降钙素基因相关肽在慢性吗啡耐受及相关痛觉过敏中的作用

疼痛是晚期恶性肿瘤患者的常见症状，是影响患者生存质量的主要因素，阿片类药物吗啡是治疗急慢性疼痛的常用药物，但长时间应用会导致吗啡耐受及其相关痛觉过敏现象的发生，制约其临床应用。本文总结分析近年相关文献，从伤害性感受角度探讨慢性吗啡耐受及其相关痛觉过敏的形成原因，重点阐述降钙素基因相关肽（calcitonin gene-related peptide，CGRP）在其中的作用，从CGRP的分子生物学特征与分布、长期吗啡应用与CGRP的关系、CGRP与痛觉过敏等方面详细分析了慢性吗啡给药所致的神经系统可塑性变化与CGRP表达上调之间的关系，并对CGRP表达上调对机体伤害性感受系统的影响进行分析，阐述了CGRP表达上调与痛觉过敏形成之间的关系。从机制上论述了CGRP表达上调所致的伤害性感受增强对吗啡耐受及其相关痛觉过敏的促进作用，为治疗吗啡耐受和进一步研究吗啡耐受机理提供了一个靶点和思路。      

中枢神经细胞凋亡与吗啡耐受相关性研究进展

<正>全球肿瘤发病率持续增高,我国已经成为肿瘤发病人数最多的国家,大多数肿瘤,特别是晚期恶性肿瘤患者,都将因癌性疼痛而服用阿片类药物止痛。长期使用阿片类药物如吗啡时,会导致药物耐受,从而影响吗啡类药物的止痛效果,最终降低和限制了阿片类药物在临床中的使用。关于吗啡药物耐受的神经生理学机制,目前认为是多方面的,而且并没有完全明了。在过去的几十年里,各国都进行了很多研     

P物质和降钙素基因相关肽在骨癌痛-吗啡耐受模型中的表达

背景与目的:多数晚期癌症患者会经历中重度癌痛折磨。阿片药物是癌痛治疗最常用和最有效的药物,但长时间使用容易造成耐受甚至痛觉过敏。P物质(substance P,SP)和降钙素基因相关肽(calcitonin gene-related peptide,CGRP)是疼痛信号传递中最重要的神经递质,但在癌痛-阿片耐受中的表达尚不清楚。本研究拟在骨癌痛-吗啡耐受大鼠模型上,探讨SP和CGRP在背根神经节(dorsal root ganglion,DRG)水平的表达特点。方法:60只Wistar大鼠鞘内置管成功后,随机分为3组:假手术组、吗啡耐受组和骨癌痛-吗啡耐受组。吗啡耐受组和骨癌痛-吗啡耐受组分别以热灭活Walker256乳腺癌细胞和Walker256乳腺癌细胞制备胫骨癌痛模型,接种后10 d时鞘内注射吗啡20μg/kg。动物行为学测试使用Von Frey纤维丝,于不同时间点测定机械刺激引起的机械缩足阈值。研究结束时,免疫组织化学分析DGR中SP和CGRP的表达,测定积分光密度IOD值。结果:行为学证实,吗啡耐受组和骨癌痛-吗啡耐受组在吗啡治疗第5天时出现耐受,骨癌痛-吗啡耐受组缩足阈值较吗啡耐受组和对照组明显降低(P<0.001)。骨癌痛-吗啡耐受组SP和CGRP积分光密度值IOD(9 917.9±2 246.1和15 021.5±2 989.7)较吗啡耐受组(5 191.7±1 052.6和9 737.1±2 239.8)和对照组(4 821.6±843.1和8 180.3±1 242.2)明显增加(P<0.001)。结论:SP和CGRP在癌痛-吗啡耐受大鼠模型DRG中表达增强,提示这两种神经递质参与了耐受产生,这将为新药治疗癌痛-吗啡耐受提供更符合临床的科学依据。     

施万细胞在恶性肿瘤进展中的作用

施万细胞（Schwann cells,SCs）是外周神经系统中最重要的神经胶质细胞类型,在神经损伤修复过程中起重要作用。近年来研究显示,SCs作为连接神经和肿瘤细胞的“桥梁分子”,通过与肿瘤细胞、免疫细胞、间质细胞等相互作用,改善局部肿瘤微环境,进而促使肿瘤嗜神经生长和神经支配、促进肿瘤的生长、迁移和侵袭,产生免疫抑制并出现肿瘤疼痛等一系列恶性生物学行为。本文就SCs在非神经肿瘤中的作用及其机制进行综述,以期为将来抗肿瘤治疗联合靶向SCs的治疗策略提供理论基础。     

抑癌基因PTEN功能失活促使神经胶质瘤表达B7-H1并介导肿瘤免疫抵抗

肿瘤免疫抵抗是原发性脑肿瘤的特征之一。美国每年新发脑肿瘤患者达到2万人，其中多形性神经胶质瘤是一种来源于神经胶质细胞的恶性肿瘤，其恶性程度极高，传统治疗手段疗效差，5年存活率小于2％。新近临床上倾向于使用实验性免疫治疗手段尝试治疗，因此探讨肿瘤免疫抵抗及逃逸机制有着重大意义。[第一段]     

大麻素受体1通过调控星形胶质细胞参与抑郁症发病机制的研究进展

抑郁症是常见的神经精神疾病之一,因其高患病率、复发率和自杀率而受到广泛关注.以往研究认为,星形胶质细胞在抑郁症病理生理过程中发挥重要功能,但星形胶质细胞参与抑郁症发病的具体机制尚不完全清楚.内源性大麻素系统与神经精神疾病密切相关,尤其是在焦虑和抑郁等情感障碍的治疗中发挥着重要作用.大麻素受体1(cannabinoid ...     

神经胶质瘤中肿瘤相关巨噬细胞研究进展

肿瘤相关巨噬细胞（TAM）是异质性细胞群体,是肿瘤微环境中炎性细胞的主要成分。这些细胞在神经胶质瘤中部分源自中枢神经系统小胶质细胞和循环单核细胞,并与神经胶质瘤的血管生成、免疫抑制、肿瘤进展和侵袭有关。文章综述了TAM通过各种途径促进神经胶质瘤发展的潜在机制,为神经胶质瘤的靶向治疗提供了新的可能性。     

小胶质细胞在脑转移癌中的作用

 小胶质细胞（MG）是中枢神经系统损伤和疾病中主要的免疫效应细胞，可以通过多种途径调节脑转移癌（BMT）的发生发展。研究MG在BMT发生发展中的作用及机制将为BMT的预防及治疗提供新思路。     

高分级胶质瘤的放化综合治疗

胶质瘤是起源于神经胶质细胞的肿瘤，主要包括星形细胞肿瘤、少突胶质细胞肿瘤和混合性胶质细胞肿瘤。星形细胞瘤是胶质瘤中最常见的类型，其中的间变性星形细胞瘤又称恶性星形细胞瘤，属WHOⅢ级。临床常将恶性星形细胞瘤和胶质母细胞瘤统称为恶性胶质瘤，而将Ⅲ级胶质瘤（如间变性星形细胞瘤，间变性少突胶质细胞瘤）、胶质母细胞瘤、胶质肉瘤等统称为高分级胶质瘤。     

乳头状胶质神经元肿瘤报告一例及文献复习

背景与目的：自中央性神经细胞瘤和胚胎发育不良性神经上皮瘤(dysembryoplastic neuroepithelial tmors，DNT)被确认以来，脑室外小圆细胞组成的肿瘤受到重视，又报道了乳头状胶质神经元肿瘤(papillary glioneuronal tumor，PGNT)和节细胞神经细胞瘤等新肿瘤。本文报道一例PGNT，复习其临床病理特征和文献，对此类肿瘤的特征进行探讨。方法：观察一例新病例的临床和病理表现，包括HE和免疫细胞化学染色并复习文献进行讨论。结果：本例(男性，32岁)肿瘤位于大脑顶叶，瘤组织由乳头状结构及少突胶质样细胞和上皮样细胞区交织构成，其中有小圆神经细胞、中等大的神经细胞和大的双核节细胞。免疫细胞化学染色中显示大多数瘤细胞和神经毯呈现S-100和Syn阳性反应，有些瘤细胞呈现GFAP阳性反应，本例病理诊断为PGNT。对肿瘤的临床和病理特征作了讨论，认为PGNT为较良性的肿瘤。结论：PGNT为一种低级别的胶质神经元肿瘤，以特异性乳头状胶质血管结构为特征。免疫细胞化学染色做NSE，Syn和GFAP等有助与中央性神经细胞瘤、DNT及其它胶质瘤相鉴别。PGNT这一新的肿瘤实体有可能成为神经元和混合性神经元胶质肿瘤中的一员。     

多肽P10581对大鼠甲状腺癌转移性骨癌痛的镇痛作用及对吗啡耐受的影响北大核心

目的:探讨多肽P10581对大鼠甲状腺癌转移性骨癌痛的镇痛作用及其对吗啡耐受的影响。方法:造模20天后,40只造模成功的甲状腺癌骨转移疼痛模型鼠被随机分为4组(雌雄各5只/组):吗啡组(5 mg/kg)、P10581 A组(7.2μg/kg)、P10581 B组(14.4μg/kg)和等体积生理盐水组,皮下注射给药并比较给药后连续5小时的大鼠机械性缩足阈值(paw withdral threshold,PWT)。在多肽对吗啡镇痛耐受的影响研究中,模型鼠分为吗啡组(5 mg/kg)、联合用药A组(0.2μg/kg P10581+5 mg/kg吗啡)、联合用药B组(0.4μg/kg P10581+5 mg/kg吗啡)和等体积生理盐水组,给药方式和分组同上,比较给药后连续4天的PWT。结果:在镇痛作用研究中,给药后1~3 h内吗啡和多肽P10581均有显著镇痛作用(P均<0.001),但吗啡镇痛效果强于多肽P10581,到第4 h时,两者的镇痛效果无差异,从第5 h开始P10581镇痛作用明显强于吗啡(t_(A)=14.35,P_(A)<0.001;t_(B)=17.60,P_(B)<0.001)。在多肽对吗啡镇痛耐受的影响实验中,吗啡组从第2天开始镇痛作用逐日下降,到第4天,吗啡完全耐受。微量多肽P10581与吗啡联合用药组,到第4天时A组和B组的镇痛百分率比吗啡组分别提高了63.86%和78.27%,仍保持明显镇痛效果(t_(A)=33.15,P_(A)<0.001;t_(B)=37.71,P_(B)<0.001)。所有实验结束后,实验鼠心、脑、肾、肝、脾、肺等重要脏器镜下观察无任何明显病理性改变。结论:多肽P10581对大鼠甲状腺癌转移性骨癌痛的镇痛作用时间明显长于吗啡,微量P10581可明显降低吗啡耐受性。     

羟考酮替换盐酸吗啡减轻阿片类药物耐药的临床研究

目的研究羟考酮替换盐酸吗啡减轻癌症病人对阿片类药物耐药的影响。方法采用前瞻性自身对照试验,以1.5∶1作为各组病人吗啡向羟考酮转换的基础比率,用数字分级评分（NRS）、卡氏行为状态量表评分（KPS）和生活质量评分（QOL）作为转换前后镇痛效果、活动能力及生活质量的评价指标。结果不同剂量组盐酸吗啡与羟考酮的平均转换比率随着吗啡剂量的增加而增加,转换比值与吗啡的的剂量呈一次线性拟合趋势（F=0.003、P=0.954）,大剂量吗啡组比小剂量吗啡组替换后羟考酮的需要量更小。结论应用羟考酮替换大剂量盐酸吗啡止痛是一种减轻阿片类药物耐药的新途径。     

Morphine or oxycodone in cancer pain?

Oxycodone is an opioid analgesic that closely resembles morphine. Oxymorphone, the active metabolite of oxycodone, is formed in a reaction catalyzed by CYP2D6, which is under polymorphic genetic control. The role of oxymorphone in the analgesic effect of oxycodone is not yet clear. In this study, controlled-release (CR) oxycodone and morphine were examined in cancer pain. CR oxycodone and morphine were administered to 45 adult patients with stable pain for 3-6 days after open-label titration in a randomized, double-blind, cross-over trial. Twenty patients were evaluable. Both opioids provided adequate analgesia. The variation in plasma morphine concentrations was higher than that of oxycodone, consistent with the lower bioavailability of morphine. Liver dysfunction affected selectively either oxycodone or morphine metabolism. Three patients with markedly aberrant plasma opioid concentrations are presented. Significant individual variation in morphine and oxycodone metabolism may account for abnormal responses during treatment of chronic cancer pain.     

Spider peptide Phα1β induces analgesic effect in a model of cancer pain

The marine snail peptide ziconotide (ω‐conotoxin MVIIA) is used as an analgesic in cancer patients refractory to opioids, but may induce severe adverse effects. Animal venoms represent a rich source of novel drugs, so we investigated the analgesic effects and the side‐effects of spider peptide Phα1β in a model of cancer pain in mice with or without tolerance to morphine analgesia. Cancer pain was induced by the inoculation of melanoma B16‐F10 cells into the hind paw of C57BL/6 mice. After 14 days, painful hypersensitivity was detected and Phα1β or ω‐conotoxin MVIIA (10–100 pmol/site) was intrathecally injected to evaluate the development of antinociception and side‐effects in control and morphine‐tolerant mice. The treatment with Phα1β or ω‐conotoxin MVIIA fully reversed cancer‐related painful hypersensitivity, with long‐lasting results, at effective doses 50% of 48 (32–72) or 33 (21–53) pmol/site, respectively. Phα1β produced only mild adverse effects, whereas ω‐conotoxin MVIIA induced dose‐related side‐effects in mice at analgesic doses (estimated toxic dose 50% of 30 pmol/site). In addition, we observed that Phα1β was capable of controlling cancer‐related pain even in mice tolerant to morphine antinociception (100% of inhibition) and was able to partially restore morphine analgesia in such animals (56 ± 5% of inhibition). In this study, Phα1β was as efficacious as ω‐conotoxin MVIIA in inducing analgesia in a model of cancer pain without producing severe adverse effects or losing efficacy in opioid‐tolerant mice, indicating that Phα1β has a good profile for the treatment of cancer pain in patients.     

Comparative-study of intramuscular ketorolac tromethamine and morphine in patients experiencing cancer pain

Ketorolac tromethamine administered intramuscularly (i.m.) 10 mg 6-hourly was compared with morphine 10 mg i.m. 6-hourly in a randomised, double-blind, cross-over trial for its analgesic efficacy and safety in 51 patients with moderate to severe cancer pain. There was no overall significant difference between the analgesic effect of the two treatments. 57% of ketorolac- and 74% of morphine-treated patients changed their analgesic. Among these, significantly more patients stopped ketorolac than morphine due to pain (p=0.007) whilst more patients discontinued morphine than ketorolac because of adverse effects (p=0.001), predominantly emesis. Only one patient (2%) stopped ketorolac because of intolerance. Ketorolac shows promise as an effective and well tolerated analgesic for cancer pain and merits further study.     

东莨菪碱、乌头注射液辅助吗啡治疗顽固性晚期癌痛的临床探讨

目的 :应用东莨菪碱、乌头注射液辅助吗啡治疗 8例顽固性癌痛患者 ,比较治疗前后的镇痛效果 ,行为、休息状况以及吗啡用量。方法 :选择 8例经吗啡反复治疗且效果欠佳的顽固性晚期癌痛患者 ,应用东莨菪碱、乌头注射液、氟哌利多持续静脉泵注治疗 ,并按患者需要给予吗啡 ,观察治疗前后的镇痛效果、行为评分 ,休息状况以及吗啡用量。结果 :8例患者经中药辅助吗啡治疗后镇痛效果、行为评分、休息评分均明显优于单纯吗啡治疗(P <0 .0 5 ) ;同时 ,治疗后吗啡用量比治疗前少 (P <0 .0 5 )。结论 :东莨菪碱、乌头注射辅助吗啡治疗顽固性晚期癌痛具有较好效果。     

Morphine: double-faced roles in the regulation of tumor development

Morphine, a highly potent analgesic, is one of the most effective drugs for the treatment of severe pain associated with cancer. It directly acts on the central nervous system to relieve pain, but also cause secondary complications, such as addiction, respiratory depression and constipation due to its activities on peripheral tissues. Besides pain relief, morphine is of great importance on cancer management with its effect on tumor development being the subject of debate for many years with some contradictory findings. Morphine has shown both tumor growth-promoting and growth-inhibiting effects in many published research studies. And various signaling pathways have been suggested to be involved in these effects of morphine. Based on a thorough literature review, we summarized the double-faced effects of morphine in tumor development, including tumor cell growth and apoptosis, metastasis, angiogenesis, immunomodulation and inflammation. And we attempted to optimize morphine administration in cancer patients to attenuate its tumor growth-promoting effects.     

病人自控式镇痛泵静脉泵入吗啡治疗难治性癌痛的临床效果观察

目的:观察使用病人自控式镇痛泵静脉泵入吗啡治疗难治性癌痛的临床效果。方法:筛选难治性癌痛患者32例,采用PCA泵静脉泵入吗啡注射液止痛治疗。回顾性分析上述病例患者的临床特征,观察镇痛过程,评价PCA泵的镇痛疗效和安全性。结果:多数难治性癌痛患者对吗啡的需求量增加,使用PCA泵静脉泵入吗啡能快速及有效的镇痛,患者的疼痛程度明显减轻,生活质量显著改善,无严重不良反应发生。结论:使用PCA泵治疗难治性癌痛,合理控制吗啡使用剂量,操作简单,提高患者用药的依从性,能够快速、及时和有效镇痛。     

Oxycodone: a pharmacological and clinical review

Oxycodone is a semi-synthetic opioid with an agonist activity on mu, kappa and delta receptors. Equivalence with regard to morphine is 1:2. Its effect commences one hour after administration and lasts for 12 h in the controlled-release formulation. Plasma half-life is 3–5 h (half that of morphine) and stable plasma levels are reached within 24 h (2–7 days for morphine). Oral bioavailability ranges from 60 to 87%, and plasma protein binding is 45%. Most of the drug is metabolised in the liver, while the rest is excreted by the kidney along with its metabolites. The two main metabolites are oxymorphone — which is also a very potent analgesic — and noroxycodone, a weak analgesic. Oxycodone metabolism is more predictable than that of morphine, and therefore titration is easier. Oxycodone has the same mechanism of action as other opioids: binding to a receptor, inhibition of adenylyl-cyclase and hyperpolarisation of neurons, and decreased excitability. These mechanisms also play a part in the onset of dependence and tolerance. The clinical efficacy of oxycodone is similar to that of morphine, with a ratio of 1/1.5–2 for the treatment of cancer pain. Long-term administration may be associated with less toxicity in comparison with morphine. In the future, both opioids could be used simultaneously at low doses to reduce toxicity. It does not appear that there are any differences between immediate and slow-release oxycodone, except their half-life is 3–4 h, and 12 h, respectively. In Spain, controlled-release oxycodone (OxyContin®) is marketed as 10-, 20-, 40-or 80-mg tablets for b.i.d. administration. Tablets must be taken whole and must not be broken, chewed or crushed. There is no food interference. The initial dose is 10 mg b.i.d. for new treatments and no dose reduction is needed in the elderly or in cases of moderate hepatic or renal failure. Immediate-release oxycodone (OxyNorm®) is also available in capsules and oral solution. Side effects are those common to opioids: mainly nausea, constipation and drowsiness. Vomiting, pruritus and dizziness are less common. The intensity of these side effects tends to decrease over the course of time. Oxycodone causes somewhat less nausea, hallucinations and pruritus than morphine.