家兔隔区和伏核内钙、镁离子对抗电针镇痛与吗啡镇痛

本文通过脑内慢性埋植套管向家兔一侧隔区或伏核内注射微量(10 nmol)CaCl_2或MgCl_2,可显著对抗吗啡镇痛和电针镇痛。注入核外则无效。家兔一侧隔区或伏核内注入阳离子螯合剂CDTA(20 nmol)加强吗啡镇痛和电针镇痛。文中就Ca~(2 ),Mg~(2 )作用的相似性,电针镇痛与吗啡镇痛机理的相似性,以及伏核和隔区在上述镇痛中的重要性进行了讨论。     

孤啡肽及其片段的合成、痛觉调节作用和对免疫功能的影响

目的：研究孤啡肽(NC)与其4个片段(NC(1-15)NH₂, NC(1-13)NH₂, NC(1-11)NH₂, NC(1-5)NH₂) 在痛觉调节和免疫活性上的变化,探讨NC的构效关系。方法：固相多肽合成法合成NC及其片段;甩尾法测定它们对小鼠的痛敏作用和对吗啡镇痛作用的拮抗;T细胞玫瑰花结形成百分率和红细胞免疫粘附能力评测对免疫功能的影响。结果：虽然NC及其片段均有痛敏作用并可拮抗吗啡的镇痛作用,但NC(1-11)NH₂和NC(1-5)NH₂比母体活性约降低100倍,而NC(1-13)NH₂和NC(1-15)NH₂与母体有相同的活性。NC及片段(0.3～3 nmol.kg^-1)对T细胞免疫功能均有促进作用;NC(1-11)NH₂(0.3 nmol.kg^-1)对红细胞的免疫粘附能力有促进作用;NC(1-5)NH₂(0.3～30 nmol.kg^-1)不影响红细胞的免疫功能。结论：C端在NC的构效关系中有重要的作用。     

可乐定镇痛与中枢Ca2+的关系

用大鼠甩尾法和放射配基结合实验,探讨了可乐定镇痛与中枢Ca²⁺的关系。CaCl₂(1μmol/rat,icv)和EGTA(0.2μmol/rat,icv)分别拮抗和增强可乐定(1mg/kg,sc)的镇痛。戊脉安(0.1μmol/rat,icy)对可乐定(1 mg/kg,sc)镇痛无明显影响,但可部分翻转CaCl₂对可乐定镇痛的拮抗。CaCl₂(1×10^-3mol)对[³H]-可乐定结合无明显抑制。结果表明可乐定镇痛与脑室周围组织中Ca²⁺浓度变化密切相关,Ca²⁺至少部分需经对戊脉安敏感的钙通道进入细胞内方可拮抗可乐定镇痛。推沦:可乐定镇痛与神经元内Ca²⁺有关。     

吗啡依赖大鼠脊髓和脑干毒蕈碱受体亚型基因的表达

目的观察吗啡依赖大鼠脊髓和脑干毒蕈碱型乙酰胆碱受体m_1～5的表达。方法以β-actin为内标,用RT-PCR方法检测m_1～5的表达。结果吗啡依赖大鼠脊髓m_1～5受体和脑干中m₁和m₂表达较正常对照组明显升高,注射纳洛酮1 h后脊髓m_1～4和脑干m₁表达较依赖组减少。东莨菪碱(0.5 mg·kg^-1,ip)或呱伦西平(10 mg·kg^-1,ip)明显减少吗啡戒断症状,呱伦西平处理后脊髓m₁,m₂,m₃和m₅表达较戒断对照组增加,东莨菪碱处理后脊髓m₂,m₃和m₄表达增加。结论脊髓M受体适应性改变是吗啡戒断症状表达的生物学基础。     

3-甲基芬太尼立体异构体的合成、绝对构型和镇痛活性

报道3-甲基芬太尼(2)四个光学异构体的合成及其绝对构型的确定,并测定了各异构体的镇痛活性(小鼠,ip,热板法)。结果表明,cis-(+)-(3R,4S)-2的镇痛作用最强,ED₅₀0.00767 mg/kg,镇痛效能是吗啡的2600倍,比其对映体cis-(-)-(3S,4R)-2以及混旋的cis-(±)-2分别强119和1.5倍;trans-(+)-(3S,4S)-2的镇痛效能是吗啡的450倍、trans-(-)-(3R,4R)-2的4倍。     

金丝桃甙镇痛作用的机制

用小鼠光热辐射甩尾模型证明,低钙和高钙分别能增强和拮抗Hyp的镇痛作用。在痛介质诱发传入神经放电的模型上,同样证明低钙或高钙能显著加强或拮抗Hyp对组胺和氯化钾诱发神经放电的抑制作用。促进Ca²⁺内流的A₂₃₁₈₇几乎完全拮抗Hyp的末梢镇痛作用,并且在蛙坐骨神经标本上,Hyp可抑制KCl诱发的Ca²⁺内流。提示Hyp的镇痛作用与减少感觉神经末梢Ca²⁺内流有密切关系。     

强啡肽A-(1-13)类似物的合成及生物活性

用固相多肽合成方法,合成了强啡肽A-(1-13)(I)及其类似物[Ala⁸,D-Pro¹⁰]-DYNA-(1-13)-NH₂(II)和[D-Ala²,Ala⁸,D-Pro¹⁰]-DYNA-(1-13)-NH2(III),并对其进行了镇痛活性试验和MVD及RVD试验。结果表明,合成产物均有镇痛活性,其中类似物III的镇痛活性是1的3.6倍,RVD试验活性比1强135倍,比已知的k-受体强激动剂U500488强11倍。     

用Fura-2测定突触体内游离Ca2+浓度及Ca2+通道激动剂和阻断剂的影响

用Fura-2测定大鼠突触体内游离Ca²⁺浓度,探讨Ca²⁺通道激动剂和阻断剂对突触体内钙浓度的影响。测得突触体内Ca²⁺浓度为200～400 nmol/L。观察了不同浓度KCl,CaCl₂,NMDA和谷氨酸对突触体内Ca²⁺增加的影响以及维拉帕米及MgCl₂对KCl和NMDA引起钙内流的阻断作用。本实验提供一个研究突触体内Ca²⁺变化的准确而稳定的方法,并对测定中几个影响因素加以讨论。     

安定在家兔体内的肠胃循环药代动力学分析

6只家兔iv安定5 mg·kg^-1后,浓度—时间数据呈现双峰形。本文提出肠胃循环动力学模型,用于分析实测数据,得到了一般动力学参数:T_1/2(α)=0.21±=0.15 h,T_1/2(β)=2.2+0.6 h,K_e=1.5±0.6 h^-1,K₁₂=2.0±1.0 h^-1,K₂₁=1.0±0.4 h^-1,V₁=3.1±1.6 L·kg^-1,AUC=1.7±0.5μg·h^-1·ml^-1。此外,还求得有关肠胃循环的参数,即:重吸收滞后时间T′=0.25±0.24h,重吸收速率常数K_A=3.5±1.4 h^-1,重吸收率R_A=24±7%。     

异紫堇啡碱对家兔窦房结及豚鼠心室肌动作电位的作用

用细胞内固定微电极技术观察了异紫堇啡碱(isocorydine)对家兔窦房结电活动、豚鼠心室肌动作电位及Ba²⁺诱发的豚鼠心室肌自发电活动的作用。结果表明,异紫堇啡碱能使窦房结细胞APA,SP₀,SP₄减小、APD₉₀延长、自律性降低。3 μM异紫堇啡碱能使心室肌细胞的APD₅₀,APD₉₀和ERP延长,300μM异紫堇啡碱则使心室肌细胞APD₅₀和APD₉₀缩短,但不缩短ERP,使ERP相对延长。300μM异紫茧啡碱亦能明显抑制Ba²⁺诱发的心室肌自发电活动。     

Locomotor activity of rats after injection of various opiods into the nucleus accumbens and the septum mediale

Summary The possible role of the nucleus accumbens (ACB) and, in some experiments, the septum mediale (SM) in mediating alterations in locomotor activity, produced by various opioids, was evaluated in the rat, the drug being injected either into the left central part of the ACB or into the left SM. Morphine, predominantly acting at the mu-type receptors, given in larger doses (13 or 40 nmol into the ACB) produced depression of locomotor activity and catalepsy, whereas 2.5 nmol were ineffective. Co-administration of naloxone into the ACB suppressed the effects of morphine.d-ala²,d-leu⁵-enkephalin (DADL), a preferential delta-type receptor agonist, produced a biphasic effect on locomotor activity, namely an inhibition of it and a catalepsy, followed by a locomotor activation. This effect was observed after 4 or 13 nmol; 1 nmol produced a delayed locomotor activation without any previous inhibition, whereas 0.4 or 0.1 nmol were ineffective. Equimolar doses of naloxone, when coadministered with DADL, only partially antagonized these effects of DADL. In contrast, co-administration of a small dose of DADL and an excess dose of naloxone into the ACB produced an immediate increase in locomotor activity. Injections of a predominant kappa type receptor agonist, MR 2033-Cl, were ineffective.Injection of DADL, either alone or combined with naloxone into the SM (1 nmol) produced an immediate stimulation of locomotor activity.The results suggest that locomotor depression and catalepsy may be mediated by opioid receptors of the mutype in the ACB, whereas locomotor stimulation is due to an action on delta type receptors, an effect which may be masked by simultaneous stimulation of mu-type receptors under certain conditions. Kappa-type receptors apparently are not involved in any of these effects. In addition, a diffusion of DADL to the adjacent SM may contribute to locomotor stimulation.     

Modulation by enkephalin analogues and neuroleptics of apomorphine-induced stereotypy and turning behaviour in rats

The aim of the present investigation was to examine which areas of the brain might mediate the anti-apomorphine action of some opioids, which were found previously to be active upon subcutaneous application. As the first step, the substances were injected intracerebroventricularly or into the nucleus accumbens, a mesolimbic region which is rich in dopamine, and the inhibition of stereotypy induced by apomorphine was quantified. In a separate group of animals (rats with unilateral lesion of the nigra) the antagonism of turning behaviour elicited by apomorphine was measured. Substances examined were morphine, a mu-selective opiate; D-Ala2,Nle5-enkephalin sulphonic acid (ES), a delta-selective opioid peptide; D-Met2,Pro5-enkephalinamide (EA), a highly potent but non-selective opioid; and two dopamine receptor blockers, haloperidol and chlorpromazine, for comparison. Examining the antagonism of turning behaviour induced by apomorphine, the order of potency was EA greater than haloperidol greater than morphine greater than ES approximately equal to chlorpromazine if injections of the substances were intracerebroventricular and EA greater than morphine much greater than haloperidol approximately equal to ES much greater than chlorpromazine when administered into the nucleus accumbens. The order of potency for the suppression of stereotypy induced by apomorphine was EA much greater than haloperidol greater than morphine greater than ES greater than chlorpromazine upon intracerebroventricular application and EA much greater than haloperidol greater than morphine ES greater than chlorpromazine if injected into the nucleus accumbens. The data indicate that endogenous opioids might inhibit the activity of dopamine in brain through the nucleus accumbens.     

Pharmacological characterization of the nociceptin receptor mediating hyperalgesia in the mouse tail withdrawal assay

1. The newly discovered neuropeptide nociceptin (NC) has recently been reported to be the endogenous ligand of the opioid-like orphan receptor. Despite its structural similarity to opioids, when injected intracerebroventricularly (i.c.v.) in the mouse, NC exerts a direct hyperalgesic effect and reverses opioid-induced analgesia. In the present investigation, these two effects of NC were evaluated under the same experimental conditions; in addition, a pharmacological characterization of the receptor mediating these central effects of NC was attempted.
2. NC caused a dose dependent (0.1–10 nmol/mouse), naloxone-insensitive reduction of tail withdrawal latency with a maximal effect of about 50% of the reaction time observed in saline injected mice. In the same range of doses, NC inhibited morphine (1 nmol/mouse) induced analgesia.
3. The effects of the natural peptide were mimicked by NCNH₂ and NC(1–13)NH₂ (all tested at 1 nmol/mouse) while 1 nmol NC(1–9)NH₂ was found to be inactive either in reducing tail withdrawal latency or in preventing morphine analgesia.
4. [Phe¹ψ(CH₂-NH)Gly²]NC(1–13)NH₂ ([F/G]NC(1–13)NH₂), which has been shown to antagonize NC effects in the mouse vas deferens, acted as an agonist, mimicking NC effects in both the experimental paradigms. In addition, when NC and [F/G]NC(1–13)NH₂ were given together, their effects were additive.
5. These results demonstrate that both the direct hyperalgesic action and the anti-morphine effect of NC can be studied under the same experimental conditions in the mouse tail withdrawal assay. Moreover, the pharmacological characterization of the NC functional site responsible for these actions compared with the peripherally active site, indicates the existence of important differences between peripheral and central NC receptors.

     

Calcium-opiate antaconism in the periaqueductal grey (PGA) region

Ca²⁺ (0.937 μmol) significantly decreased the antinociceptive activity produced by the administration of equi-analgetic doses of morphine (16 nmol), β-endorphin (14 nmol) or [D-Ala²,Met²]enkephalinamide (136, 68 nmol) into the periaqueductal grey (PGA) area, The results are consistent with earlier findings with morphine and support the hypothesis that Ca²⁺ may participate in median sms which mediate the antinoeiceptive action of opioid peptides.     

Neuropeptide FF receptors control morphine-induced analgesia in the parafascicular nucleus and the dorsal raphe nucleus

The ability of (1DMe)Y8Fa (D.Tyr–Leu–(NMe)Phe–Gln–Pro–Gln–Arg–Phe–NH₂), a selective neuropeptide FF analog resistant to enzymatic degradation, to control morphine-induced analgesia was investigated in rat after microinfusion into the dorsal raphe nucleus and the nucleus parafascicularis of the thalamus. Infusion of (1DMe)Y8Fa (2.5 nmol) in the nucleus raphe dorsalis did not modify the animal response in the tail-immersion test but significantly reversed analgesia induced by coinjected morphine (27 nmol). Similarly, (1DMe)Y8Fa (5 nmol) inhibited morphine effects in the hot-plate test after co-injection into the parafascicular nucleus. Furthermore, (1DMe)Y8Fa injected into the parafascicular nucleus attenuated analgesia induced by morphine injected into the nucleus raphe dorsalis and similarly, the neuropeptide FF analog in the nucleus raphe dorsalis decreased the effects of 27 nmol morphine injected in the parafascicular nucleus. The density of neuropeptide FF receptors did not decrease in the nucleus raphe dorsalis after lesion of serotonergic neurons by 5,7-dihydroxytryptamine. However, after this lesion, (1DMe)Y8Fa injected in the nucleus raphe dorsalis was no longer able to modify analgesic effects of morphine in hot-plate and tail-immersion tests. Similarly, the serotonin (5-HT) depletion induced by a systemic administration of para-chlorophenylalanine did not modify morphine analgesia microinjected into the nucleus raphe dorsalis and the parafascicular nucleus but blocked the ability of (1DMe)Y8Fa to reverse morphine effects in both nuclei. These data show that neuropeptide FF exerts anti-opioid effects directly into both the nucleus raphe dorsalis and the parafascicular nucleus and acts also at distance on opioid functions. Furthermore, anti-opioid effects of neuropeptide FF require functional serotonergic neurons although neuropeptide FF receptors are not carried on these neurons.     

去甲肾上腺素能系统对埃必定镇痛作用的影响

在大鼠电刺激甩尾测痛模型上,sc或icv埃必定(ipalbidine,Ipa)均具有剂量依赖性的镇痛作用,而脊髓蛛网膜下腔注射Ipa人产生镇痛作用;预先给予利血平可以取消scIpa的镇痛作用,这一作用可被icv补充NE所翻转;电解损毁大鼠叹侧蓝斑,ip二乙基二硫代氨基甲酸钠200mg·kg^-1,酚妥拉明ip10mg·kg^-1或icv150μg和sc哌唑嗪5mg·kg^-1均能使Ipa的镇痛作用明显减弱或消失,而sc育亨宾5mg·kg^-1和ip普萘洛尔10mg·kg^-1对Ipa的镇痛作用无明显影响。上述结果提示Ipa在中枢有镇痛作用,其部位主要在脊髓以上的神经结构,Ipa的镇痛作用可能与去甲肾上腺素能系统的a₁受体有关,而与a₂和β受体无明显关系。     

Effect of antidepressant drugs on dopamine D1 and D2 receptor expression and dopamine release in the nucleus accumbens of the rat

This study examined the effect of repeated treatment with the antidepressant drugs, fluoxetine, desipramine and tranylcypromine, on dopamine receptor expression (mRNA and binding site density) in sub-regions of the nucleus accumbens and striatum of the rat. The effect of these treatments on extracellular levels of dopamine in the nucleus accumbens was also measured. Experiments using in situ hybridisation showed that the antidepressants caused a region-specific increase in D₂ mRNA, this effect being most prominent in the nucleus accumbens shell. In contrast, none of the treatments increased D₁ mRNA in any of the regions examined. Measurement of D₂-like binding by receptor autoradiography, using the ligand [³H]YM-09151-2, revealed that both fluoxetine and desipramine increased D₂-like binding in the nucleus accumbens shell; fluoxetine had a similar effect in the nucleus accumbens core. Tranylcypromine, however, had no effect on D₂-like binding in the nucleus accumbens but decreased binding in the striatum. In microdialysis experiments, our data showed that levels of extracellular dopamine in the nucleus accumbens were not altered in rats treated with either fluoxetine or desipramine, but increased by tranylcypromine. From our findings, we propose that the antidepressant drugs tested enhance dopamine function in the nucleus accumbens through either increased expression of postsynaptic D₂ receptors (fluoxetine and desipramine) or increased dopamine release (tranylcypromine). Received: 5 January 1998/Final version: 6 April 1998     

Ethanol, like psychostimulants and morphine, causes long-lasting hyperreactivity of dopamine and acetylcholine neurons of rat nucleus accumbens: possible role in behavioural sensitization

Repeated treatment of rats with ethanol (1 g/kg, once daily for 15 days) enhanced the locomotor effect of morphine, 3 weeks post-treatment. This ethanol-induced long-term behavioural sensitization to morphine was associated with an increase in the electrically evoked release of [³H]dopamine (DA) and [¹⁴C]acetylcholine (ACh) from nucleus accumbens slices. A similar enhanced responsiveness of accumbal dopaminergic and cholinergic neurons to depolarization was apparent 3 weeks after repeated morphine, amphetamine or cocaine administration. Prior ethanol exposure also caused a long-term enhancement of electrically evoked release of [³H]DA and [¹⁴C]ACh from slices of the caudate-putamen. Unlike the locomotor effect of morphine, that of amphetamine was not enhanced in ethanol-pretreated rats. These data indicate that ethanol administration may cause long-term behavioural sensitization associated with adaptive changes in dopaminergic and cholinergic neurons of rat nucleus accumbens and caudate-putamen. Furthermore, an enhanced reactivity of nucleus accumbens dopaminergic nerve terminals and dopamine-sensitive cholinergic neurons appears to be a common long-term neuroadaptive effect of distinct types of addictive drugs. However, since repeated ethanol exposure did not cause a long-term increase in the locomotor effect of amphetamine, these neuroadaptations may not always be sufficient to cause long-lasting behavioural (cross-)sensitization. Received: 15 January 1997 / Final version: 25 March 1997