateral or third ventricle elicited dose-dependent generalization to the training drug (TRH 20 mg/kg, i.p.), suggesting a CNS mechanism of action for this effect of TRH.     

Antagonizing effects of YM-14673, a new TRH derivative,on behavioral and electroencephalographic changes in reserpinized animals

Effects of YM-14673 (N-[{(S)-4-oxo-2-azetidinyl}-carbonyl]-l-histidyl-l-prolinamide dihydrate), a new TRH derivative, on reserpine-induced behavioural and electroencephalographic changes were observed in comparison with those of TRH. YM-14673 antagonized reserpine-induced hypothermia and decrease in convulsion threshold in mice. The number of PGO waves recorded from the lateral geniculate body was decreased by administration of YM-14673 in reserpinized cats. The anti-reserpine activity of intravenous YM-14673 was about 8–20 times more potent than that of TRH. In inhibiting reserpine-induced hypothermia, the oral ED_2°C relative to IV ED_2°C as an indirect indication of absorption rate of the drugs was 15 for both YM-14673 and TRH. These results suggest that YM-14673 possesses more potent facilitatory effects on the central monoamine systems than TRH.     

Antagonism of the analeptic activity of thyrotropin-releasing hormone (TRH) by agents which enhance GABA transmission

Administration of 10 mg/kg TRH to mice was found to reduce the sleep and hypothermia induced by 4.7 g/kg ethanol. However, TRH did not reduce the sleep of mice that were given -hydroxybutyric acid (GHBA), baclophen, or aminooxyacetic acid (AOAA) in combination with 3 g/kg ethanol. TRH also failed to reverse the hypothermia induced by the combination of ethanol and baclophen or GHBA, and the characteristic neurological effects of TRH e.g. tremor, increased muscle tone, and increased respiratory rate were reduced. In addition, TRH-induced locomotor stimulation was prevented by pretreatment with small doses of the GABA-ergic agents, and while 30 mg/kg TRH reduced the hypothermia produced by large doses of the GABA-ergic drugs, it did not antagonize the locomotor retardation produced by baclophen or GHBA. A hypothesis that the analeptic effects of TRH may be mediated via an inhibition of GABA systems is discussed.     

Effects of a new TRH analogue,YM-14673 on a passive avoidance test as a possible criterion of improvement in cognitive disturbance in rodents

Summary Effects of a new TRH analogue, YM-14673 (N-[[(S)-4-oxo-2-azetidinyl carbonyl]-l-histidyl-L-prolinamide dihydrate) on cognitive disturbance of passive avoidance response were studied in rodents in comparison with those of TRH and CDP-choline. The latency for entering from the illuminated into the dark compartments was shortened in anoxia and scopolamine-treated rats, cycloheximidetreated mice and cerebral ischemic gerbils. The shortened latency in these models was prolonged by administration of both YM-14673 and TRH in doses without effect on spontaneous movement. YM-14673 was about 10 times more potent than TRH in ameliorating the cognitive disturbance, whereas CDP-choline showed no influence on the learning ability. These results suggest that YM-14673 and TRH possess facilitatory effects on cerebral function and that YM-14673 was distinct from CDP-choline in pharmacological profile. Send offprint requests to M. Yamamoto at the above address     

Investigations on the interaction of thyrotropin-releasing hormone (TRH) and MK-771 with central noradrenergic mechanisms

Thyrotropin-releasing hormone (TRH) and a structurally related analogue of TRH, MK-771, administered IP or orally, restored flexor reflex activity in rats with acute spinal transections. The effect of MK-771 in this test was not modified by pretreatment with reserpine plus -methyl-p-tyrosine but was antagonized by the -adrenergic blocking agent, phenoxybenzamine. However, another -adrenergic blocking agent, HEAT, was ineffective in this regard. Additionally, TRH and MK-771 restored the anticonvulsant actions of methazolamide in mice pretreated with reserpine or picolinic acid. These data, along with the findings that MK-771 and TRH enhance depletion of brain norepinephrine induced by -methyl-p-tyrosine, indicate that these agents may affect central noradrenergic mechanisms. Whether the mechanism of their proposed effect upon noradrenergic systems is direct or mediated by an interaction with another neurotransmitter system which influences noradrenergic function cannot be determined on the basis of the present studies.     

Kinetics and Pattern of Degradation of Thyrotropin-Releasing Hormone (TRH) in Human Plasma

The kinetics and mechanism of degradation of the tripeptide TRH (pGlu-His-Pro-NH₂) and its various primary and secondary degradation products (TRH-OH, His-Pro-NH₂, and His-Pro) have been determined in human plasma at 37°C. The rates of degradation of both TRH and TRH-OH (pGlu-His-Pro) showed mixed zero-order and first-order kinetics. At low substrate concentrations first-order kinetics occurred, with TRH and TRH-OH degradation half-lives of 9.4 and 27 min, respectively. The initial step in the plasma-catalyzed degradation of TRH is due to hydrolysis of the pGlu-His bond by the TRH-specific pyroglutamyl aminopeptidase serum enzyme, resulting in the exclusive formation of histidyl-proline amide (His-Pro-NH₂). Using specific HPLC methods the major degradation route (67%) of this dipeptide in human plasma was hydrolysis of the peptide bond to yield His and Pro-NH₂, whereas deamidation to yield His-Pro accounted for 29% of the total degradation. A minor pathway (4%) was spontaneous cyclization to yield cyclo(His-Pro). Both His-Pro-NH₂ and His-Pro degraded by first-order kinetics and faster than TRH, with half-lives of 5.3 and 2.2 min, respectively, in 80% plasma.     

Effects of a new TRH analogue,YM-14673 on the central nervous system

Summary The effects of a new TRH analogue, YM-14673 (N-[{(S)-4-oxo-2-azetidinyl}carbonyl]-L-histidyl-L-prolinamide dihydrate) on the central nervous system were compared with those of TRH. YM-14673 was 10–40 times more potent than TRH in antagonizing pentobarbital-induced sleep and hypothermia, and ethanol-induced hypothermia in mice. YM-14673 accelerated recovery from disturbed consciousness induced by concussive head trauma in mice and normalized the behavior and spontaneous EEG disturbed by electrolytic lesion of the hypothalamus in cats with 25 -100 times greater potency than that of TRH. In the tests on pentobarbital sleeping time and EEG disturbance, the cerebral activating activity of YM-14673 was 8 –36 times longer-lasting than that of TRH. These results indicate that YM-14673 possesses potent arousal effects on the central nervous system. The mode of action of YM-14673 was also discussed. Send offprint requests to M. Yamamoto