可乐定降低眼内压的中枢肾上腺素能机制

目的　探讨可乐定对眼内压 (IOP)的影响以及中枢α 肾上腺素能神经元作用的机制。方法　 3种不同方法给药 :(1)眼球表面滴注可乐定 ;(2 )侧脑室内微量注射育亨宾或哌唑嗪后 ,再分别用可乐定侧脑室内注射和滴眼 ;(3)蓝斑内微量注射可乐定 ,分别观察IOP的变化。结果　可乐定 3种给药方法均有明显降低IOP的效应 ,脑室注射育亨宾能翻转可乐定脑室注射和滴眼降低IOP的效应。结论　通过外周或中枢给可乐定都能降低IOP ,说明中枢α2 受体参与了这一作用     

可乐定降低眼内压的中枢肾上腺素能机制

目的探讨可乐定对眼内压(IOP)的影响以及中枢α-肾上腺素能神经元作用的机制.方法 3种不同方法给药(1)眼球表面滴注可乐定 ;(2)侧脑室内微量注射育亨宾或哌唑嗪后,再分别用可乐定侧脑室内注射和滴眼;(3)蓝斑内微量注射可乐定,分别观察IOP的变化.结果可乐定3种给药方法均有明显降低IOP的效应,脑室注射育亨宾能翻转可乐定脑室注射和滴眼降低IOP的效应.结论通过外周或中枢给可乐定都能降低IOP,说明中枢α2受体参与了这一作用.     

CVLM咪唑啉-I和α_2-肾上腺素受体共同参与可乐定的降压效应

目的　探讨大鼠尾端延髓腹外侧区 (CVLM)咪唑啉 I受体 (I1R)和α2 肾上腺素受体 (α2 AR)在介导可乐定中枢降压机制中的作用。方法　在氨基甲酸乙酯麻醉SD大鼠中 ,观察CVLM内局部给予I1R和α2 AR阻断剂后对基础血压(BP)、心率 (HR)以及外周给予可乐定导致降压效应的变化。结果　双侧CVLM分别微量注射选择性α2 AR阻断剂育亨宾 (单侧剂量 5 0 0 pmol·L-1,10 0nl,n =8)或I1R和α2 AR混合性阻断剂idazoxan(单侧剂量 2nmol·L-1,10 0nl,n =10 )后不仅明显降低BP和HR(P <0 0 1) ,而且能明显减弱静脉给予可乐定 (5 μg·kg-1)导致的降压效应 (P <0 0 1) ,此外 ,idazoxan对可乐定降压效应的减弱作用高于育亨宾 (P <0 0 1)。结论　CVLM内I1R和α2 AR共同参与维持紧张性心血管活动和介导可乐定的降压效应     

可乐定中枢降压作用与中枢胆碱能神经系统的关系

从猫第四脑室给药。毒扁豆碱降压作用可被阿托品及育亨宾阻断;可乐定降压作用可被育亨宾、密胆碱及阿托品阻断,不被可卡因阻断,破坏中枢去甲肾上腺素能末梢后,阿托品的阻断作用消失;可乐定减少脑室灌流液Ach释出量。提示猫延髓胆碱能和去甲肾上腺素能神经在心血管调节功能上相互影响,它们似有可能同在一心血管神经原形成突触联系共同对血压行抑制性调节;可乐定可能通过激动通路上突触后α₂受体产生降压作用。     

可乐定镇痛机制研究概况

<正> 可乐定(Clonidine)是咪唑啉类肾上腺素能α-受体激动剂,具有多种药理作用。近年来许多学者对其镇痛机制进行了研究。可乐定在多种镇痛实验模型均呈现镇痛效应,在有些模型镇痛其作用甚至强于吗啡。鉴于可乐定镇痛机制完全不同于阿片类药物,故对其镇痛机制研究有一定的理论意义。 可乐定镇痛作用部位 可乐定同类物ST91[2-(2,6—二氯氨基苯)—2—咪唑啉]为低脂溶性不易透过血脑屏障的药物,外周给药产生可     

可乐定对梭曼中毒的预防作用(英文)

研究了可乐定对梭曼中毒的预防作用 .结果显示试管内可乐定仅在高浓度 ( 1 - 1 0 mmol· L-1)时对 Ch E产生抑制 ,在小鼠体内 1 mg·kg-1,ip时对脑 Ch E也只产生轻微的抑制 .给小鼠先 ip可乐定对梭曼中毒小鼠脑和全血 Ch E活性无明显影响 ,却使中毒小鼠惊厥发生率及死亡率显著下降 .育亨宾可以明显对抗可乐定对梭曼中毒的预防作用 .说明 α2 肾上腺素受体可能介导了可乐定对梭曼中毒的预防作用 .     

β-内啡肽:可能参与中枢α-受体激动而产生的抗高血压效应

吗啡及某些内源性阿片样物质降低血压、减慢心率的作用部分是因激活延髓阿片受体,减低交感张力而产生。激活同脑区内α-肾上腺素能受体的抗高血压药氯压定(Clonidine)具有同吗啡作用相似的作用(如降低血压、减慢心率、镇痛等)。氯压定停药产生的症状与阿片戒断症状相似,阻滞氯压定与中枢α-受体交互作用的药物育亨宾、哌氧环烷亦能引起类似阿片戒断的症状,而氯压定可逆转阿片成瘾者的戒断症状。这些相似性说明,中枢阿片受体与α-受体系统之间存在着某种交互作用。作者等最近报道,纳洛酮抑制氯压定和α-甲基多巴对自发性高血压大鼠的降压作用,但不能拮抗     

中枢与外周α-肾上腺素能受体激动效应不一致性的原理分析

对戊巴比妥钠麻醉家兔,静脉注射α-肾上腺素能受体拮抗剂育亨宾(Yohimbine)或γ-氨基丁酸(GABA)受体拮抗剂苦味毒(picrotoxin)均可明显对抗侧脑室注射氯压定(clonidine)的降血压作用。但是育亨宾不能阻断侧脑室注射GABA的中枢降压作用,而苦味毒则能完全阻断其降压效应。 家兔经GABA合成抑制剂氨基脲(Semicarbazide)静脉注射予处理后,动物于给药后3～4小时出现强烈惊厥,说明脑内GABA已降低到一定水平。此时用局部麻醉剂及肌松剂处理,在人工呼吸情况下,氯压定静脉注射的降压作用比不给氨基脲予处理的对照组动物显著减弱。 以上结果启示,中枢肾上腺素能受体激动而产生的降压作用有可能是通过GABA能抑制性神经元而实现。     

中枢与外周α-肾上腺素能受体激动效应不一致性的原理分析

对戊巴比妥钠麻醉家兔,静脉注射α-肾上腺素能受体拮抗剂育亨宾(Yohimbine)或γ-氨基丁酸(GABA)受体拮抗剂苦味毒(picrotoxin)均可明显对抗侧脑室注射氯压定(clonidine)的降血压作用。但是育亨宾不能阻断侧脑室注射GABA的中枢降压作用,而苦味毒则能完全阻断其降压效应。家兔经GABA合成抑制剂氨基脲(Semicarbazide)静脉注射予处理后,动物于给药后3～4小时出现强烈惊厥,说明脑内GABA已降低到一定水平。此时用局部麻醉剂及肌松剂处理,在人工呼吸情况下,氯压定静脉注射的降压作用比不给氨基脲予处理的对照组动物显著减弱。以上结果启示,中枢肾上腺素能受体激动而产生的降压作用有可能是通过GABA能抑制性神经元而实现。     

纳洛酮在儿科急救中的应用

随着儿科急救医学的发展及对纳洛酮药理研究的不断深入,纳洛酮在儿科急救中的应用得到广泛关注.纳洛酮为阿片受体竞争性药物,与分布在脑干等部位的阿片受体结合后能有效阻断内源性阿片样物质所介导的各种效应.给药后吸收快:静脉或气管给药1～3分钟产生效应,肌注或皮下注射5～10分钟见效,通过血脑屏障的速度为吗啡的12倍.现将其在儿科中的应用简述如下.     

Interaction between the inhibitory effects of morphine and clonidine on intestinal transit in mice

Both clonidine and morphine dose-dependently inhibited intestinal transit in mice. This inhibitory effect of clonidine was antagonized by prior administration of yohimbine but not by naloxone, while morphine's effect was antagonized by both yohimbine and naloxone. Morphine pretreatment did not induce any apparent tolerance to the effect of clonidine and morphine tested 4 h later. However, yohimbine became more potent in antagonizing the effect of clonidine while naloxone remained ineffective. Morphine pretreatment enhanced the antagonistic effectiveness of both yohimbine and naloxone against morphine. Clonidine pretreatment at a dose that did not induce any tolerance slightly enhanced the antagonistic effects of yohimbine and naloxone against morphine. Yohimbine also became more effective against clonidine but naloxone remained ineffective. At higher doses of clonidine pretreatment tolerance to the effects of morphine and clonidine were observed. These results suggest that both alpha 2-adrenoceptors and opioid receptors are involved in the inhibitory action of morphine on intestinal transit, while clonidine mainly acts through the alpha 2-adrenoceptors. In addition, there is a close interaction between the alpha 2-adrenoceptors and opioid receptors in the intestine.     

Peripheral analgesic action of clonidine: mediation by release of endogenous enkephalin-like substances

Clonidine analgesia was tested on the hyperalgesia induced by intraplantar injection of prostaglandin E2 or carrageenin. The antinociceptive effect of clonidine was dose-dependent and was abolished by local administration of the selective alpha 2-adrenoceptor blocker, yohimbine or of the opioid antagonists naloxone or quaternary nalorphine. St-91, a clonidine analog which does not cross the blood-brain barrier also promoted significant antinociception. Repeated administration of drugs possessing a central mechanism of analgesic action leads to the development of tolerance in this test. Significant analgesic tolerance was observed following repeated (5 days) morphine (8 mg/kg) or high doses of clonidine (0.5 mg/kg). In contrast, no tolerance was detected to the analgesic effect of low doses of clonidine (0.15 mg/kg) or of St-91 (0.5 mg/kg). These results suggest that, in addition to its central analgesic action, clonidine can induce peripheral antinociception by an alpha 2-adrenoceptor-mediated local release of enkephalin-like substances.     

Tramadol antinociception is potentiated by clonidine through α₂-adrenergic and I₂-imidazoline but not by endothelin ET(A) receptors in mice

Tramadol is a centrally acting analgesic that acts via μ-opioid agonism and by blocking the neuronal uptake of norepinephrine and serotonin. Clonidine potentiates the antinociceptive effects of tramadol; however the receptors involved in this potentiation have not been studied. Endothelin ET(A) receptor antagonists potentiate antinociceptive effects of morphine and oxycodone; however the effects of endothelin ET(A) receptor antagonists on tramadol antinociception have not been evaluated. This study was conducted to determine the effect of clonidine on tramadol antinociception; the role of opioid, α?-adrenergic and I?-imidazoline receptors in clonidine potentiation of tramadol antinociception; and the effect of endothelin ET(A) receptor antagonists in modulating tramadol antinociception. Antinociceptive (tail-flick and hot-plate) latencies were measured in male Swiss Webster mice treated with tramadol; clonidine plus tramadol; or antagonists plus tramadol. Mice were pretreated with naloxone (opioid antagonist), yohimbine (α?-adrenoceptor antagonist), idazoxan (α?-adrenoceptor/I?-imidazoline antagonist), BMS182874 or BQ123 (endothelin ET(A) receptor antagonists) to study the involvement of these receptors. Tramadol produced a dose dependent increase in antinociceptive latencies. Tramadol antinociception was partially blocked by naloxone but not by yohimbine or idazoxan. Clonidine potentiated tramadol antinociception; potentiation was blocked by naloxone, yohimbine and idazoxan. Idazoxan produced a more pronounced blockade of potentiation than yohimbine. BMS182874 or BQ123 had no effect on tramadol antinociception, indicating that endothelin ET(A) receptors are not involved in tramadol antinociception in mice. Results demonstrate the involvement of opioid but not α?-adrenergic/I?-imidazoline receptors in tramadol antinociception and that opioid, α?-adrenergic and I?-imidazoline receptors are involved in clonidine potentiation of tramadol antinociception.     

JB-9322, a new selective histamine H2-receptor antagonist with potent gastric mucosal protective properties.

1. The opioid activity of the amphibian peptide, [Lys7]dermorphin, was studied in rats and mice. When administered intracerebroventricularly (i.c.v.), intravenously (i.v.) or subcutaneously (s.c.) it produced a long lasting analgesia. Its antinociceptive potency exceeded that of morphine 290 times by i.c.v. injection, and 25-30 times by peripheral administration. 2. The dose-response curves of [Lys7]dermorphin antinociception were shifted to the right by the pretreatment with naloxone (0.1 mg kg-1, s.c.) or with the mu 1-selective antagonist, naloxonazine (10 mg kg-1, i.v. 24 h before peptide injection). 3. The peptide also displayed potent antinociceptive effects in a chronic inflammatory pain model (rat Freund's adjuvant arthritis). In this pain model, systemic administration of the peptide raised the nociceptive threshold more in inflamed than in healthy paw. 4. High central and peripheral doses of [Lys7]dermorphin in rats produced catalepsy. The cataleptic response was antagonized by naloxone but left unchanged by naloxonazine pretreatment. 5. In rats and mice, central or peripheral administration of [Lys7]dermorphin induced a significantly slower development of tolerance to the antinociceptive effect than did morphine. 6. Upon naloxone precipitation of the withdrawal syndrome, [Lys7]dermorphin-dependent mice made fewer jumps and lost less weight than the morphine-dependent animals. Withdrawal hyperalgesia did not develop in [Lys7]dermorphin-dependent mice. 7. In conclusion, [Lys7]dermorphin seems to be a unique opioid peptide having a high penetration into the blood-brain barrier despite its low lipid solubility. This peptide causes fewer side-effects than other opioids and appears less likely than morphine to cause physical dependence in rats and mice.     

Antinociceptive effect of spinally administered cannabinergic and 2-adrenoceptor drugs on the formalin test in rat: possible interactions

The current experiments were designed to study the antinociceptive effects of intrathecal (i.t.) administration of cannabinoid CB1 receptor and 2-adrenoceptor drugs in the nociceptive processing and also their receptor interactions. Different doses of a cannabinoid receptor agonist, CP 55,940, and an 2-adrenoceptor agonist, clonidine induced a dose-dependent antinociception in both phases of the formalin test.CP 55,940-induced antinociception was reduced by pretreatment of a selective cannabinoid CB1 receptor antagonist, SR 141716A, but not by pretreatment with an 2-adrenoceptor antagonist, yohimbine in both phases of the test. However, yohimbine and SR 141716A attenuated the antinociception induced by clonidine in the early phase but not in the late phase of the test. While SR 141716A by itself did not influence pain behaviour, the reversal effect of clonidine by SR 141716A indicate that clonidine stimulate the release of endocannabinoid(s).In conclusion, our findings may suggest that: (1) spinal cannabinoid and 2-adrenoceptor systems are able to induce antinociception in both phases of formalin test, and (2) the cannabinoid system may be involved in the antinociception induced by adrenoceptors in the early phase.     

Water soluble fraction (<10 kDa) from bee venom reduces visceral pain behavior through spinal alpha 2-adrenergic activity in mice

We have previously shown that subcutaneous bee venom (BV) injection reduces visceral pain behavior in mice, but it is not clear which constituent of BV is responsible for its antinociceptive effect. In the present study, we now demonstrate that a water-soluble subfraction of BV (BVA) reproduces the antinociceptive effect of BV in acetic acid-induced visceral pain model. We further evaluated three different BVA subfractions that were separated by molecular weight, and found that only the BVAF3 subfraction (a molecular weight of <10 kDa) produced a significant antinociceptive effect on abdominal stretches and suppressed visceral pain-induced spinal cord Fos expression. Injection of melittin (MEL), a major constituent of BVAF3, also produced a visceral antinociception. However, melittin's antinociception was completely blocked by boiling for 10 min at 100 degrees C, while boiling either whole BV or BVAF3 did not prevent their antinociception. The antinociceptive effect of BVAF3 was completely blocked by intrathecal pretreatment with the alpha2-adrenoceptor antagonist, yohimbine (YOH), while intrathecal pretreatment with the opioid antagonist, naloxone (NAL) or the serotonin antagonist, methysergide, had no effect. These data demonstrate that BVAF3 is responsible for the visceral antinociception of whole BV and further suggest that this effect is mediated in part by spinal alpha2-adrenergic activity.     

The effect of naloxone on restraint-induced antinociception in mice.

Restraint for a period from 15-60 min induced significant antinociceptive effect in both male and female mice. The restraint animals all showed an increase in response time to the hot plate test at 55 degrees C. The antinociceptive activity was still apparent one hour after restraint. In the male animals, prior administration of naloxone s.c. 15 min before restraint for 60 min did not affect the degree of antinociceptive activity induced by restraint. In addition, naloxone administered s.c. immediately after restraint for 60 min also did not affect the degree of antinociceptive activity in male mice. These findings indicate that in male animals the endogenous opioid mechanism is most likely not involved in the restraint-induced antinociception. However, for the female mice naloxone administered s.c. either before or immediately after restraint for 60 min dose-dependently suppressed the antinociceptive activity induced by restraint. It is concluded that restraint can induce antinociceptive activity in mice; however, different mechanisms may be involved in the antinociception observed. In male mice the endogenous opioid systems do not seem to play a significant role in restraint-induced antinociception, while for female animals blockade of opioid receptors would greatly diminish the antinociception observed after restraint.     

Role of the NO-cGMP pathway in the systemic antinociceptive effect of clonidine in rats and mice

The mechanism underlying the analgesic effect of clonidine, an alpha(2)-adrenoceptor agonist, remains uncertain. Activation of alpha(2)-adrenoceptor induces the release of nitric oxide (NO) from endothelial cells, which has led us to test the hypothesis that the observed antinociceptive effect induced by the systemic administration of clonidine depends on the NO-cGMP pathway. The possible involvement of an opioid link in the antinociceptive effect of clonidine was also evaluated. The antinociceptive effect induced by systemic administration (intravenous or intraperitoneal) of clonidine was evaluated using the rat paw formalin, mice tail-flick and writhing tests. Clonidine (3-120 microg/kg) induces a dose-dependent antinociceptive effect in the formalin, tail-flick and writhing tests. The antinociceptive effect of clonidine in a dose that had no sedative effect assessed by rota rod test, was significantly reduced by NO-synthase and guanylyl cyclase inhibition. The antinociceptive effect of morphine, but not clonidine, was inhibited by naloxone. Our current results suggest that the antinociceptive effect of systemic clonidine does not involve the opioid receptor and is modulated by the NO-cGMP pathway.     

Atropine reverses the antinociception of nonsteroidal anti-inflammatory drugs in the tail-flick test of mice

The nonsteroidal anti-inflammatory drugs (NSAIDs) clonixin, diclofenac, piroxicam, ketoprofen, meloxicam, and paracetamol induced antinociception after intraperitoneal or intrathecal administration in mice submitted to an acute thermal algesiometric test without inflammation (tail-flick). Antinociception was evaluated by the increase in reaction time difference (Delta latency), between readings obtained before and after the administration of drugs. The antinociception induced by doses of NSAIDs producing between 20% and 30% of the maximum possible effect (MPE) 30 min after intraperitoneal and 15 min after intrathecal injections was compared with the antinociception obtained after pretreatment with 1 mg/kg atropine ip, 30 min before. Systemic atropine (1 mg/kg) significantly antagonized NSAID-induced antinociception in all cases, both after intraperitoneal and intrathecal administration. Cholinergic depletion by intracerebroventricular hemicholinium-3 (HC-3, 5 microg) 5 h before prevented the antinociceptive effect of all NSAIDs. These observations suggest that intrinsic muscarinic cholinergic facilitatory pathways represent an important modulating system in pain perception in this animal model of acute thermal pain. The results of the present work support the increasingly accepted notion that NSAIDs are effective analgesics even when inflammation is not present, acting by mechanisms that involve actions on spinal and supraspinal nociceptive transmission. It is suggested that, similar to morphine and clonidine, the active mechanism of NSAIDs may involve the release of acetylcholine (ACh) in the spinal cord.     

Further study on the effects of histamine H2 receptor agonist and antagonists on restraint-induced antinociception in mice.

In previous studies, histamine was shown to affect the antinociceptive activity induced by stress in mice. The present work was carried out to further examine the role of histamine in this phenomenon. Restraint for 1 h induced significant antinociceptive activity as assessed by the hot plate test in both male and female mice. The antinociceptive activity was enhanced by prior administration of the histamine H2 receptor agonist dimaprit (6.0 mg/kg s.c.) 15 min before restraint. Furthermore, the induction of antinociceptive activity by restraint was antagonized by prior administration of histamine H2 receptor antagonists (10.0 mg/kg s.c.), cimetidine or zolantidine. In the male mice, naloxone (4.0 mg/kg s.c.) administered 10 min before or immediately after restraint did not affect the antinociception induced by restraint. In addition, the potentiating effect of dimaprit and the inhibitory effect of cimetidine and zolantidine were not affected by administration of naloxone. However, in female mice, naloxone given 10 min before restraint completely abolished the induction of antinociceptive activity by restraint and the effects of histamine H2 receptor agonist and antagonists on restraint induced antinociception were not observed. Moreover, the antinociceptive activity induced by restraint and the dimaprit-induced potentiation of antinociceptive activity were diminished by naloxone administered immediately after the restraint. The present findings further support our previous studies which suggested that the histamine H2 receptor most probably is involved in enhancing the intensity of stress in restraint-induced antinociception thus altering the degree of antinociception observed.