阿片类药物成瘾的生化代谢和病理学变化的研究进展

综合性论述阿片类药物成瘾的生化代谢和病理学变化的研究进展．     

磷脂酰肌醇3激酶/丝苏氨酸蛋白激酶信号转导通路在芬太尼后处理和远隔缺血后处理心肌保护中的作用

目的 在心肌缺血/再灌注损伤(ischemia/reperfusion injury,I/RI)大鼠探讨磷脂酰肌醇3激酶/丝苏氨酸蛋白激酶(phosphoinositide 3 kinase/serine-threonine kinase,PI3K/Akt)信号转导通路在芬太尼后处理和远隔缺血后处理心肌保护中的作用.方法 将32只成年雄性SD大鼠(体重250g～350 g)麻醉后,采用计算机产生的随机数随机分为4组:对照组(C组)、芬太尼后处理组(F组)、肢体远隔缺血后处理组(R组)及联合应用芬太尼后处理和肢体远隔缺血后处理组(F-R组).在结扎大鼠冠状动脉左前降支(left anterior descending coronary artery,LAD)30 min造成局部心肌缺血后,开放心肌再灌注60 min建立大鼠心肌I/RI模型.采用SA Bioscience公司功能分类基因芯片和免疫蛋白印迹分析法检测再灌注60 min后缺血区心肌内与PI3K/Akt相关基因的表达和磷酸化Akt蛋白的表达情况.结果 利用基因芯片检测的与PI3K/Akt相关的基因中,与C组比较,F组共有9个基因的表达显著上调,而R组仅2个基因的表达显著上调;但F-R组共有33个基因的表达较C组显著上调.蛋白印记分析结果显示,与C组比较,F组、R组和F-R组心肌标本内磷酸化Akt蛋白表达量均增高;而与F组和R组比较,F-R组心肌标本内磷酸化Akt蛋白表达量进一步增高.结论 联合应用芬太尼后处理和肢体远隔缺血后处理可明显增强PI3K/Akt信号转导通路激活.     

Effects of central application of naloxone on the skin temperature response in morphine-dependent rats

This study was designed to identify if the surge in tail skin temperature (TST) observed following systemic administration of naloxone to morphine-dependent rats is mediated by a specific brain locus. Female rats were fitted with cannula located either in the preoptic area-anterior hypothalamus, locus coeruleus, or the frontal cortex. TST was monitored every 5 min for 60 min following central administration of naloxone (1-40 micrograms/0.4 microliters), in morphine-dependent rats. Regardless of the central site of naloxone injection, TST was significantly increased 4-5 degrees C. A threshold dose of 20 micrograms/0.4 microliters (10 micrograms/0.2 microliters, bilaterally) of naloxone was identified to produce this surge in TST in all three brain regions. These results suggest that morphine dependency sensitizes several brain regions to administration of naloxone such that the narcotic antagonist produces a similar change in TST as is observed following its systemic administration. These data further support the use of our morphine-dependent rat model to study the central mechanisms of the menopausal hot flush, and provide additional evidence that the flush response is centrally mediated.     

Endogenous opioid systems regulate cell proliferation in the developing rat brain

The role of endogenous opioid systems in modulating the proliferation of developing cerebellar cells was examined autoradiographically in 6-day-old rats. The blockade of endogenous opioid-opioid receptor interaction by naltrexone, a potent opioid antagonist, was accompanied within 1–2 h by an increased proportion of cells incorporating [³H]thymidine. When high doses of naltrexone (50 mg/kg) were administered this index was still elevated 12 h later; however, when low doses of naltrexone (1 mg/kg) were administered the index of labeled cells was decreased markedly. Injection of methionine-enkephalin, an endogenous opioid peptide, also resulted in a decrease in the proportion of cells incorporating [³H]thymidine. Concomitant injection of 1 mg/kg naloxone, however, blocked the inhibitory effects of methionine-enkephalin on cell division but did not itself affect cell generation. These studies demonstrate that endogenous opioid systems can regulate the proliferation of cell populations in the developing nervous system and do so through an inhibitory mechanism.     

Development of opioid systems: peptides, receptors and pharmacology

The understanding of opioid system function in the adult has progressed markedly in the last decade. This in turn has led to an increased knowledge of how opioid function develops in the embryo and in the postnatal period.With respect to the ontogenetic profile of the opioid peptide products of the 3 opioid precursors, all are detectable during gestation and their development in rodents is not completed until well after birth, the third postnatal week often exhibiting the most marked increases. There is not an exact parallel development of the precursors and there may be regional fluctuations for some of the peptides in the postnatal period. All of the indications are that the ontogenesis of the 3 precursors occurs independent ly, and that their opioid peptide products have distinct ontogenetic profiles (Section 2.2.–2.4.). Indeed in a comparative immunocytochemical study for dynorphin-A and enkephalin³⁶ the patterns of deveopment in the hippocampal formation were dissimilar. In addition the differences observed in ontogenetic patterns for the precursor products may well reflect differential activities of the processing cleavage enzymes in the developing animal. Indeed a comparative ontogenetic study of ACTH and β-endorphin^64,65 showed a dissimilar profile during early development in rat brain and pituitary. Whilst these may be due to different processing patterns, the possibility of differential release, secretion or degradation of these peptides cannot be excluded and may be independent of the synthesis of the precursor.There is also a differential ontogeny of the opioid receptor subtypes and the recent evidence with highly selective binding ligands has provided a clear pattern, μ- And κ-sites are the first to appear though δ-receptors are absent until the second postnatal week in the rat. In this species the full development of μ- and δ-sites occurs in the third and fourth weeks respectively.There is still some argument about the ontogenetic profile for κ-sites though, like the δ-receptors, full development is probably later than for the μ-sites. Ontogenetic profiles of opioid receptors have also been demonstrated in the chick, sheep and mouse. Too few studies have looked at peptide and recep tor development in parallel and it is still unclear if specific peptide development is directly linked with development of a single receptor site.The postnatal development of both opioid peptides and receptors is mirrored by pharmacological actions of opioids which differ in the neonate. Their pharmacological effects are not solely dependent on the number of receptors but also on the ontogenetic pattern of the metabolising enzymes and on bloodbrain barrier development. There are some anomalous responses to opioids in the neonate and these include locomotion, respiratory depressant activity and effects on corticosterone release.There are also indications that the opioid system is particularly sensitive to insult during the developing period. In particular toxic effects at low doses have been shown for lead exposure, diazepam and haloperidol treatment. It may be that the complexity of opioid function increases the risk of disruption or it may reflect a ubiquitous involvement of the endogenous opioid peptides in the control of several neurochemica in the brain.The future needs more studies in animals other than the rat and a clearer picture of the genetic profile of the precursors and the processing of the same during development. This information should not be long in coming.     

Rostral hypothalamus: A new neuroanatomical site of neurochemically-induced emesis in the cat

The localized effect of noradrenergic agonists administered directly in the anterior hypothalamic preoptic area (AH/POA) in inducing emesis in the cat was investigated. Of the noradrenergic agonists tested, which included norepinephrine, clonidine, phenylephrine and methoxamine, only clonidine in doses of 5.0-50.0 micrograms was found to evoke emesis consistently when micro-injected in a volume of 1.0 microliter into AH/POA of the unrestrained cat. The emetic response to clonidine was short-lasting, generally dose-dependent in terms of latency and frequency, and occurred in bouts of one to three episodes. The sequence of the vomiting response, beginning with licking and retching, functionally resembled a normal pattern of an emetic response. The clonidine-induced emesis was not antagonized by the following antagonists micro-injected in AH/POA just prior to clonidine: alpha-adrenergic blocking agents, yohimbine, RX 781094 and phentolamine; the antimuscarinic drug, atropine; the serotonin antagonist, methysergide; the opioid antagonist, naloxone; and the dopamine antagonist, chlorpromazine. Therefore, it would appear that clonidine-induced emesis is not mediated by alpha noradrenergic, serotonergic, dopaminergic, muscarinic and opiate receptor systems within the AH/POA of the cat. Finally, the obtained results show that apart from the area postrema and a circumscribed zone of the brain-stem reticular formation, the hypothalamus is now implicated as a neuroanatomical site in the central nervous system mechanism underlying neurochemically-induced emesis.     

阿片受体的病理生理研究进展

阿片受体属G蛋白偶联受体,其配体是阿片肽物质.阿片受体在人体内广泛存在,有着复杂的生物学效应,除了既往研究比较多的镇痛、耐受、成隐机制以及对神经系统的影响和呼吸抑制的效应外,其对心血管循环系统、免疫系统等也有着很重要的影响.阿片受体有许多亚型,最常见的三种经典阿片受体为μ、δ、κ受体,它们各自有其特异的内源性配体,发挥不同的生物效应.应激状态下,内啡肽的升高成为纳洛酮在急危重症的应用基础.对阿片受体生物效应的深入研究有助于更进一步明确纳洛酮的药理机制,为开发特异性阿片受体阻断剂和激动剂提供理论基础.     

同步荧光扫描导数法测定延胡索药材中原阿片碱含量

目的：建立同步荧光扫描导数法测定延胡索药材中原阿片碱含量的方法。方法：采用同步荧光扫描导数法以Δλ=10 nm,激发波长扫描范围200～400 nm,扫描结果经一阶导数处理,在290 nm峰位波长处采用标准加入法测定原阿片碱的荧光强度。结果：原阿片碱在1.6～12.00μg.mL^-1浓度范围之间线性关系良好,r=0.9991。原阿片碱加样回收率为95.2%,RSD为1.1%。结论：该方法快速准确,灵敏度高,选择性好,可用于延胡索药材中原阿片碱的含量测定。     

Strengthening systems of care for people with or at risk for HIV,HCV and opioid use disorder: a call for enhanced data collection

BackgroundThe syndemic between opioid use disorder (OUD), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) results in excessive burdens on the healthcare system. Integrating these siloed systems of care is critical to address all three conditions adequately. In this implementation project, we assessed the data capacity of the health system to measure a cascade of care (COC) across HIV, HCV and OUD services in five states to help guide public health planning.Materials and methodsData for this study were gathered from publicly available datasets and reports from government (SAMSHA, CMS, HRSA and CDC) sites. We created, where possible, COCs for HIV, HCV, and OUD spanning population estimate, diagnosis, treatment initiation, treatment retention, and patient outcomes for each of five states in the study.ResultsThe process of data collection showed that baseline COCs examining the intersections of OUD, HIV, and HCV cannot be produced and that there are missing data in all states examined. Collection of specific data points is not consistent across all states. States are better at reporting HIV cascades due to federal requirements. Only gross estimates could be made for OUD cascades in all states because data are separated by payer source, leaving no central point of data collection from all sources. Data for HCV were not publicly available.ConclusionIt is difficult to assess the strategies needed or the progress made towards increasing treatment access and decreasing the burden of disease without the ability to construct an accurate baseline. Using integrated COCs with relevant benchmarks can not only guide public health planning, but also provide meaningful targets for intervention.

KEY MESSAGES

• While HIV COCs are available for most states at least annually, they are not disaggregated for populations with co-occurring OUD or HCV.
• Data to calculate HCV COC are not available and data to calculate OUD COC are partially available, but only for specific payers.
• States do not have systems in place to measure the scope of the syndemic or to identify targets for quality improvement activities.

     

乌香痛消膏联合阿片类药物治疗中重度癌性疼痛60例临床研究

目的观察乌香痛消膏联合阿片类药物治疗中重度癌性疼痛的临床疗效。方法将120例中重度癌性疼痛患者随机分为2组。治疗组60例予乌香痛消膏联合阿片类药物治疗,对照组60例予安慰剂联合阿片类药物治疗,共治疗7 d。观察2组治疗前后疼痛程度数字评分(NRS)、镇痛起效与缓解持续时间、首日与全程等效吗啡消耗量。结果 2组治疗后NRS评分均降低,组内配对比较差异均有统计学意义(P0.05);2组治疗后NRS评分组间比较差异无统计学意义(P0.05)。2组组间镇痛起效时间比较差异无统计学意义(P0.05),镇痛缓解持续时间有统计学意义(P0.05)。2组首日吗啡消耗量比较差异无统计学意义(P0.05),全程吗啡消耗量比较差异有统计学意义(P0.05)。结论乌香痛消膏联合阿片类药物治疗中重度癌性疼痛可以明显缓解疼痛程度,延长镇痛缓解持续时间,减少爆发痛的发生次数,减少阿片类药物的消耗量,减轻毒副反应,提高镇痛效果和患者的生活质量。