止痛胶囊对大鼠镇痛作用的实验研究

目的：探讨止痛胶囊对于大鼠的镇痛作用及其机理。方法：采用光热刺激鼠尾－逃避法（Ｔａｉｌ ｆｌｉｃｋ ｔｅｓｔ）测定大鼠痛阈。结果：止痛胶整能剂理依赖性地提高大鼠光热刺激鼠尾－逃避法的痛阈；纳洛酮能部分翻转止痛胶囊的镇痛作用。结论：止痛胶囊具有镇痛作用，其镇痛作用可能涉及阿片受体。     

褪黑素对大鼠和小鼠的镇痛作用

采用直流串单方波电刺激鼠尾部引起鼠嘶叫的电流值为动物痛阈指标,观察褪黑素（ＭＴ）对大鼠和小鼠的镇痛作用;进而观察纳络酮的拮抗作用,以探讨ＭＴ的镇痛作用与内源性阿片肽系统的关系。结果表明,ｉｐＭＴ显著提高大鼠痛阈,具有明显的量效和时效关系;ｉｐＭＴ也显著提高小鼠痛阈。表明ＭＴ对大鼠和小鼠均可产生显著的镇痛作用。纳洛酮拮抗ＭＴ对大鼠、小鼠的镇痛作用,提示ＭＴ的镇痛作用与内源性阿片肽系数有关。     

中药复方止痛胶囊抗风湿作用机理研究

目的 :探讨止痛胶囊抗风湿作用机理。方法 :建立佐剂性关节炎 (adjuvantarthritis ,AA)大鼠模型。观察止痛胶囊的抗炎消肿作用以及对AA大鼠白细胞介素 -1(IL -1)、肿瘤坏死因子 (TNF)、前列腺素E2 (PGE2 )活性的影响 ,并同时观察AA大鼠膝关节病理切片和止痛胶囊镇痛作用。结果 :止痛胶囊可显著减轻AA大鼠膝关节炎症等病理反应 ;能显著减轻角叉菜胶所致的大鼠足跖肿胀 (P <0 0 5 ) ;对二甲苯所致的小鼠耳廓肿胀也有明显的抑制作用 (P <0 0 0l) ;在抑制大鼠琼脂肉芽肿方面同样具有显著作用 ( P <0 0 1) ;还能显著拮抗 5 -HT引起的血管通透性增加 ( P <0 0 1) ;止痛胶囊能明显降低AA大鼠血清中IL -1、TNF和PGE2的含量 ,与对照组比较有显著差异 (P <0 0 0l) ;止痛胶囊还可显著降低AA大鼠的痛阈 (P <0 0 1)。结论 :止痛胶囊可通过抗炎消肿 ,调整机体免疫功能 ,改善局部病理反应而达到抗风湿作用。     

韩氏穴位神经刺激仪对大鼠佐剂性关节炎的治疗作用

以佐剂性关节炎大鼠作为病理性疼前的实验动物模型，用韩氏穴位神经刺激仪进行治疗，结果发现：关节炎大鼠痛阈较正常鼠明显降低，体温及患肢直径也明显增加；但经过一个疗程治疗后，关节炎大鼠的症状有明显的改善，表现为痛阈显著提高，体温恢复正常和患肢肿胀程度减轻；腹腔注射维生素Ｂ６能显著加强治疗的镇痛作用。结果表明：佐剂性关节为大鼠可作为病理性疼痛的实验动物模型；韩氏穴位神经刺激仪对关节炎大鼠上有良好的治疗作用     

中药复方止痛胶囊抗风湿作用机理研究

目的：探讨止痛胶囊抗风湿作用机理。方法：建立佐剂性关节炎（adjuvant arthritis,AA)大鼠模型。观察止痛胶囊的抗炎消肿作用以及对AA大鼠白细胞介素－1（IL－1）、肿瘤坏死因子（TNF）、前列腺素E2（PGE2）活性的影响,并同时观察AA大鼠膝关节病理切片和止痛胶囊镇痛作用。结果：止痛胶囊可显著减轻AA大鼠膝关节炎症等病理反应;最显著减轻角叉菜胶所致的大鼠足跖肿胀（P＜0．05）;对二甲苯所致的小鼠耳廓肿胀也有明显的抑制作用（P＜0．001）;在抑制大鼠琼脂肉芽肿方面同样具有显著作用（P＜0．01）;还能显著拮抗5-HT血管通透性增加（P＜0．01）;止痛胶囊能明显降低AA大鼠血清中IL－1、TNF和PGE2的含量,与对照组比较有显著差异（P＜0．001）;止痛胶囊还可显著降低AA大鼠的痛阈（P＜0．01）。结论：止痛胶囊可通过抗炎消肿,调整机体免疫功能,改善局部病理反应而达到抗风湿作用。     

中脑导水管周围灰质内催产素对痛阈和电针镇痛效应的影响

本工作以钾离子透入法引起大鼠甩尾反应的电流强度（ｍＡ）为痛反应指标，观察了中脑导水管周围灰质（ＰＡＧ）腹外侧区注射催产素（ＯＴ）和抗催产素血清（ＡＯＴＳ）对大鼠痛阈和电针镇痛效应的影响。结果表明，ＰＡＧ注射ＯＴ能增加大鼠痛阈和电针镇痛效应；注射ＡＯＴＳ以中和内源性的ＯＴ后，对大鼠痛阈虽克明显影响，但能显著降低电针期的停针后的电针镇痛效应。提示ＰＡＧ内生理水平的ＯＴ在电针镇痛中发挥一定作用。     

尾核内催产素对痛阈的调制作用及其机制研究

目的:探讨大鼠尾核内催产素(oxytocin,OT)在痛行为调制中的作用,及其与内源性阿片肽系统之间的关系。方法:用WQ-9E型钾离子透入痛阈测量仪测痛。以引起大鼠甩尾反应的最小电流强度(m A)作为痛行为反应值,将间隔1 min的3次痛行为反应值的平均值作为一次痛阈,每间隔10 min测定痛阈一次,取给药前的两次痛阈的平均值作为基础痛阈,给药后各次的痛阈与其相比,计算痛阈变化的百分数(%)。实验分三部分进行,第一部分观察尾核内注射OT对大鼠痛行为的影响;第二部分观察尾核内注射抗催产素血清(anti-OT serum,AOTS)对大鼠痛行为的影响;第三部分观察尾核内注射纳洛酮(Naloxone,Nx)对OT在痛行为中作用的影响。结果:尾核内注入OT后,大鼠的痛阈明显增加,并在一定范围内呈明确的剂量-效应关系;向尾核内注入AOTS以中和内源性OT后,大鼠痛阈有降低趋势,但无统计学意义;向尾核内注入Nx后,不能完全阻断OT在痛行为反应中的作用。结论:尾核内OT参与大鼠痛行为调制的复杂过程,引起痛行为反应的阈值增加,此作用不完全依赖于内源性的阿片肽系统。     

大鼠中缝大核内一氧化氮在痛觉调制和针刺镇痛中的作用

背景L-精氨酸是内源性一氧化氮的前体物质,而一氧化氮参与外周脊髓水平和脊髓水平以上痛觉的调制.目的探讨延髓中缝大核内一氧化氮在痛觉调制和针刺镇痛过程的作用.设计以动物为观察对象的随机对照实验.单位咸宁学院医学院生理教研室.材料实验于2002-05/2003-03在咸宁学院医学院生理教研室完成.选用63只Wistar大鼠,随机分为7组,每组9只大鼠①L-精氨酸量效关系实验分为5组生理盐水组,L-精氨酸1,2,4,8 mmol组.②L-精氨酸与电针镇痛关系实验分为两组生理盐水+电针组,L-精氨酸+电针组.方法①L-精氨酸量效关系实验5组大鼠分别延髓中缝大核微量注射生理盐水及L-精氨酸1,2,4,8 mmol,容积均为1.5 μL.给药后每隔10 min以(50 ±0.5)℃热水刺激甩尾测定痛阈,连续观察90min.②L-精氨酸与电针镇痛关系实验两组大鼠分别延髓中缝大核微量注射生理盐水1.5μL及L-精氨酸8mmol(1.5 μL),10min后电针刺激大鼠双侧后肢"足三里"穴位,频率为4～16 Hz,强度按1,2,3 V顺序递增电压,每一强度电针10 min,共电针30 min并测痛3次,停针后继续每隔10min测痛1次,直至注药后90min.主要观察指标各组大鼠不同时间点痛阈变化.结果63只大鼠进入结果分析.①L-精氨酸1 mmol组大鼠各个时间点痛阈低于生理盐水组,但统计学分析无差异(P＞0.05),L-精氨酸2,4,8 mmol组大鼠各个时间点痛阈均显著低于生理盐水组(P＜0.001),作用持续至给药后80 min;且随着浓度的增加,大鼠痛阈降低的幅度增加.②L-精氨酸+电针组大鼠给药后20～50 min痛阈明显低于生理盐水+电针组(P＜0.01).结论①延髓中缝大核微量注射L-精氨酸具有降低痛阈作用,其作用呈剂量依赖性.②电针能提高痛阈,L-精氨酸可削弱电针镇痛效应.③以上提示延髓中缝大核内一氧化氮参与痛和电针镇痛的病理生理过程,其含量增加明显降低痛阈.     

中脑导水管周围灰质5-HT_7受体在神经病理性疼痛中的镇痛作用研究

目的:探讨神经病理性疼痛大鼠中脑导水管周围灰质外侧区(l PAG)中5-羟色胺7(5-HT7)受体活化在神经病理性疼痛中的镇痛作用。方法:SD大鼠60只,均分为5组:正常组、神经病理性疼痛组(CCI组)、假CCI组、CCI加AS-19和CCI加SB-269970组。制备CCI大鼠模型,检测各组大鼠机械痛阈变化;免疫印迹法检测l PAG中5-HT7受体蛋白表达情况;在CCI大鼠l PAG中微量注射5-HT7受体特异性激动剂AS-19(6μmol/0.3μl)以及特异性拮抗剂SB-269970(3μmol/0.3μl)后观察药物对CCI大鼠机械痛阈的影响。结果:神经病理性疼痛大鼠机械痛阈下降伴l PAG中5-HT7受体蛋白表达上调,与假手术组大鼠比较差异有统计学意义(P<0.001)。CCI大鼠l PAG注射AS-19后,机械痛阈显著上升(P<0.001)且可被预先注射SB-269970所抑制。结论:l PAG中5-HT7受体活化后通过激活机体内源性镇痛系统对神经病理性疼痛大鼠产生镇痛作用。     

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。     

Specific effect of venlafaxine on single and repetitive experimental painful stimuli in humans

BACKGROUND: Tricyclic antidepressants relieve neuropathic pain, and the analgesic properties of tricyclic antidepressants are substantiated in human experimental pain models. It has been speculated that drugs with a selective inhibition of presynaptic reuptake of both serotonin and noradrenaline could have an analgesic effect comparable to the analgesic effect of tricyclic antidepressants. OBJECTIVE: Our objective was to evaluate the analgesic effect of the serotonin-noradrenaline reuptake inhibitor venlafaxine in human experimental pain models. METHOD: The study was carried out as a randomized, placebo-controlled, double-blind, crossover experiment that included 16 healthy volunteers. A 37.5-mg dose of venlafaxine was given orally 4 times with 12-hour intervals, and pain tests were performed before and 3 hours after the second and fourth doses. Pain tests included the determination of pain detection and tolerance thresholds to pressure, pain detection and tolerance thresholds on single electrical transcutaneous stimulation of the sural nerve, pain temporal summation on repetitive electrical sural nerve stimulation, and pain experienced during the cold pressor test. RESULTS: Venlafaxine increased thresholds for pain tolerance after single electrical stimulation (P =.005) and pain summation (P =.01) on repetitive stimulation but did not alter the thresholds for pain detection after single electrical sural nerve stimulation. Venlafaxine did not alter pain experienced during the cold pressor test or increase the pressure pain thresholds. CONCLUSION: Venlafaxine increases the pain tolerance threshold to electrical sural nerve stimulation and the threshold at which pain increases (pain summation). The impact of venlafaxine on pain summation in this experimental pain model on repetitive stimulation may indicate a potential analgesic effect for clinical neuropathic pain.     

The study of the central grey matter in mechanisms of different kinds of analgesia: effects of lesions

The effect of the central grey matter (CG) on pain sensitivity has been investigated in rats. It has been demonstrated that baseline pain thresholds, tested by the hot plate method (HPM) after surgical operation, were significantly greater in CG-lesioned rats than in controls. Baseline tail flick latencies did not differ from those in the control group of animals. In the CG-lesioned rats, the latencies of pain responses, measured by the hot plate and tail flick tests after stress and auricular electroacupuncture, were significantly shorter than in the control group. The analgesia in the CG-lesioned rats after auricular electrostimulation was less than that after stress. Obtained data suggest: (1) significance of the CG in the regulation of baseline pain sensitivity, tested by different methods, is variable. CG mechanisms do not play a leading role in producing the tail flick response, whereas hind paw licking is mediated through CG-dependent mechanisms. (2) Antinociceptive effect of stress and acupuncture is mediated by the CG. (3) The role of the CG in analgesic mechanisms is greater in acupuncture than in stress. (4) Apart from the CG, other antinociceptive systems are involved in the mechanisms of stress-induced analgesia.     

坐骨神经切断大鼠脑脊液中CCK-8含量的动态变化及其与吗啡镇痛的关系

目的：研究神经源性疼痛时吗啡镇痛效应的降低与中枢八肽胆囊收缩素(CCK-8)的释放量之间的关系。方法：以切断大鼠单侧坐骨神经作为引起神经痛的动物模型，用放射免疫分析法，观察术后第3，7，10和14天脑脊液中CCK-8-ir含量的变化，并在相应的时间点分别皮下注射吗啡(4mg／kg)和CCKB受体拮抗剂L-365，260(0．5mg,／kg)，观察痛阈(辐射热甩尾潜伏期)的变化。结果：(1)大鼠单侧坐骨神经切断后一周，脑脊液中CCK-8样免疫活性物质(CCK-8-ir)的浓度(代表中枢CCK-8的释放量)增加了125％，此时吗啡的镇痛效果降低，而CCK拮抗剂使吗啡镇痛效果提高。(2)坐骨神经切断后1．5～2周，中枢CCK-8释放减少或保持正常水平，此时吗啡镇痛效果正常，CCK拮抗剂也不能使其效应进一步提高。(3)假手术组大鼠于第14天(第四次注射吗啡)时，吗啡作用减弱(发生耐受)，此时CCK拮抗剂显示出对吗啡镇痛的加强作用。结论：单侧坐骨神经切断后一周吗啡镇痛效果减弱，可能与当时中枢CCK-8释放过多有关。切断坐骨神经后中枢释放CCK-8水平的变化，是影响阿片镇痛的重要因素。     

中药复方止痛胶囊对大鼠佐剂性关节炎模型IL-1、TNF和PGE_2的影响

目的 :探讨止痛胶囊对佐剂性关节炎大鼠模型 (AA大鼠 )白细胞介素 1(IL -1)、肿瘤坏死因子 (TNF)、前列腺素E2 (PGE2 )活性的影响。方法 :建立佐剂性关节炎 (adjuvantarthritis ,AA)大鼠模型。用双抗体夹心ELISA法测AA大鼠IL -1活性。用放射免疫法检测TNF和PGE2 活性。结果 :止痛胶囊能显著降低AA大鼠血清中IL -1、TNF和PGE2 的含量。结论 :IL -1、TNF、PGE2 在类风湿关节炎 (RA)发病机理中占重要地位 ;止痛胶囊能控制AA大鼠血清中IL -1、TNF、PGE2 等炎症介质的活性 ,对类风湿性关节炎具有治疗作用     

Specific effect of levetiracetam in experimental human pain models.

BACKGROUND: Levetiracetam is a new antiepileptic drug. There is only limited experience with levetiracetam in clinical neuropathic pain. AIM: To test the analgesic effect of levetiracetam in a human experimental pain model in order to obtain preclinical evidence for its potential effect in neuropathic pain. METHODS: Sixteen healthy volunteers completed a randomized, double-blind, cross-over trial with a single oral dose of 1500 mg levetiracetam against placebo. Pain tests included pain detection and tolerance to single electrical stimulation and temporal pain summation threshold to repetitive electrical stimulation (3 Hz) of the sural nerve. RESULTS: Levetiracetam significantly increased the pain tolerance thresholds (p=0.04), and the pain detection thresholds tended to be increased (p=0.06), whereas levetiracetam had no effect on temporal pain summation thresholds (p=0.30). CONCLUSION: Levetiracetam has an analgesic effect in the electrical sural nerve stimulation pain model, but it did not increase temporal pain summation threshold. Levetiracetam may still be effective in clinical neuropathic pain.     

The apparent antinociceptive effect of desipramine and zimelidine in the tail flick test in rats is mainly caused by changes in tail skin temperature

Tricyclic antidepressants have shown antinociceptive properties in some, but not in all, animal studies using the tail flick test. Tail flick latency has been found to be strongly negatively correlated to tail skin temperature with its highest correlation found when the temperature is measured close to the heated spot. The selective 5-HT reuptake inhibitor zimelidine, as well as the noradrenaline reuptake inhibitor desipramine, increased tail flick latencies. However, this increase could largely be explained by a concomitant reduction in tail skin temperature. The highest dose of desipramine investigated (25 mg/kg) seemed to possess antinociceptive properties in this test also after correction for the fall in tail skin temperature. Lower doses of desipramine (5 and 15 mg/kg) and zimelidine (5, 20 and 30 mg/kg) were either inactive or their effect on tail flick latency could be explained by the fall in tail skin temperature. The apparent antinociceptive effect of zimelidine in the tail flick test thus seems to be due to an effect on tail skin temperature. Desipramine also seems to have its main effect due to a similar mechanism; however, the highest dose of desipramine used induced significant antinociception.     

Spinal cord monoamines modulate the antinociceptive effects of vaginal stimulation in rats

Perispinal administration (into the lumbar intrathecal space) of phentolamine (40 micrograms), an alpha-adrenergic receptor blocking agent, reduced the analgesic effect of vaginal stimulation by 39.7% (measured by tail flick latency) and 57.1% (measured by vocalization threshold) as compared to controls. Perispinal administration of methysergide (10 micrograms), a serotoninergic receptor blocking agent, reduced the analgesic effect of vaginal stimulation by 48.5% (measured by vocalization threshold), although it did not significantly affect the tail flick measure. In a separate experiment, vaginal stimulation activated the release of norepinephrine and serotonin into a superfusate of the spinal cord. During vaginal stimulation, levels of norepinephrine and serotonin increased about 2-fold above resting levels. These findings indicate that vaginal stimulation releases norepinephrine and serotonin into the spinal cord, thereby exerting an analgesic effect.     

Nociceptin-induced apparent hyperalgesia in mice as a result of the prevention of opioid autoanalgesic mechanisms triggered by the stress of an intracerebroventricular injection

Summary— The effects on nociperception of nociceptin/Orphanin FQ (noc/OFQ), the endogenous ligand of the ORL1 (opioid receptor like 1) receptor, have been evaluated in mice upon intracerebroventricular injection of 10 to 10 000 ng doses of the peptide. In the hot plate test (55 °C) the licking, rearing and jump latencies were significantly reduced by noc/OFQ (100–250 ng). Noc/OFQ (100–1000 ng) also reduced the latency to tail withdrawal in the tail flick test. In the formalin test (injection in a hind paw of a formalin solution), noc/OFQ (100 ng) increased significantly the duration of paw licking and/or biting at the earliest period of observation. In the writhing test, the number of writhes evoked by intraperitoneal administration of dilute acetic acid was not modified by noc/OFQ at doses in the range of 10–1000 ng, but was decreased by 10 000 ng. The reduction in jump latency in the hot plate test was observed even when mice were pretreated with morphine (2 mg/kg, sc). The analgesic effect of acetorphan (5 mg/kg, iv) was also reduced by nociceptin (100 ng); on the other hand the hyperalgesic effect of naloxone (4.5 mg/kg, sc) was not additive with that of nociceptin (100 ng). Comparing in various tests the nociceptive thresholds of uninjected mice to that of saline icv injected mice, it appeared that the latter injection induced an increase in these thresholds which was prevented by nociceptin. It is suggested that nociceptin displays hyperalgesic effects by preventing autoanalgesic (opioidergic) mechanisms triggered by the stress elicited by intracerebroventricular injection.     

The integrity of the anterior pretectal nucleus and dorsolateral funiculus is necessary for electroacupuncture‐induced analgesia in the rat tail‐flick test

Previous studies have indicated that the anterior pretectal nucleus (APtN) is implicated in pathways that descend through the dorsolateral funiculus (DLF) to modulate nociceptive inputs in the spinal dorsal horn. The activation of descending inhibitory mechanisms also seems to be involved in electroacupuncture (EA)‐induced analgesia. This study utilized the tail‐flick test to examine the changes produced by DLF lesion or injection of 2% lidocaine into the APtN in the analgesia induced by 2 or 100 Hz EA applied to the Zusanli (ST36) and Sanyinjiao (SP6) acupoints in lightly anesthetized rats. Tail‐flick latency was significantly increased by EA, the effect of 2 Hz EA lasting longer than that produced by 100 Hz EA. The effect of either 2 or 100 Hz EA did not occur in DLF lesion rats. The effect of 2 Hz EA did not occur in rats with neural block of the whole or dorsal APtN. In contrast, the effect of 100 Hz EA was reduced in rats with neural block of the whole APtN, but remained unchanged in rats with neural block of the dorsal APtN. We thus conclude that the integrity of the APtN and DLF is necessary for EA‐induced analgesia in the rat tail‐flick test. In addition, the integrity of the dorsal APtN is necessary for the analgesic effect of 2 but not 100 Hz EA.     

Analgesic effects of metapramine and evidence against the involvement of endogenous enkephalins in the analgesia induced by tricyclic antidepressants

In several pain models, tricyclic antidepressants (TCAs) have been shown to reduce nociception. In the present study, we evaluated the antinociceptive effect of metapramine (META) in 4 nociception tests: (1) the hot plate test; (2) the phenylbenzoquinone-induced writhing; (3) the tail flick test; and (4) the test of electrical stimulation of the tail. We further analysed, using META and clomipramine (CLOM), the eventual role of endogenous opioids in analgesia induced by TCAs. The analgesic effects of META and CLOM in the hot plate test and in the test of electrical stimulation of the tail were reversed by naloxone. On the other hand, we failed to demonstrate a potentiation of META- or CLOM-induced analgesia by acetorphan, an inhibitor of 'enkephalinase.' We also failed to show a potentiation of Met5-enkephalin intracerebroventricularly injected by the two TCAs. Moreover, the administration of the enzymatic inhibitor or of Met5-enkephalin led to a slight decrease of the analgesic effect of the TCAs. These results (1) indicate that in our 4 pain tests, META clearly reduces nociception and (2) provide evidence that the involvement of endogenous enkephalins in the analgesia induced by TCAs is improbable.