吗啡依赖状态下大鼠脑组织左旋精氨酸脱羧酶活性的测定

阿片类药物的耐受和躯体依赖不仅与阿片受体本身的代偿性适应有关,而且还涉及到许多非阿片受体和递质系统.一方面当改变这些非阿片受体的功能后会影响阿片类药物的药理作用,例如抑制5-HT重吸收可以增加吗啡镇痛[1];另一方面阿片类药物慢性处理会引起这些受体系统发生代偿性适应性变化,例如吗啡急性处理能抑制5-HT释放,而慢性处理反而导致5-HT释放增多[2].     

电压门控钙通道及其对阿片类物质药理作用的调节

电压门控型钙通道依据其生理和药理特性可分为L，N，P／Q，R，T等型。L型钙通道阻断剂能增强阿片类物质镇痛，抑制阿片类物质的耐受和依赖，其作用机制与阻断钙通道、激活阿片受体、影响阿片代谢、抑制蛋白激酶及神经递质的释放有关。N型钙通道阻断剂具有明显的镇痛作用，尤其对神经源性痛具有强大的镇痛作用，且此作用不易耐受，作用机制与抑制C纤维和细的Aδ纤维活化及Ca^2＋介导的炎性因子的合成相关。N型钙通道阻断剂也能增强吗啡镇痛。P／Q型钙通道阻断剂对锐痛和炎性痛的镇痛作用比吗啡更佳，作用机制与N型钙通道阻断剂相类似。T型钙通道阻断剂对神经源性痛有一定的镇痛作用，能增强阿片类物质镇痛，预防和治疗阿片类物质的耐受和依赖，作用机制与抑制C纤维及细的Aδ纤维活化、抑制阿片受体信号转导通路和效应器系统及去甲肾上腺素的释放有关。作者综述了电压门控钙通道在调节阿片类物质的药理作用方面的研究进展。     

三种非阿片小肽对吗啡耐受调节的研究进展

吗啡等阿片类镇痛药反复使用造成的镇痛耐受是临床上的一大难题.近期的研究表明,内皮素、P物质前体分子-前体速激肽及黑皮素等三种非阿片小肽与吗啡镇痛和耐受密切相关.内皮素通过内皮素A受体(ETAR)、黑皮素通过黑皮素4受体(MC4R)分别以不同机制调节吗啡镇痛并能够预防其耐受的发生,而前体速激肽则可能是调控吗啡镇痛和耐受的关键分子,本文综述了上述非阿片小肽对吗啡耐受调节的研究进展,以期为吗啡耐受的治疗提供新的思路.     

丁丙诺啡复合芬太尼术后静脉镇痛效果观察

阿片类镇痛药芬太尼临床应用自控静脉镇痛（Patient—controlled intravenous analgesia,PCIA）广泛,但它对呼吸中枢及平滑肌有一定的抑制。丁丙诺啡是混合型阿片受体激动一拮抗剂,可以选择性地激动κ、μ受体,在硬膜外镇痛效应强、持续时间久,呼吸抑制和药物依赖发生率较低,但在静脉镇痛中报道较少。本研究应用丁丙诺啡复合芬太尼于术后自控静脉镇痛,观察镇痛效应及不良反应,了解丁丙诺啡复合芬太尼在患者自控镇痛中的作用特点。     

μ阿片受体在吗啡镇痛耐受中的研究进展

罂粟未成熟蒴果浆汁的干燥物称为阿片,含20余种生物碱,吗啡是其中之一。具有镇静、镇痛、镇咳及抑制肠蠕动的作用,广泛用于临床。研究显示[1],中度至重度疼痛的治疗大部分依赖于阿片类药物的使用,但长期使用可产生吗啡耐受。"耐受"是指持续应用某物质一定时间后,继续应用相同数量的物质产生的效应降低,必须增加剂量方可达到先前的效应强度。吗啡耐受常使其临床应用受到影响和限制。吗啡主要通过激动μ阿片受体(mu-opioid receptor,     

骨转移癌疼痛治疗现状

1药物治疗1．1非甾体消炎药物和阿片类药物治疗非甾体消炎药物通过抑制环氧化酶,减少损伤组织中炎症介质的生成;阿片类药物则通过与中枢神经系统内外特异性受体结合而产生镇痛效果,两者镇痛机制不同,联合用药比单独用药效果好且不良反应少。非甾体消炎药物对轻度疼痛非常有效,但其镇痛作用有极限,且有肝、肾损害和出血、溃疡等不良反应,因此,老年患者应特别注意;阿片类药物没有镇痛极限,可把剂量调整至获得最大疗效。     

舒芬太尼的研究进展

阿片类药物的镇痛效应主要是激动μ1受体,而μ2受体兴奋可导致呼吸抑制和成瘾等不良反应。舒芬太尼对μ1受体具有高度选择性,对δ受体亲和力小。因而它是芬太尼家族中镇痛作用最强、镇痛持续时间最长的阿片受体激动剂。因其强大的镇痛作用和较长的镇痛时间,临床上广泛用于全麻诱导、维持及术后镇痛等。与等效剂量的芬太尼相比,在     

瑞芬太尼对中老年患者心率变异性的影响

瑞芬太尼是一种新型阿片受体激动剂,药效强、起效快、剂量容易控制。但瑞芬太尼也像其它阿片类药物一样,除了有镇痛作用之外,也有呼吸抑制和循环抑制、肌僵直、术后恶心、     

一种新发现的内阿片肽-孤啡肽及其受体

一种新发现的内阿片肽－孤啡肽及其受体张秀琳刘明远关键词阿片肽孤啡肽中图法分类号Ｒ９６９６６内源性阿片肽及外源性阿片生物碱通过中枢及外周阿片受体发挥多种生物学作用及药理作用，如镇痛、缩瞳、呼吸抑制、欣快感及耐受。自从１９７３年ｓｙｎｄｅｒ等三个实验室...     

CREB-药物依赖性和某些CNS疾病药物治疗的潜在新靶标

cAMP反应元件结合蛋白（CREB）药物依赖性产生研究方面已经取得了有意义的进展,特别是阿片类药物依赖性的产生以及产生的CREB机制方面,为研究药物依赖性的产生及防治提供了新思路。已知G蛋白-cAMP-CREB途径是躯体依赖和精神依赖共同的受体后机制,是阿片类药物依赖性产生的主要途径之一,CREB通过影响基因表达而影响药物依赖性产生。此外,CREB还促进长时程记忆和可能参与抑郁症发病机制。CREB可能成为某些中枢神经疾病药物治疗的新靶标。     

吗啡代谢产物的药理作用

吗啡主要在肝脏与葡糖苷酸结合并产生两种代谢产物：吗啡-3-葡糖苷酸(M3G)和吗啡-6-葡糖苷酸(M6G)。M6G能结合阿片受体，动物实验显示其镇痛作用比吗啡强，不良反应较轻微。M3G与阿片受体亲和力较低，没有镇痛作用，且动物实验表明M3G能对抗吗啡和M6G的镇痛作用，可能参与吗啡耐受的形成。本文综述了吗啡的代谢过程及其代谢产物的药理作用。     

IL—6相关基因的克隆与鉴定

目的：克隆和鉴定IL－6作用相关基因将有助于揭示IL－6信号转导机制和发现新的信号分子,方法：以来源于IL－6处理和未处理的U937细胞mRNA的双链cDNA作为检测子和驱动子,进行cDNA代表性异分析,结果：分离了14个差异表达基因序列（EST）,反向RNA Nortghern杂交筛选到9个差异表达序列,经测序及序列分析,其中7个差异表达的EST代表在细胞生命活动或信号转导中有重要的作用的已知基因,2个EST代表与IL－6作用相关的新基因,Northern印迹和时间表达普进一步证明了P52和P31代表的新基因与IL－6作用的相关性,结论：上述结果提示这些差异cDNA序列可能与IL－6信号转号作用密切相关。     

SPECT、PET神经受体和转运体显像技术在海洛因成瘾研究中的应用

海洛因滥用导致了严重的社会、经济和健康问题。目前对海洛因成瘾机制的研究有了一定的进展,但是其神经递质、受体机制仍不清楚。该文综述了海洛因成瘾的潜在神经生物学机制及SPECT、PET神经受体和转运体显像技术在海洛因成瘾研究中的应用。     

Antioxidant regulation of cell adhesion

Cell-cell and cell-matrix contacts are dependent on cell surface density, localization, and avidity state of surface-localized adhesion molecules. Cell adhesion represents a process that is centrally important in immune function and inflammation. This process is sensitive to various agonists including oxidants. Oxidants may directly as well as indirectly induce cell adhesion. In other cases, cytokines and related agents may induce cell adhesion by oxidant-dependent mechanisms. Various redox-sensitive sites in the signal transduction path leading to cell adhesion have been identified. Different chemical classes of nutritional antioxidants regulate cell adhesion by modulating specific signal transduction pathways. Numerous studies have confirmed that physical exercise influences the redox status of various cells and tissues. Recent evidences also show that physical exercise influences several cell adhesion related molecules. Whether such regulation has a redox component remains to be tested. Antioxidant supplementation studies testing the effect of exercise on cell adhesion should provide critical insight.     

50-Hz magnetic field induces EGF-receptor clustering and activates RAS

PURPOSE: In a previous study, we found that exposure to a 50 Hz magnetic field (MF) could activate stress-activated protein kinase (SAPK) and P38 mitogen-activated protein (MAP) kinase (P38 MAPK) in Chinese hamster lung (CHL) fibroblast cells, and simultaneous exposure to a 'noise' MF of the same intensity inhibited these effects. In order to explore the possible target sites and upstream signal transduction molecules of SAPK and P38 MAPK, and further validate the interference effects of 'noise' MF on 50 Hz MF, the effects of MF exposure on clustering of epidermal growth factor (EGF) receptors and Ras protein activation were investigated. MATERIALS AND METHODS: CHL cells were exposed to a 50 Hz sinusoidal MF at 0.4 mT for different durations, and clustering of EGF receptors on cellular membrane and Ras protein activation were analyzed using immunofluorescence confocal microscopy and co-precipitation technology. EGF treatment served as the positive control. RESULTS: The results showed that, compared with sham-exposed cells, exposure to a 50 Hz MF at 0.4 mT for 5 min slightly induced EGF receptor clustering, whereas exposure for 15 min enhanced receptor clustering significantly. Corresponding to receptor clustering, Ras protein was also activated after exposure to the 50 Hz MF. Exposure to a 'noise' MF (with frequency ranges from 30 - 90 Hz) at the same intensity and durations, did not significantly affect EGF receptor clustering and Ras protein. However, by superimposing the 'noise' MF, receptor clustering and Ras activation induced by 50 Hz MF were inhibited. CONCLUSION: The results suggested that membrane receptors could be one of the most important targets where extremely low frequency (ELF) MF interacts with cells, and Ras may participate in the signal transduction process of 50 Hz MF. Furthermore, a 'noise' MF could inhibit these effects caused by ELF-MF.     

Opioids and exercise. An update

A number of endogenously produced opioid peptides interact with centrally and peripherally located specific receptors to form a widespread neuroendocrine system with many implications for human function. It is becoming increasingly evident that moderately high and high intensity exercise stimulate the release of the opioid peptide beta-endorphin to the circulation and this event may be subject to considerable intra- and interindividual variation. Moreover, endorphin levels probably remain elevated for 15 to 60 minutes following exercise. The duration of exertion does not seem to be critical, and low or moderate (less than 75% VO2max) intensity efforts do not stimulate this response. It also appears (mostly from animal model research) that exercise might elicit central opioid effects, but there is conflicting evidence on this topic. Physical training may encourage adapted opioid system function (e.g. altered peptide response to exercise or receptor number), but these adaptations are not well elucidated by the few existing studies. The significance of peripherally released opioid peptides during exercise has frequently been questioned. Exercise-induced affective response (e.g. mood enhancement), analgesia, food intake suppression and reproductive dysfunction are often mentioned as potentially controlled by an opioid mediated mechanism. While most of these events are normally considered under central control, it is time we begin entertaining the notion of peripheral effects (e.g. altered catecholamine release) and afferent input affecting central function in some of these phenomena. Additionally, evidence exists to suggest peripherally released enkephalins may cross the blood-brain barrier, but this is probably not true for endorphins. A number of other reported exercise-related events could possibly involve an underlying opioid mechanism. Exercise-associated metabolic regulation, immunosuppression, and cardiovascular function are areas for future opioid research.     

50-Hz magnetic field induces EGF-receptor clustering and activates RAS

Purpose: In a previous study, we found that exposure to a 50 Hz magnetic field (MF) could activate stress-activated protein kinase (SAPK) and P38 mitogen-activated protein (MAP) kinase (P38 MAPK) in Chinese hamster lung (CHL) fibroblast cells, and simultaneous exposure to a ‘noise’ MF of the same intensity inhibited these effects. In order to explore the possible target sites and upstream signal transduction molecules of SAPK and P38 MAPK, and further validate the interference effects of ‘noise’ MF on 50 Hz MF, the effects of MF exposure on clustering of epidermal growth factor (EGF) receptors and Ras protein activation were investigated.

Materials and methods: CHL cells were exposed to a 50 Hz sinusoidal MF at 0.4 mT for different durations, and clustering of EGF receptors on cellular membrane and Ras protein activation were analyzed using immunofluorescence confocal microscopy and co-precipitation technology. EGF treatment served as the positive control.

Results: The results showed that, compared with sham-exposed cells, exposure to a 50 Hz MF at 0.4 mT for 5 min slightly induced EGF receptor clustering, whereas exposure for 15 min enhanced receptor clustering significantly. Corresponding to receptor clustering, Ras protein was also activated after exposure to the 50 Hz MF. Exposure to a ‘noise’ MF (with frequency ranges from 30 – 90 Hz) at the same intensity and durations, did not significantly affect EGF receptor clustering and Ras protein. However, by superimposing the ‘noise’ MF, receptor clustering and Ras activation induced by 50 Hz MF were inhibited.

Conclusion: The results suggested that membrane receptors could be one of the most important targets where extremely low frequency (ELF) MF interacts with cells, and Ras may participate in the signal transduction process of 50 Hz MF. Furthermore, a ‘noise’ MF could inhibit these effects caused by ELF-MF.     

GABAergic mechanisms of heroin-induced brain activation assessed with functional MRI.

Heroin has been hypothesized to activate opiate receptors and inhibit gamma-aminobutyric acid (GABA) release from inhibitory GABAergic interneurons which, in turn, activates dopamine projection cells. Since the distal sites and consequences of this disinhibition are not well understood on a systems level, heroin-induced brain activity was measured using functional MRI (fMRI) in rats. A significant blood oxygen level-dependent (BOLD) signal increase was seen in cortical regions, including prefrontal cortex, cingulate, and olfactory cortex following acute heroin administration. In contrast, a significant signal decrease was seen in several subcortical areas, including the caudate and putamen, nucleus accumbens, thalamus, and hypothalamus. Pretreatment of gamma-vinyl GABA (GVG), an irreversible GABA transaminase inhibitor, significantly attenuated the heroin-induced BOLD signal changes. Pretreatment of naloxone, an opiate mu receptor antagonist, eliminated the heroin-induced BOLD signal changes and posttreatment of naloxone reversed the heroin-induced BOLD signal changes. It is suggested that the heroin-induced negative and positive BOLD changes are due to direct inhibitory and indirect disinhibitory mechanisms of GABAergic activities. Administration of GVG altered these mechanisms and further suggested that involvement of the opiate's pharmacological actions can, at least in part, be mediated by inhibiting brain GABA release.     

Cellular and neurophysiological effects of high ambient pressure.

The observed cellular effects of pressure are entirely compatible with the acute manifestations of CNS hyperexcitability. Inhibition of the glycine receptor will reduce post-synaptic inhibition, leading to increased excitability (cf 'Startle Disease', an hereditary disease with increased excitability arising from a genetic modification to the glycine receptor (Becker et al., 2002)). Since glycine-mediated neurotransmission is particularly associated with motor reflex circuits (Lynch, 2004) it is not surprising that many of the acute manifestations of pressure involve motor dysfunction. Potentiation by pressure of the NR1-NR2C subtype of the NMDA-sensitive glutamate receptor will lead to increased excitability within the cerebellum (where this receptor sub-type is most highly expressed (Monyer et al., 1994)). Although the cerebellum receives input from many parts of the nervous system, it projects primarily to the motor and frontal lobe cognitive areas. Thus dysfunction of the glutamate-mediated excitatory neurotransmission in this area is most likely to result in locomotor and cognitive symptoms, characteristic of acute pressure effects. Finally, the effects observed on AC/cAMP intracellular signalling, probably mediated via dopamine receptors, is also likely to produce motor dysfunction (cf Parkinson's disease). The observed cellular effects also suggest potential mechanisms that could result in long-term CNS dysfunction. Potentiation of glutamate neurotransmission is likely to lead to excessive calcium entry into those neurons. This may trigger excitotoxicity via a signal cascade in which neuronal NO synthase is activated producing the toxic free radical peroxynitrite and activation of the proapoptotic protein poly(ADP-ribose) polymerase (Aarts & Tymianski, 2005). An additional mechanism, also initially triggered by a rise in intracellular calcium through NR1-NR2C receptors, involves activation of a member of the Transient Receptor Potential (TRP) channel superfamily, the TRPM-7 channel. Activation of these channels will cause a further rise in intracellular calcium, creating a positive feedback and generating more neuronal death through the toxic signal cascade (Aarts & Tymianski, 2005). Neuronal cell death within the cerebellum might be expected to give rise to delayed motor and cognitive dysfunction the magnitude of which would tend to be related to the extent of hyperbaric exposure. There is at present no evidence that these excitotoxic mechanisms are triggered by exposure to pressure but future experimental work should investigate the extent to which pressure might activate them.