N—乙酰—5—甲氧色胺镇痛作用的实验研究

目的 为了寻找新型镇痛药物，对N-乙酰-5-甲氧色胺（Mel)的镇痛作用及其与哌替啶（Pt)的协同作用进行探索性研究。方法 采用小鼠热板法及冰乙酸致小鼠扭体为疼痛模型，观察Mel对痛阈的影响。结果 Mel 30,60,120mg/kg剂量依赖性地增加小鼠痛阈，且于给药后1h达高峰，持续至2h仍有效。此外，无镇痛效应的Mel(10mg/kg)与哌替啶（10mg/kg)合用，能明显提高小鼠痛阈。结论 Mel具有良好的镇痛作用，增大剂量完全能达到哌替啶的镇痛效应，且与哌替啶有明显协同效应。     

N-乙酰-5-甲氧色胺对创伤痛的影响及作用部位分析

目的：研究N-乙酰-5-甲氧色胺对创伤痛的影响，并对其可能作用部位进行分析。方法：以大鼠截肢结合50℃热水刺激举尾作为创伤痛模型，大鼠创伤后即刻、1d、2d、3d腹腔注射不同剂量的Mel(30,60，120mg／kg）、Pt 20mg／kg、Mel Pt(10 10mg／kg)及溶媒，于创伤前及最后一次给药后20min、40min、80min、120min观察痛阈(50℃刺激举尾潜伏期)变化情况。观察创伤后3d侧脑室注射Mel(0．25、0．5、1．0mg／kg)后20min、40min、80min、120min的痛阈变化情况。结果：创伤后3d痛阈降至最低，7d恢复至正常。腹腔注射Mel(30-120mg/kg)或侧脑室注射Mel(0．25-1．0mg／kg)均剂量依赖性地增加了创伤大鼠的痛阈，且于给药后40min达高峰，持续至120min仍有效。Mel(10mg／kg)与Pt(10mg／kg)合用，能明显提高小鼠痛阈。结论：Mel对创伤痛具有良好的镇痛作用，其主要作用部位在中枢。Mel与哌替啶有明显协同镇痛效应。     

干扰素-α对小鼠神经源性痛的镇痛作用

目的:研究干扰素-α(IFN-α)对神经源性痛的镇痛作用及可能机制,为临床治疗神经源性痛筛选新的、毒副作用小的镇痛药物奠定基础。方法:单侧L5/L6脊神经结扎痛模型小鼠腹腔注射不同剂量IFN-α(1.0,2.5和5.0×106U/kg)后,利用机械刺激和冷刺激诱发的痛觉超敏实验测定模型小鼠患侧脚掌给药前后的痛阈变化;同时,通过给药前30m in注射纳洛酮(1mg/kg)观察阿片受体拮抗剂对其镇痛作用的影响。结果:腹腔注射IFN-α可产生剂量依赖性镇痛作用,其中5.0和2.5×106U/kg IFN-α均可产生明显的镇痛作用,镇痛效应分别维持60和30 m in,而1.0×106U/kgIFN-α无明显的镇痛作用。IFN-α产生的镇痛效应可被阿片受体拮抗剂纳洛酮完全阻断。结论:IFN-α对小鼠神经源性痛具有镇痛作用,其镇痛效应可能通过阿片受体介导。     

莨菪类生物碱对吗啡依赖小鼠痛阈影响的比较

目的:观察莨菪类生物碱对吗啡依赖小鼠痛阈的影响。方法:连续腹腔注射吗啡(10mg/kg,1次/d,共7d)建立小鼠依赖模型,并腹腔注射莨菪类生物碱(4mg/kg,1次/d,共7d)。结果:吗啡组小鼠痛阈明显下降。东莨菪碱能显著提高吗啡依赖小鼠的痛阈。同剂量山莨菪碱和阿托品均有对抗吗啡依赖小鼠的痛阈下降的现象。结论:莨菪类生物碱中,东莨菪碱在提高吗啡依赖小鼠痛阈的作用最强。     

土鳖虫酶解物镇痛作用的研究

目的:探讨土鳖虫酶解物的镇痛作用,为将其开发成新药提供依据。方法:土鳖虫酶解物160 mg/kg、40 mg/kg、20mg/kg、10 mg/kg灌胃给药(小鼠),土鳖虫酶解物160 mg/kg、40 mg/kg灌胃给药(大鼠),用醋酸致小鼠扭体模型,测定小鼠扭体次数;用无菌铬肠线结扎制备大鼠坐骨神经慢性压迫性神经病理性疼痛模型,测定大鼠压力痛阈值。结果:土鳖虫酶解提取物超高、高、中剂量组能显著降低醋酸所致小鼠扭体反应次数(P<0.01),并与剂量呈一定的依赖关系。土鳖虫酶解提取物40 mg/kg、160mg/kg能显著提高大鼠压力痛阈(P<0.01),并呈剂量依赖关系。结论:土鳖虫酶解提取物具有镇痛作用。     

河豚毒素与阿司匹林的协同镇痛作用

目的:对比单独应用河豚毒素和单独应用阿司匹林及与两者合用的镇痛效应。方法:实验于2003-10/2005-03在北京大学基础医学院药理学系完成。选用昆明健康小鼠230只。随机分为单用河豚毒素组、单用阿司匹林组和小剂量河豚鼠与阿司匹林联合用药组三大组,共23个亚组,每亚组均为10只。采用小鼠醋酸扭体致痛实验观察合用后是否具有镇痛增强或协同效应。结果:230只大鼠均进入结果分析。①单用河豚毒素组的镇痛作用:河豚毒素组(0.5～4.0)×10-3mg/kg时,小鼠扭体半数抑制量为2.1×10-3mg/kg;当河豚毒素的剂量用到4.0×10-3mg/kg时,小鼠醋酸扭体反应的抑制率为65.2%;②单用阿司匹林的镇痛作用:阿司匹林组(12.5～200)×103mg/kg的镇痛半数抑制量为64.0mg/kg,相应的镇痛抑制百分率为15.8%到93.2%。③小剂量河豚毒素(即0.79×10-3mg/kg,0.39×10-3mg/kg)与阿司匹林联合应用时,镇痛作用明显增强,此时阿司匹林的半数抑制量下降至5.8mg/kg和12.6mg/kg。结论:小剂量河豚毒素和阿司匹林联合应用时能明显提高镇痛疗效。     

极小剂量纳洛酮增强电针的镇痛作用但不影响电针对吗啡戒断症状的抑制作用

目的:纳洛酮(naloxone,NX)是一种阿片受体拮抗剂,应用于大鼠,在1～10mg/kg范围内能对抗吗啡镇痛和电针(electroacupuncture,EA)镇痛。但有人报道,极小剂量NX可加强吗啡镇痛。本工作观察极小剂量NX是否能加强大鼠电针镇痛,及电针对大鼠吗啡戒断的抑制作用。方法:选用成年雄性SD大鼠,分两批进行实验。第一批以辐射热甩尾阈(TFL)作为大鼠痛阈指标,检测腹腔注射(i.p.)NX10ng/kg对2Hz EA和100Hz EA镇痛效应的影响。第二批在慢性吗啡依赖大鼠模型上,以体重丢失作为吗啡戒断反应指标,观察i.p NX 10 ng/kg对 2Hz EA和 100Hz EA抑制 NX(lmg/kg,i.p.)诱发的体重丢失的影响。结果:(1)EA之前10分钟 i.p. NX 10 ng/kg,不仅能显著增强2Hz EA的镇痛作用(P<0.05),而且可使其镇痛效应延长至120分钟;同样剂量NX对100 Hz EA的镇痛效应无明显影响(P>0.05)。(2)EA之前10分钟i.p. NX 10 ng/kg,对两种频率EA抑制吗啡戒断大鼠体重丢失的效应均无显著影响。结论:极小剂量的NX能增强和延长2Hz EA的镇痛作用,该发现可能具有临床应用意义。极小剂量的NX未能影响EA抑制吗啡戒断大鼠体重丢失的作用,这可能与吗啡戒断状态下阿片受体的功能改变有关。     

莨菪类生物碱对吗啡依赖小鼠痛阈影响的比较

目的：观察莨菪类生物碱对吗啡依赖小鼠痛阈的影响。方法：连续腹腔注射吗啡(10mg／kg，1次／d，共7d)建立小鼠依赖模型，并腹腔注射莨菪类生物碱(4mg／kg，1次／d，共7d)。结果：吗啡组小鼠痛阈明显下降。东莨菪碱能显著提高吗啡依赖小鼠的痛阈。同剂量山莨菪碱和阿托品均有对抗吗啡依赖小鼠的痛阈下降的现象。结论：莨菪类生物碱中，东莨菪碱在提高吗啡依赖小鼠痛阈的作用最强。     

三叶委陵菜乙醇提取物镇痛作用的研究

目的研究三叶委陵菜乙醇提取物的镇痛作用.方法热板法和扭体法.结果热板法中,灌胃三叶委陵菜乙醇提取物(0.5 g/kg,1.25g/kg,2.5g/kg)15,30,60和90min后,小鼠的痛阈均明显延长,其中灌胃2.5g/kg提取物90min后的镇痛效应比氨基比林(100 mg/kg i.m.)的好.在对非甾体药敏感的扭体法中,不同剂量的三叶委陵菜醇提物(0.5 g/kg,1.25g/kg,2.5g/kg o.p.)均能显著抑制0.7%醋酸引起的扭体反应.结论三叶委陵菜具有镇痛效应,民间用三叶委陵菜医治牙痛及其它疼痛症的疗效得到了验证.     

不同剂量喷他佐辛抑制吗啡的镇痛作用

目的:研究不同剂量喷他佐辛对吗啡镇痛效果的影响及可能机制。方法:60只C57BL/6J小鼠随机分为10组(n=6),其中5组喷他佐辛注射前2小时预先注射生理盐水,另外5组预先注射kappa受体拮抗剂nor-BNI(10 mg/kg),随后各组同时皮下注射不同剂量喷他佐辛(0、10、30、56、100 mg/kg)和吗啡(10 mg/kg),分别于药物注射前和注射后30、60、90、120 min对小鼠进行机械痛阈(压尾试验)和热痛阈(热板试验,甩尾试验)测定,并分别计算药物时效的曲线下面积(area under curve,AUC)作为药物镇痛效应的量化指标。结果:1不同剂量喷他佐辛(0、10、30、56、100 mg/kg)在与吗啡合用后的压尾AUC分别为(244.1±19.5)、(166.5±9.6)、(146.6±8.3)、(130.7±7.8)、(124.5±10.1)(g·h);热板AUC分别为(27.9±4.0)、(24.4±1.6)、(22.8±1.6)、(23.3±2.1)、(22.7±1.2)(s·h);甩尾AUC分别为(13.1±1.9)、(12.0±1.7)、(10.4±0.8)、9.5±0.9)、(9.7±1.3)(s·h)。这提示喷他佐辛可剂量依赖地抑制吗啡的镇痛作用。2使用κ受体拮抗剂nor-BNI后,不同剂量喷他佐辛(0、10、30、56、100 mg/kg)与吗啡合用后的压尾AUC分别为(252.2±16.7)、(167.7±11.0)、(145.1±9.8)、(132.6±5.1)、(127.3±8.0)(g·h);热板AUC分别为(28.0±1.7、(25.0±1.6)、(23.0±1.2)、(22.0±1.4)、(21.2±1.3)(s·h);甩尾AUC分别为(14.4±1.8)、(11.2±1.4)、(10.2±0.8)、(9.7±0.7)、(10.1±0.8)(s·h),与上述未使用nor-BNI的各组相比差异均无统计学意义(P>0.05),结果表明kappa受体拮抗剂存在的情况下,大剂量喷他佐辛对吗啡镇痛依然存在抑制作用。结论:喷他佐辛可剂量依赖地抑制啡产生的镇痛作用,该抑制作用与kappa受体激动无关。     

Effects of human placental extract on chemical and thermal nociception in mice

Several reports indicate that pregnancy and parturition are associated with elevated maternal pain thresholds to noxious stimuli. The objective of this study was to examine whether the human placental extract, a clinically used preparation, can inhibit experimental nociception. Nociception was assessed in mice using acetic acid-induced writhing and hot-plate tests. The human placental extract (200 and 400 mg/kg, i.p.) elicited dose-related antinociception in the acetic acid-induced writhing test. Furthermore, it (200 mg/kg, i.p.) potentiated the morphine-induced antinociception (1.25 mg/kg, s.c.). In the hot-plate test, the human placental extract (100, 200 and 400 mg/kg, i.p.) per se, displayed no significant antinociception but potentiated the duration of morphine (10 mg/kg, s.c.) analgesia. The potentiation by the extract of the morphine-induced antinociception in both acetic acid and hot-plate tests was, however, found to be naloxone sensitive. Mice treated with the extract (400 mg/kg, i.p.) neither manifested any overt behavioural change in the open-field test nor demonstrated significant influence on pentobarbital sleeping time, suggesting that it has no central depressant or sedative activity. The data provide evidence to show that the human placental extract has a peripheral analgesic property possibly mediated by an opioid mechanism.     

蝎毒镇痛活性肽镇痛作用的研究

本文以行为及电生理反应方法研究了蝎毒镇痛活性肽（ＳＡＰ）的镇痛作用。ＳＡＰ是由东亚钳蝎毒经Ｓｅｐｈａｄｅｘ柱层析反复分离纯化而成的多肽物物质。实验中利用大鼠光热甩尾法、小鼠热板法及本法证明ＳＡＰ有很强的镇痛作用。ＳＡＰ对大鼠三叉神经下颌分支刺激引起的皮层诱导电位Ｎ波有较强的抑制作用。对吗啡耐受的大鼠仍有较强的镇痛作用。     

癌症止痛栓剂的药理学研究

癌症止痛栓剂（下称癌痛栓）是一种“中空囊栓剂”（国家专利专利号：ＺＬ９２２０８３５５Ｘ）。中空囊内含有小剂量９９ｍＴＣ（锝），和具有抗癌止痛作用的蛇毒。肛门给药，经小鼠热板法、电刺激法及醋酸扭体反应实验，结果显示该制剂具有显著的止痛作用。     

臭牡丹根提取物对小鼠的镇痛效应

背景臭牡丹属马鞭草科植物,现代药理学研究表明臭牡丹具有抗炎,抗肿瘤,提高机体非特异性免疫,兴奋子宫圆韧带肌电作用与激动α肾上腺受体有关,关于镇痛作用的实验研究较少.目的通过热板法和扭体法观察臭牡丹的乙醇提取物对小鼠的镇痛作用.设计以动物为观察对象,随机对照实验.单位赣南医学院的药理学教研室.材料实验于2004-03/06在赣南医学院药理教研室完成,选择昆明种小白鼠120只,体质量(20±2)g,由赣南医学院实验中心提供.干预50只小白鼠用于扭体法实验,随机分为生理盐水组,氨基比林0.1 g/kg组,吗啡0.01 g/kg组,臭牡丹提取物20 g/kg组,臭牡丹提取物40 g/kg组,每组10只,分别经腹腔注射给药,40 min后腹腔注射6 mL/L乙酸溶液(10 mL/kg),5 min后开始观察小鼠扭体数和扭体抑制率,共观察10 min.40只小白鼠用于热板法实验,随机分为生理盐水组,吗啡0.01g/kg组,臭牡丹提取物20 g/kg组,臭牡丹提取物40 g/kg组,每组10只,经腹腔注射给药后即刻置于热板金属表面,温度控制在(55±0.5)℃,分别记录给药后15,30,60 min痛阈值.30只小白鼠用于对抗纳洛酮的热板法实验,随机分为纳洛酮0.04 g/kg+吗啡0.01 g/kg组,纳洛酮0.04 g/kg+臭牡丹提取物40 g/kg组,纳洛酮0.04 g/kg+生理盐水组,经腹腔注射给药,记录给药后15,30,60,90 min痛反应时间值.主要观察指标①小白鼠扭体次数和扭体抑制率.②痛反应时间.③纳洛酮对抗后,痛反应时间.结果120只小白鼠全部进入结果分析.①扭体次数和扭体抑制率通过腹腔注射臭牡丹提取物20和40 g/kg后小白鼠的扭体次数为2.4±2.5,0.6±1.7,它们对6 mL/L乙酸溶液引起的疼痛反应的抑制率为93.3%,98.3%.②热板法实验给药后15,30,60 min的痛阈值给予臭牡丹提取物20 g/kg后15,30,60 min痛阈值为[(121.2±98.7)s,(191.2±78.6)s,(133.1±91.1)s];给予臭牡丹提取物40 g/kg后15,30,60 min痛阈值为[(233.9±70.4)s,(219.6±78.2)s,(218.3 ±92.6)s],均高于生理盐水组[(13.7±15.2)s,(9.7±12.5)s,(22.1±15.6)s](P＜0.01～0.001).③在纳洛酮对抗吗啡的实验中,吗啡0.01 g/kg+纳洛酮0.04 g/kg组给药后15,30,60 min的痛域明显小于臭牡丹提取物40 g/kg+纳洛酮0.04 g/kg组[(1.7±5.2)s,(124.9±79.4)s,P＜0.001;(6.4±8.6)s,(139.3±72.9)s,P＜0.001;(21.8±34.0)s,(137.9±60.8)s,P＜0.001].结论臭牡丹的乙醇提取物具有很强的镇痛作用,这种镇痛作用不是通过激动阿片受体而发挥镇痛效应的.     

Neurotensin-induced antinociception in mice: antagonism by thyrotropin-releasing hormone

Neurotensin (NT), administered intracisternally to mice, produced significant dose-dependent antinociception in three analgesic tests: tail immersion, hot-plate and acetic acid writhing. Naloxone (1-5 mg/kg), an opiate antagonist administered i.p. 20 min before NT administration, did not significantly alter NT-induced antinociception in any of these tests; naloxone did significantly reverse beta-endorphin-induced antinociception. However, centrally and peripherally administered thyrotropin-releasing hormone antagonized NT-induced (but not beta-endorphin-induced) antinociception. Equimolar doses of another tripeptide (Pro-Leu-Gly-NH2; melanostatin) did not alter the effects of NT. The data obtained in this study confirm NT-induced antinociception, provide further evidence that NT does not activate naloxone-sensitive opiate receptors and demonstrate that this brain effect of NT is antagonized by thyrotropin-releasing hormone. These findings therefore support the hypothesis that NT and thyrotropin-releasing hormone are functional antagonists in the central nervous system.     

Peripheral and preemptive opioid antinociception in a mouse visceral pain model

Recent studies suggest that opioids can produce analgesia through peripheral mechanisms following inflammation of peripheral tissue. This study examined whether opioids administered prior to inflammation can produce antinociception by peripheral mechanisms in a model of visceral pain. Mice were injected intraperitoneally (i.p.) with 1% acetic acid to evoke abdominal writhing, a standard model of visceral pain. The number of writhes that occurred during 30 min after acetic acid were determined. Intraperitoneal injection of morphine sulfate (60, 90, 100 or 120 microg/0.3 ml) or the peripherally acting opioid loperamide (0.12, 0.36, 1.2 or 3.6 mg/0.3 ml) given 5 min after acetic acid decreased writhing in a dose-dependent fashion. Morphine (100 microg) produced an 70% attenuation in the number of writhes while loperamide (1.2 mg) decreased writhing by 56%. These antinociceptive effects were blocked by pretreatment with the opioid receptor antagonists naloxone (10 mg/kg) and its quarternary version naloxone methiodide (10 mg/kg). To determine whether opioids produced preemptive antinociception via peripheral mechanisms, mice received i.p. injections of morphine (1, 5, and 10 microg/0.3 ml) or vehicle 5 min before acetic acid. Doses of 5 and 10 microg morphine inhibited the number of writhes by 51 and 93%, respectively. The highest dose (10 microg) was ineffective when given intravenously 5 min before acetic acid, suggesting that antinociception following i.p. administration was acting via peripheral mechanisms. These data demonstrate that low doses of opioids, given before or after acetic acid, produce visceral antinociception through peripheral mechanisms. This may be clinically relevant for the management of postoperative abdominal pain.     

Comparative effects of different uptake inhibitor antidepressants in two pain tests in mice

The purpose of this study was to compare the analgesic effect of acute injections (1.25 and 20 mg/kg, ip) of several antidepressants with different effects on monoamine reuptake, on two pain tests in mice (hot-plate and phenylbenzoquinone-induced abdominal writhes). Serotonergic inhibitors (citalopram, fluvoxamine and clomipramine) were more effective in the hot-plate test whereas noradrenaline reuptake inhibitors (desipramine and maprotilline) were more effective in the writhing test. The mixed antidepressants (amitriptyline and to a lesser degree trimipramine) were more effective in the two tests than the other antidepressant drugs. Changes in motor activity of clomipramine and amitriptyline could not account for the modifications of pain threshold. Amineptine (a dopamine reuptake inhibitor) failed to induce any antinociceptive effect in the hot-plate test and was hyperalgesic in the writhing test, which could be explained by an increased motor activity. These findings indicate that the antinociceptive potency of reuptake inhibitors varies according to their monoamine specificity and the nature of stimuli. They would suggest that the preferential choice of serotonergic antidepressants in the management of chronic pain is arguable.     

Targeting pain-suppressed behaviors in preclinical assays of pain and analgesia: effects of morphine on acetic acid-suppressed feeding in C57BL/6J mice.

Pain increases the rate, frequency, or intensity of some behaviors (eg, withdrawal responses) and suppresses other behaviors (eg, feeding). Our laboratories are developing assays to test analgesic drug candidates using measurements of pain-suppressed rather than pain-elicited behaviors. Such assays may model important aspects of clinical pain and provide a means for distinguishing true analgesics from drugs that produce motor impairment. The present study compared effects of the mu opioid analgesic morphine and the nonanalgesic neuroleptic haloperidol on intraperitoneal acetic acid-induced writhing (a pain-elicited behavior) and suppression of feeding behavior (a pain-suppressed behavior). In feeding studies, C57BL/6J mice were given access to a dish containing 8 mL Ensure(trade mark) liquid food (0-100% in water) during daily sessions (7.5-120 min). Levels of consumption were dependent on both Ensure concentration and session duration. Intraperitoneal injection of acetic acid (0.10-0.56%) produced a time- and concentration-dependent decrease in Ensure consumption. Morphine (1 mg/kg) prevented both acid-induced writhing and acid-induced suppression of feeding, whereas the dopamine antagonist haloperidol inhibited writhing without preventing acid-induced suppression of feeding. The effects of morphine were time-dependent, selective for acid-suppressed feeding, and naltrexone-reversible. These results suggest that assays of pain-suppressed behaviors may complement assays of pain-elicited behaviors in preclinical studies of candidate analgesics. PERSPECTIVE: This paper presents a new preclinical strategy for assessing pain and analgesia in mice that is congruent with current methods of pain assessment in the clinic. This strategy may therefore be a useful complement to more traditional procedures for assessing pain and analgesia.     

氯丙米嗪镇痛抗炎作用研究

目的：研究氯丙米嗪镇痛抗炎作用。方法：采用小鼠热板实验、醋酸扭体实验和福尔马林实验。结果：腹腔注射氯丙米嗪10mg/kg可延长小鼠舔脚潜伏期，减少小鼠扭体次数，抑制福尔马林引起的疼痛反应，能减轻福尔马林所致小鼠足跖水肿。结论：氯丙米嗪具有明显的镇痛作用，在镇痛剂量时能抑制皮下注射福尔马林引起的水肿。