白介素-2研究进展

白细胞介素-2是白细胞介素家族中的重要成员之一,它的生物学作用是以刺激T细胞增生为主,故又称T细胞生长因子,除此之外还有其它重要功能。以重组白细胞介素-2(IL-2)为物质基础的肿瘤治疗研究,在近20年来一直都很活跃。本文对介素-2的结构、生物学功能,及国内外相关研究作一介绍。     

白介素-2的抗炎作用和免疫调节作用

研究重组人白介素-2(rhI卜2)的抗炎和免疫调节作用。选择小鼠鼠耳肿胀和大鼠足拓肿胀模型研究，hlL-2的抗炎作用；选择碳廓清率实验、迟发性变态反应实验研究rhIL2的免疫调节作用。RhlL-2注射液，剂量为20，10，5，2．5．1．25万u／kg时，对小鼠鼠耳肿胀模型有抑制作用，其中剂量为2．5～5万u／kg时，抑制率最大；剂量为2．5万u／kg时，对大鼠足拓肿胀模型有显著的抑制作用；rhIL-2注射液每日SC用药剂量为10万u／kg，连续给药9d后，可以明显增强小鼠单核吞噬细胞功能；rhIL-2注射液每日SC用药剂量为5万u／kg，连续给药6d后，可明显减轻由免疫抑制剂引起的小鼠迟发性变态反应降低的强度。rhIL-2在一定剂量范围内可以起到抗炎和免疫调节作用。     

白介素-2通过阿片κ受体抑制心肌细胞的收缩作用

本文采用酶解分离大鼠心室肌细胞 ,用视频跟踪系统测定单个心室肌细胞收缩 ,以研究白介素 2(IL 2 )对心肌细胞的作用及其机理 .结果发现 :①IL 2 (0 .5～ 2 0 0kU·L- 1)浓度依赖性地抑制成年鼠单个心室肌细胞的收缩 ;②纳洛酮 (10nmol·L- 1)和nor binaltorphimine(nor BNI,10nmol·L- 1)可阻断IL 2的收缩抑制作用 ;③百日咳毒素 (PTX ,5mg·L- 1)预处理后 ,取消了IL 2对心肌细胞收缩的抑制作用 ;④U7312 2预处理可阻断IL 2的收缩抑制作用 .结果表明 ,IL 2对酶解分离心室肌细胞收缩的抑制作用 ,是通过心肌细胞上κ阿片受体介导的 ,其下游途径包括PTX敏感的Gi蛋白和磷脂酶C     

内吗啡肽—1的镇痛作用

目的：研究内吗啡肽－1（EM－1）的镇痛作用。方法：采用电刺激鼠尾－嘶叫法、扭体法、佐剂性关节炎以及神经源性疼痛等多种疼痛模型,观察腹腔注射EM－1的镇痛作用,并和脊髓蛛网膜下腔注射和侧脑室注射EM－1的镇痛作用进行比较。结果：1）EM－1能剂量依赖地提高大鼠电刺激鼠尾－嘶叫法的痛阈;能抑制醋酸引起的小鼠扭体反应;在佐剂性关节炎所致的炎症性痛觉过敏及坐骨神经部分结扎所引起的神经源性痛觉过敏中,EM－1与有镇痛作用。2）中枢给EM－1的镇痛作用比外击给药出现得较快,而且较强。3）阿片受体拮抗选择性拮抗剂cyprodime也能翻转EM－1的镇痛作用;反复给予EM－1具有确切的镇冯作用,其镇痛作用由中枢μ阿片受体介导。     

白介素-1受体拮抗剂EBS抗类风湿性关节炎作用研究

白介素-1（IL-1）主要由单核细胞和巨噬细胞产生，是引起炎症反应的重要细胞因子之一。该因子通过与IL-1受体（IL-1R）特异性结合，激活系列蛋白激酶，最终激活转录因子NF-KB，从而导致多种其它细胞因子和淋巴因子的释放，形成炎症反应。类风湿性关节炎（RA）是以关节炎症和骨质破坏为主要病理特征的自身免疫性疾病，动物和临床试验证明，抑制IL-1的作用可以改善关节病变进程和减轻疾病症状。     

帕罗西汀对脑卒中后抑郁患者的血浆白介素-2和白介素-6的影响

目的 探讨帕罗西汀对脑卒中后抑郁(PSD)患者的白介素-2(IL-2)和白介素-6(IL-6)含量的影响及疗效观察.方法 选择80例PSD患者,随机分为帕罗西汀组和对照组.对照组予以常规脑血管病治疗和康复训练.帕罗西汀组在对照组治疗的基础上加用帕罗西汀治疗,剂量为20～40mg·d-1,疗程均为8周.结果 经过8周治疗后,帕罗西汀组患者HAMD及NIHSS评分明显下降,ADL评分明显提高(P＜0.05或P＜0.01);同时血摹IL-2含量均明显增加.IL-6含量均明显降低(均P＜0.05).而对照组治疗前后HAMD及NIHSS评分、ADL评分、血浆IL2和IL-6含量无明显变化(P＞0.05).结论 帕罗西汀可有效地改善PSD患者的抑郁情绪,并能改善患者神经功能及日常生活能力,且不良良反应轻微,顺应性好,是治疗PSD较为理想的药物.改善免疫功能,调节细胞因子平衡可能是帕罗西汀治疗PSD的另外一种作用机制.     

阿片受体激动剂吗啡对心脏作用的研究进展

阿片类物质及其受体自从被发现以来。已历经了数百年的时间。人类最早把阿片类药物用于镇痛，吗啡作为阿片类药物首先被分离出来并应用于临床，在一定时期内吗啡对于治疗减轻癌症等引起的疼痛起到了不可替代的作用。随着医学科学技术的发展，吗啡等阿片类受体激动剂已经不仅仅局限在治疗疼痛这一方面，其对于心肌细胞的保护作用的研究近年来尤为突出。在细胞、分子水平上。吗啡可作用于K、6和μ受体，通过PTX-敏感性G蛋白、IP3、PKC及KATP等通路封心肌细胞产生保护作用，促进心肌细胞存活、增殖；抑制心肌细胞凋亡。通过上述机制吗啡在心肌缺血预适应、心肌缺血-再灌注、心肌肥厚以及心力衰竭等方面可发挥重要的保护作用。     

吗啡依赖大鼠脑组织内吗啡的免疫组织化学研究

目的··：研究吗啡依赖后大鼠脑内吗啡含量变化。方法··：对慢性染吗啡大鼠脑组织内的吗啡进行了原位免疫组织化学研究。结果··：染毒７ｄ大鼠脑组织内未能检出吗啡,染毒１４ｄ大鼠脑组织内出现了强弱不一的免疫反应。结·论·：大鼠对吗啡依赖形成过程中,脑组织内吗啡含量增高,且吗啡的分布与μ阿片受体分布一致。     

白介素—2治疗恶性胸腔积液36例临床观察

目的:观察白介素-2结合全身化疗或再结合淋巴因子-激活杀伤(细胞)治疗肺癌胸腔积液的临床疗效。方法:采用白介素-2 化疗法时,给予患者注射白介素-240万单位,每周2次,4周为一疗程,并加用卡铂、顺铂、阿霉素和长春花碱酰胺等药的联合化疗;采用白介素-2 化疗 淋巴因子-激活杀伤(细胞)治疗时,白介素-2和化疗用法同上,另外输注淋巴因子-激活杀伤(细胞)。结果:在对于肿瘤的客观疗效方面,病灶大小的改变总有效率为22％,胸腔积液改变的总有效率为67％。主观症状有明显改善的占55％。结论:在癌性胸水的治疗中使用白介素-2能体现较好的疗效。     

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。     

Role of cholecystokinin in the reduction of endomorphin-2-induced antinociception in diabetic mice

We examined the role of cholecystokinin in the reduction of endomorphin-2-induced antinociception in diabetic mice. Endomorphin-1 (1-10 microg, i.c.v.) and endomorphin-2 (3-30 microg, i.c.v.) dose dependently inhibited the tail-flick response in non-diabetic and diabetic mice. There was no significant difference between the antinociceptive effect of endomorphin-1 in non-diabetic and diabetic mice. On the other hand, the antinociceptive effect of endomorphin-2 in diabetic mice was significantly less than that in non-diabetic mice. Cholecystokinin octapeptide (CCK-8) dose dependently reduced the antinociceptive effects of endomorphin-1 and endomorphin-2 in non-diabetic mice. However, in diabetic mice, CCK-8 significantly inhibited the antinociceptive effect of endomorphin-1, but not of endomorphin-2. In non-diabetic mice, CI-988 ((R-[R*,R*])-4-([3-1H-indol]-3-yl)-2-methyl-1-oxo-2-([(tricyclo(3.3.1.1)dec-2-yloxy)carbonyl] amino)propylamino-1-phenyl-ethylamino-4-oxybutanoic acid) had no significant effect on either endomorphin-1- or endomorphin-2-induced antinociception. In diabetic mice, while CI-988 had no significant effect on endomorphin-1-induced antinociception, it dose dependently enhanced the antinociceptive effect of endomorphin-2. The results indicated that the reduction of endomorphin-2-induced antinociception in diabetic mice might be due, at least in part, to the activation of CCK(2) receptors.     

Swim-stress-induced antinociception in young rats.

1. Opioid and non-opioid mechanisms have been implicated in the phenomenon of stress-induced antinociception in adult rodents. We have studied stress-induced antinociception in developing rats and characterized differences in the neurochemical basis of this effect in pre- and post-weanling animals. 2. Twenty and 25 day old rats were stressed using warm water (20 degrees C) swimming for 3 or 10 min periods and antinociception was assessed by the tail immersion test (50 degrees C). 3. A 3 min swim in 20 and 25 day old rats produced marked antinociception which was blocked by naloxone, Mr 1452, 16-methyl cyprenorphine and levallorphan but not Mr 1453 or N-methyl levallorphan. The delta-opioid receptor antagonist ICI 174,864 attenuated stress-induced antinociception in 25 day old rats but was without effect in 20 day old animals. 4. A 10 min swim in 25 day old rats produced antinociception which was non-opioid in nature. In contrast, antinociception was not observed in 20 day old rats after a 10 min swim-stress. 5. Pretreatment of animals with dexamethasone blocked 3 min swim-stress antinociception in 20 and 25 day old animals but had no effect on antinociception induced by a 10 min swim. 6. Swim-stress-induced antinociception can be observed in young rats and dissociated into opioid and non-opioid types dependent on the duration of swimming stress. The non-opioid type appears to develop more slowly and cannot be observed in preweanling rats. The opioid type is a predominantly mu-receptor phenomenon in preweanling animals but delta-receptor components are observable in postweanling rats.     

Nifedipine potentiates gabapentin antinociception in rats

To evaluate the involvement of Ca++ channels in Gabapentin antinociception. In healthy male albino rats formalin (50 microliters, 5%) was injected at the planter surface of the paw. Pain score was calculated. Antinociceptive effect of (10, 30 mg/kg) gabapentin and (3, 10 mg/kg) nifedipine alone and on co-administration of sub analgesic doses was studied 30 minutes after formalin injection and reduction in pain scores was calculated. Gabapentin (30 mg/kg) and nifedipine (10 mg/kg) reduced the pain score in formalin injected rats. Gabapentin (10 mg/kg) and nifedipine (3 mg/kg) given alone did not modify pain score, however, on co-administration they significantly reduced the pain score. Study provides evidence of involvement of Ca++ channels in gabapentin antinociception.     

Dextromethorphan differentially affects opioid antinociception in rats

Opioid drugs such as morphine and meperidine are widely used in clinical pain management, although they can cause some adverse effects. A number of studies indicate that N-methyl-D-aspartate (NMDA) receptors may play a role in the mechanism of morphine analgesia, tolerance and dependence. Being an antitussive with NMDA antagonist properties, dextromethorphan (DM) may have some therapeutic benefits when coadministered with morphine. In the present study, we investigated the effects of DM on the antinociceptive effects of different opioids. We also investigated the possible pharmacokinetic mechanisms involved. The antinociceptive effects of the mu-opioid receptor agonists morphine (5 mg kg(-1), s.c.), meperidine (25 mg kg(-1), s.c.) and codeine (25 mg kg(-1), s.c.), and the kappa-opioid agonists nalbuphine (8 mg kg(-1), s.c.) and U-50,488H (20 mg kg(-1), s.c.) were studied using the tail-flick test in male Sprague-Dawley rats. Coadministration of DM (20 mg kg(-1), i.p.) with these opioids was also performed and investigated.The pharmacokinetic effects of DM on morphine and codeine were examined, and the free concentration of morphine or codeine in serum was determined by HPLC.It was found that DM potentiated the antinociceptive effects of some mu-opioid agonists but not codeine or kappa-opioid agonists in rats. DM potentiated morphine's antinociceptive effect, and acutely increased the serum concentration of morphine. In contrast, DM attenuated the antinociceptive effect of codeine and decreased the serum concentration of its active metabolite (morphine).The pharmacokinetic interactions between DM and opioids may partially explain the differential effects of DM on the antinociception caused by opioids.     

Influence of nicotinic receptor modulators on CB2 cannabinoid receptor agonist (JWH133)-induced antinociception in mice

Delta9-tetrahydrocannabinol is the active component in cannabis and has long been associated with pain relief. This effect is believed to be mediated through central and peripheral CB1 and peripheral CB2 receptors. We have explored the possible antinociceptive effect of a CB2 receptor agonist, JWH133, using the formalin test in mice. The drug was administered by the intracerebroventricular and intraperitoneal routes. Although no antinociceptive effect was observed after intracerebroventricular administration of JWH133, when the drug was administered by the intraperitoneal route, it produced an analgesic effect. The influence of nicotinic cholinergic receptor modulators, nicotine and mecamylamine, on antinociceptive effect of JWH133 was also studied. Nicotine increased and mecamylamine decreased the antinociceptive effect of JWH133. It is concluded that JWH133-induced analgesia is influenced by nicotinic cholinergic receptor activity.     

2-Deoxy-D-glucose antinociception and serotonin receptor subtype antagonists: test-specific effects in rats.

The antinociceptive actions of 2-deoxy-D-glucose (2-DG) are mediated in part by endogenous opioid, dopaminergic, cholinergic, histaminergic, and neurohormonal influences. Although 2-DG antinociception was not affected by tryptophan hydroxylase inhibition, a possible serotonergic role in 2-DG antinociception was investigated because of the existence of serotonin [5-hydroxytryptamine (5-HT)] receptor subtypes. The present study examined the effects of general (methysergide: 5 and 10 mg/kg), 5-HT2 (ritanserin: 2.5 mg/kg), and 5-HT3 (ICS-205,930: 0.25-5 mg/kg) receptor subtype antagonists upon 2-DG antinociception on the tail-flick and jump tests in rats. On the tail-flick test, 2-DG (450 mg/kg) antinociception was significantly reduced by all ICS-205,930 doses (48-58%) but unaffected by either methysergide (22-29% reduction) or ritanserin (6% reduction). In contrast, 2-DG antinociception on the jump test was significantly potentiated across the 120-min time course and across the 2-DG dose-response curve (100-650 mg/kg) by methysergide, ritanserin, and ICS-205,930 pretreatment. Each of the three antagonists produced significant leftward shifts in the peak and total 2-DG dose-response curve for the jump test. These data suggest different sites of action for 2-DG antinociception as a function of the pain test employed and a differential modulation by serotonin receptor subtypes at those sites.     

Dipyrone potentiates morphine-induced antinociception in dipyrone-treated and morphine-tolerant rats

Coadministration of morphine and dipyrone produces acute and chronic antinociceptive potentiation in drug-naive rats. In this work, the effectiveness of the combination was determined in rats pretreated with morphine or dipyrone. Nine groups of male rats received (i.v.) 3.1 mg/kg morphine, 600 mg/kg dipyrone, or the morphine-dipyrone combination twice a day for five administrations (three groups per treatment). From the 6th to the 10th administration, one group out of each treatment continued without change, while the other two were switched to one of the other two possible treatments. In morphine-tolerant rats, morphine plus dipyrone produced a transient antinociceptive potentiation. In dipyrone-treated animals, this combination produced a long-lasting potentiation. In animals only treated with the combination, antinociception was clear since the beginning, although it decreased after the 6th injection. No cross-tolerance was seen between morphine and dipyrone. These data suggest that dipyrone potentiates morphine-induced antinociception in dipyrone-treated as well as in morphine-tolerant rats.     

Low-level lead exposure alters morphine antinociception in neonatal rats

Administration of lead (at 300 and 1000 ppm) in the maternal drinking water from conception to weaning impaired the antinociceptive activity of morphine in 10-day-old neonatal rats. Blood lead levels in these animals were below 50 μ/100 ml in the high lead dose group and below 35 μg/100 ml in the low lead dose group. The differences in the antinociceptive potency of morphine between normal and lead-exposed animals were not observed at later time points (21 and 30 days). It is suggested that lead disrupts the development of opioid receptor systems in the central nervous system and that this disruption occurs early in development.     

Modification of local anesthetic-induced antinociception by fentanyl in rats

In clinical practice, using the lowest doses of drugs for anesthesia or analgesia is the main goal. Opioid combinations with local anesthetics can be preferable for achieving adequate anesthesia or analgesia. The primary purpose of this study was to examine possible thermal antinociceptive effects of the opioid -fentanyl and the amide local anesthetics levobupivacaine and lidocaine when locally administered alone or in combination. The paw withdrawal latencies to noxious thermal stimuli in rats were measured to assess the antinociceptive actions of drugs after subcutaneous intraplantar injection into the hind paw. All drugs examined in this study produced dose- and time-dependent increases in the paw withdrawal latencies. Fentanyl is approximately 125 and 500 times more potent than levobupivacaine and lidocaine, respectively. At the same dose, the antinociceptive potency of levobupivacaine was 3.6-fold higher than that of lidocaine. Co-injection of the lowest doses of levobupivacaine and lidocaine dramatically increased the paw withdrawal latency. However, in the presence of fentanyl, the effects of levobupivacaine and lidocaine were different. Although co-injection of levobupivacaine with fentanyl both enhanced and prolonged antinociceptive action, the lidocaine-fentanyl combination did not significantly change the paw withdrawal latency. These results suggest that intraplantar co-administration of fentanyl with levobupivacaine, but not lidocaine, may provide more effective antinociception without increasing the dose requirements.