痛稳素碳末端八肽翻转弧啡肽对抗吗啡镇痛的作用

目的：观察痛稳素碳末端八肽在小鼠脑内对孤啡肽对抗吗啡的镇痛作用的影响。方法：固相多肽合成法合成了痛稳素碳末端八肽,用辐射热甩尾测定痛阈,观察（1）小鼠脑室注射（icv)孤啡肽对吗啡镇痛作用的影响;（2）小鼠脑室注射（icv）痛隐素碳末端八肽对小鼠基础痛阈的影响;（3）小鼠脑室联合注射（icv）痛稳素碳末端八肽和孤啡肽对吗啡镇痛作用的影响。结果：弧啡肽 抗吗啡的镇痛作用;痛稳素碳末端八肽本身不影响小鼠的基础痛阈,但可逆转孤啡肽对抗吗啡的镇痛作用。结论：痛稳素碳末端八肽在脊髓以上水平可以逆转弧肽对抗吗啡的镇痛作用。     

痛稳素和痛稳素(10～17)对孤啡肽对抗内吗啡肽-1及内吗啡肽-2镇痛作用的影响

目的研究痛稳素及其碳末端八肽在小鼠脑内对孤啡肽对抗内吗啡肽-1及内吗啡肽-2镇痛作用的影响。方法以固相多肽合成法合成了痛稳素及其碳末端八肽,侧脑室注射孤啡肽、痛稳素及其碳末端八肽,用辐射热甩尾法测定痛阈。结果孤啡肽可对抗内吗啡肽-1及内吗啡肽-2的镇痛作用;痛稳素及其碳末端八肽不影响小鼠的基础痛阈,但可逆转孤啡肽对抗内吗啡肽-1及内吗啡肽-2的镇痛作用。结论痛稳素及其碳末端八肽在脊髓以上水平可逆转孤啡肽对抗内吗啡肽-1及内吗啡肽-2的镇痛作用。     

孤啡肽与八肽胆囊收缩素在大鼠脑内拮抗吗啡镇痛的协同作用

目的观察孤啡肽（ＯＦＱ）和八肽胆囊收缩素（ＣＣＫ ８）在大鼠脑内拮抗吗啡镇痛是否具有协同作用。方法应用等高线法设计实验,用辐射热甩尾法测定痛阈。皮下注射吗啡（５ｍｇ·ｋｇ－１）２０ｍｉｎ之后,选择有明显镇痛效应的大鼠,侧脑室（ｉｃｖ）分别注射不同剂量的ＯＦＱ和ＣＣＫ ８以及由两者不同比例（５∶１,２５∶１）不同剂量组成的混合物,观察对吗啡镇痛效应的影响。结果联合应用ＯＦＱ和ＣＣＫ ８所产生的抗吗啡镇痛作用明显大于单独使用ＯＦＱ或ＣＣＫ ８。结论ＯＦＱ和ＣＣＫ ８在一定比例、一定剂量组合范围内,对抗吗啡镇痛具有协同效应。     

大鼠脑室或脊髓蛛网膜下腔注射八肽胆囊收缩素抗血清翻转吗啡耐受

连续6天给大鼠皮下注射递增剂量的盐酸吗啡(5～30mg/kg),则吗啡镇痛效果逐渐减弱,产生耐受。给吗啡耐受的大鼠侧脑室(icv)注射八肽胆囊收缩素(CCK-8)抗血清2μl,可使吗啡耐受作用被翻转50％(P<0.001)。给吗啡耐受的动物以电针刺激,表明电针与吗啡镇痛两者之间有交叉耐受。icv注射CCK-8抗血清可使电针交叉耐受翻转50％以上(P<0.001)。脊髓蛛网膜下腔(ith)注射CCK-8抗血清也可产生类似的作用,但不如icv注射的明显。单独icv或ith注射CCK-8抗血清对痛阈无显著影响。以上结果表明中枢神经系统CNS)中CCK-8可能参与吗啡耐受的形成机理。     

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。     

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。     

八肽胆囊收缩素(CCK-8)的合成及其药理评价

本文用Merrifield固相合成法合成八肽胆囊收缩紊(CCK-8)。酪氨酸酚羟基硫酯化反应用吡啶-三氧化硫络合物进行,快原子轰击质谱和氨基酸组分分析结果与理论值一致。在离体豚鼠胆囊收缩活性实验中,证实了CCK-8的缩胆囊作用。     

八肽胆囊收缩素对抗吗啡抑制大鼠脑突触小体钙摄取的作用

用大鼠脑的膜制备观察吗啡和CCK-8对突触小体摄取~(45)Ca~(2+)的影响。吗啡(10 nmol/L～1μmo1/L)抑制突触小体对~(45)Ca的摄取,该作用能被1μmol/L纳洛酮完全阻断。CCK-8(10nmol/L～1μmol/L)本身能抑制突触小体~(45)Ca摄取,但它在10nmol/L和100 nmol/L时能对抗吗啡对~(45)Ca摄取的抑制作用,浓度提高到1μmol则不能对抗吗啡的这一作用。CCK-8抑制突触小体摄取~(45)Ca,以及对抗吗啡的~(45)Ca摄取抑制的作用,皆能被CCK受体拮抗剂丙谷酰胺(2μmol/L)所阻断.捉示CCK-8是通过激动CCK受体而拮抗吗啡抑制~(45)Ca摄取的,CCK-8的这一拮抗作用可能是其抗阿片作用的机理之一.     

吗啡控释片联合甘露聚糖肽注射液治疗晚期癌痛的疗效观察

目的观察硫酸吗啡控释片联合甘露聚糖肽注射液治疗癌痛的近期疗效。方法将68例癌痛患者随机分成治疗组和对照组,分别给予硫酸吗啡控释片联合甘露聚糖肽注射液和单用硫酸吗啡控释片治疗,观察两组患者的止痛效果。结果治疗组癌痛显效率87.87%,总有效率93.93%;对照组癌痛显效率65.71%,总有效率82.85%。两组患者显效比较差异有统计学意义(P<0.05)结论吗啡控释片联合甘露聚糖注射液治疗癌痛疗效较好。     

普兰林肽的固相合成

目的:探索普兰林肽的固相合成、氧化条件及纯化方法。方法:采用Fmoc固相多肽合成法,以Rink Amide-AM树脂做载体,HBTU/HOBt/DIEA做缩合剂,逐步缩合得到全保护线性普兰林肽树脂,以TFA/苯甲硫醚/苯酚/H2O/EDT/TIS配比的裂解液脱除保护基团,分别采用空气,二甲基亚砜,双氧水氧化两个半胱氨酸的巯基形成一对二硫键,半制备反相高效液相色谱法纯化。结果:合成含37个氨基酸以及一对二硫键的普兰林肽经RP-HPLC和MALDI-TOF-MS确证,粗品纯度在50.0%以上,粗品经半制备型反相高效液相色谱纯化,所得精肽的纯度大于95.0%,总收率为30.5%。结论:该方法简单,合成的产品成本低,纯度高,可为工业化生产提供借鉴。     

生长抑素及其拮抗剂对小鼠吗啡镇痛的影响(英文)

AIM: To study the effects of somatostatin (SST) andits antagonist cyclo- (7 - aminoheptanoyl- Phe-D-Trp-Lys-Thr [Bzl]) (SSA) on morphine-induced analgesia.METHODS: The pain assays were the hot plate andthe tail flick test. RESULTS: SST or SSA per seadministered intracerebrally at the doses of 0.1 and Img/mouse did not change the pain threshold of miceboth in the hot plate and in the tail flick test.However, at the higher dose (10 mg/mouse), SST andSSA decreased the pain threshold in the tail flick test     

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.

     

利鲁唑对吗啡镇痛、耐受和依赖作用的影响(英文)

目的　研究利鲁唑对阿片镇痛、耐受及躯体功能的调节。方法　采用冰醋酸扭体 ,5 5℃热板法和热辐射甩尾法观察利鲁唑对小鼠痛阈及吗啡镇痛效应的影响 ;采用小鼠急性和慢性吗啡耐受模型及小鼠吗啡依赖模型 ,观察利鲁唑对吗啡耐受和依赖的作用。结果　单独皮下注射利鲁唑 2 .5～ 10mg·kg- 1在以上 3种模型无镇痛作用 ,然而能剂量依赖性地增强吗啡镇痛效应。利鲁唑 2 .5～ 10mg·kg- 1剂量依赖性地对抗吗啡引起的急性和慢性耐受。在小鼠吗啡依赖模型中 ,利鲁唑 2 .5～ 10mg·kg- 1剂量依赖性地抑制吗啡戒断症状的产生。结论　利鲁唑自身无镇痛作用 ,但能显著增强吗啡镇痛效应 ,并能预防吗啡所引起的耐受和依赖     

The effect of fluoxetine on morphine analgesia,respiratory depression,and lethality

The analgesic effect of morphine in a mouse writhing assay was enhanced by the simultaneous administration of fluoxetine, an inhibitor of serotonin uptake. Fluoxetine reduced the ED₅₀ for morphine and extended the duration of morphine analgesia. The potentiation of morphine analgesia was particularly striking in mice made tolerant by repeated morphine injections. Potentiation of morphine by fluoxetine was also observed in a rat tail jerk test for analgesia. The acute lethality of morphine in rats and mice was altered by fluoxetine, yet the therapeutic index of morphine (ratio of LD₅₀ to ED₅₀) was unchanged. The decrease in blood pO₂ produced by morphine at doses of 1 and 4 mg/kg in rats was attenuated by fluoxetine, which by itself increased blood pO₂. These findings strengthen earlier evidence for an involvement of serotoninergic neurons in the analgesic effects of morphine and support the idea that enhanced serotoninergic function might be a useful means of enhancing morphine's actions in clinical therapy.     

小儿术前应用不同剂量氯胺酮的超前镇痛效果

目的通过术前肌注不同剂量氯胺酮对小儿骶管吗啡镇痛作用的影响,探讨氯胺酮超前镇痛在小儿麻醉中的应用。方法60例ASAⅠ级进行下腹部手术的患儿分为3组,术前分别肌注氯胺酮1mg/kg、2mg/kg及0.9%NaCl1ml;手术结束时行骶管阻滞,注入0.8%利多卡因和0.02mg/kg吗啡的混合液,容积为0.6ml/kg。观察术后2、4、8、122、4h疼痛情况,并用视觉模拟评分法进行评估,记录各时点的血压、脉搏、脉搏血氧饱和度以及恶心呕吐、尿潴留等副作用。结果术前肌注氯胺酮1mg/kg能增强骶管阻滞的镇痛效果,而肌注氯胺酮2mg/kg临床作用与之相似,但副作用却显著增高。结论术前肌注氯胺酮1mg/kg能增强骶管吗啡的镇痛效果,并可减少吗啡的副作用。     

Endogenous orphanin FQ: evidence for a role in the modulation of electroacupuncture analgesia and the development of tolerance to analgesia produced by morphine and electroacupuncture

1. Our previous work has demonstrated that exogenously administered orphanin FQ (OFQ) antagonizes morphine analgesia and electroacupuncture analgesia (EAA) in the brain and potentiates morphine analgesia and EAA in the spinal cord of the rat. In the present study we evaluated the role of endogenously released OFQ in the development of tolerance to morphine and electroacupuncture (EA) and the analgesia produced by electroacupuncture, by use of the IgG fraction of an anti-OFQ antibody (OFQ-Ab) microinjected into the rat central nervous system (CNS).
2. EAA was produced by stimulating rats at a frequency of 100 Hz. Rats were classified as either high responders (HR) or low responders (LR) based on the analgesic effects of EA. LRs could be converted into HRs by the intracerebroventricular (i.c.v.) microinjection of OFQ-Ab at both 1 : 1 and 1 : 10 dilutions but not 1 : 100. HRs could be changed into LRs by the intrathecal (i.t.) injection of OFQ-Ab at both 1 : 1 and 1 : 10 dilutions, but not 1 : 100.
3. Acute morphine tolerance was induced in rats by repeated subcutaneous (s.c.) injections of morphine (5 mg  kg, every 2 h) for 16 h. When injected i.c.v. the OFQ-Ab (1 : 1 dilution) had no effect on the development of acute morphine tolerance.
4. Chronic morphine tolerance was produced in rats by repeated injection of morphine (5–60 mg  kg, s.c., 3× a day) for 6 days. I.c.v. injection of OFQ-Ab (1 : 1 dilution) reversed this type of morphine tolerance in rats by 50% (P<0.01).
5. Acute tolerance to the analgesia produced by EA developed after 6 h of continuous (100 Hz, 3mA) stimulation. This tolerance was almost completely reversed by the i.c.v. injection of OFQ-Ab (1 : 1 dilution) (P<0.05).
6. Chronic tolerance to the analgesic effect of EA was produced by repeatedly administering increasing current (1, 2 and 3 mA, each lasting for 10 min, for a total of 30 min) at a frequency of 100 Hz once a day for 6 days. I.c.v. injection of OFQ-Ab (1 : 1 dilution) reversed this kind of tolerance by 50% (P<0.01).
7. Together these results suggest that 100 Hz EA may enhance the release of endogenous OFQ in the CNS of the rat, which in turn may act to antagonize EA-produced analgesia in the brain but potentiate EA produced analgesia in the spinal cord. Therefore, OFQ appears to play an important role in the development of tolerance to the analgesic effects produced by EA.
8. The mechanisms underlying the development of acute morphine tolerance and chronic morphine tolerance appear to be different. Central OFQ may play an important role in the development of tolerance after chronic morphine administration.

     

病人自控镇痛中吗啡的药物动力学及血药浓度监测

目的：研究病作人镇痛（ＰＣＡ）时吗啡（Ｍｏｒ）的药物动力学,在硬膜外麻醉病人自控镇痛时以负荷剂量－持续注射（ＬＣＰ）模式给药时血药浓度的波动要用放射免疫法测定Ｍｒｏ血药浓度。结果：Ｍｏｒｉｖ时符合开放型二室模型。在ＬＣＰ模式给药时,Ｍｏｒ的平均血药浓度在２７３．９４～７４．５μｇ／Ｌ之间,此时镇痛效果良好,病人无明显不良反应结论：本实验为Ｍｏｒ应用于ＬＣＰ模式中的安全性提供一定的理论依据。     

Etoposide modulates the effects of oral morphine analgesia by targeting the intestinal P-glycoprotein

Objectives Opioids and anticancer compounds such as etoposide (ETP) are substrates of P‐glycoprotein (P‐gp), an ATP‐dependent efflux pump. Chemotherapy compounds may impact on the analgesic effect of opioids such as morphine when the two drugs are co‐administered. In this study, we used a mouse model to determine if there is a pharmacological interaction between ETP and morphine, focusing on the involvement of intestinal P‐gp. Methods P‐gp drug efflux activity was measured by an in‐situ closed loop method with Rhodamine 123, a P‐gp substrate. The analgesic effect of morphine was determined by the tail‐flick test. Intestinal P‐gp expression levels were determined by Western blot. Key findings ETP and morphine significantly decreased the intestinal Rhodamine 123 efflux activity of P‐gp. Oral morphine analgesia was significantly enhanced when co‐administered with ETP. However, repeated pretreatment (7 days) with oral ETP significantly decreased the oral morphine‐induced analgesia, in a cyclosporine A (a P‐gp inhibitor) reversible manner. Furthermore, repeated ETP significantly up‐regulated intestinal P‐gp expression. Conclusions It may be important to consider aspects of therapeutic design such as the administration route or scheduling of drugs in patients receiving concurrent chemotherapy and opioid therapy to avoid pharmacokinetic interactions between the two agents.     

吗啡联合赖氨匹林用于小儿术后静脉镇痛临床观察

目的:观察吗啡联合赖氨匹林用于小儿术后静脉镇痛的效果和不良反应。方法:60例腹部手术患儿随机分为两组,术后分别采用吗啡(M组)和吗啡联合赖氨匹林(M+L组)行静脉镇痛治疗,观察各组疼痛评分、镇静评分、HR、M AP、RR、SpO2、T和主要不良反应的发生率。结果:疼痛评分两组相似(P>0.05),镇静评分术后4h、12 h时两组相似(P>0.05),但24 h、36 h、48 h时M组高于M+L组(P<0.05),M组恶心、呕吐、皮肤瘙痒发生率高于M+L组(P<0.05)。结论:吗啡联合赖氨匹林用于小儿术后静脉镇痛效果确切,不良反应少于等效量吗啡。