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鞘内注射NMDA拮抗吸入麻醉药的镇痛作用 总被引:11,自引:10,他引:11
目的探讨脊髓NMDA受体与吸入麻醉药安氟醚、异氟醚、七氟醚镇痛作用的关系。方法建立小鼠注射吸入麻醉药镇痛模型,用热板法和扭体法实验分别观察鞘内注射(it)不同剂量的NMDA对其痛阈的影响。结果NMDA2.5、5、10 ng it对清醒小鼠热板法痛阈(Pain threshold in hot-p late test,HPPT)和扭体次数无明显影响(P>0.05);NMDA2.5、5、10 ng it可剂量依赖性地减少安氟醚、异氟醚、七氟醚镇痛小鼠的HPPT(P<0.05)和增加扭体反应的次数(P<0.05)。结论脊髓的NMDA受体是吸入麻醉药安氟醚、异氟醚、七氟醚镇痛作用的重要靶位。 相似文献
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神经元再生已受到越来越多学科的重视。要减少脑中风后遗症和脑脊髓外伤等所致的残疾,关键是实现神经元再生,修复受损的神经网络环路。在神经元再生过程中,r-氨基丁酸(GABA)受体和N-甲基-D-天门冬氨酸(NMDA)受体起着十分重要的作用。一些麻醉药物正是通过与GABA受体和NMDA受体结合起麻醉作用的。本文就麻醉药物影响神经元再生的研究进展进行综述。 相似文献
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全身麻醉是由全身麻醉药可逆地改变行为和生理状态--意识消失、遗忘、镇痛以及肌肉松弛,同时伴随自主神经系统、心血管系统、呼吸系统和体温调节系统的变化[1]。全身麻醉药物导致意识消失的过程需要大脑不同区域共同参与,研究显示全身麻醉药的重要靶点γ‐氨基丁酸A型(γ‐aminobutyric acid type A ,GABAA)受体和N‐甲基天冬氨酸(N‐methyl‐Daspartate ,NMDA)受体广泛分布于皮层、丘脑、脑干和纹状体[2];脑功能成像研究发现麻醉药导致的意识消失与深睡眠之间有一定的相似性[3],毁损或失活睡眠‐觉醒相关核团,如蓝斑,桥脑脚被盖核和结节乳头状核,可增强全身麻醉的效能[4]。探寻全身麻醉意识消失机制需对中枢神经系统进行深入研究,即探讨全麻药物在特定神经环路的作用以及全身麻醉意识消失与睡眠‐觉醒环路的关系。 相似文献
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全身麻醉药主要通过正向调控中枢γ-氨基丁酸A型受体使意识可逆性消失,是外科手术中达到理想全身麻醉状态的必须药物.随着全身麻醉药临床应用经验的积累以及新研究技术、方法的发展,其具有的一些潜在临床应用方向和线索被发现,如器官保护作用、抗肿瘤作用、抗精神病作用和抗癫痫作用.不同的全身麻醉药在药效作用和临床应用方向上存在差异,... 相似文献
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《中国新药与临床杂志》2015,(5)
越来越多研究表明,除单胺神经递质外,谷氨酸及相关受体在抑郁症病因中也扮演了重要的角色,特别是N-甲基-D-天冬氨酸(NMDA)受体,有证据表明NMDA受体的过度激活是抑郁障碍的病理生理机制之一。本文总结了谷氨酸及相关受体与抑郁障碍的关系,对NMDA受体成为潜在抗抑郁药靶点做一简要讨论。 相似文献
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胍丁胺是一种新的神经递质和/或神经调质,是咪唑啉受体的内源性配体。它作为一种阳离子胺类物质,除了咪唑啉受体外,在生物体内还存在多个作用靶点,NMDA受体是其中最重要的作用靶点之一。本文就胍丁胺与NMDA受体在中枢神经系统的分布、胍丁胺在NMDA受体上的作用位点以及胍丁胺通过NMDA受体介导的药理作用等几个方面进行了综述。 相似文献
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Laura C. Daniell 《Pharmacology, biochemistry, and behavior》1991,40(4):767-769
CGS 19755 is a competitive N-methyl-D-aspartate (NMDA) receptor antagonist which penetrates the blood-brain barrier. The effect of pretreatment with subanesthetic doses of CGS 19755 on general anesthetic potency was determined in mice. Mice were pretreated with saline or CGS 19755 by intraperitoneal (IP) administration 30 min before IP administration of an anesthetic dose of ethanol or pentobarbital or measurement of the volatile anesthetic minimum alveolar concentration (MAC). CGS 19755 increased the duration of ethanol- and pentobarbital-induced loss of righting reflex in a dose-dependent manner. The highest dose of CGS 19755 tested, 50 mg/kg, increased duration of loss of righting reflex by about four- and twofold for ethanol and pentobarbital, respectively. CGS 19755 also decreased the MAC for halothane. However, CGS 19755 pretreatment had no effect on the MAC for diethyl ether. These results suggest that the potency of certain general anesthetic agents can be increased by antagonism of brain NMDA receptors. 相似文献
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The noncompetitive N-methyl-D-aspartate antagonists, MK-801, phencyclidine and ketamine, increase the potency of general anesthetics 总被引:5,自引:0,他引:5
L C Daniell 《Pharmacology, biochemistry, and behavior》1990,36(1):111-115
The potency of general anesthetics from different chemical classes was tested after pretreatment with subanesthetic doses of noncompetitive N-methyl-D-aspartate (NMDA) antagonists in mice. Changes in general anesthetic potency were assessed by determination of alteration of duration of loss of righting reflex for ethanol and pentobarbital and changes in the minimum alveolar concentration (MAC) for the volatile anesthetics, halothane and diethyl ether. The ability of the noncompetitive NMDA antagonists, MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclo-hepten-5,10-imine ], phencyclidine (PCP) and ketamine, to increase the potency of general anesthetics paralleled their potency as NMDA antagonists and their affinity for the PCP receptor site of the NMDA receptor-ionophore complex (MK-801 greater than PCP greater than ketamine). These results indicate that block of central NMDA receptors may contribute to the production of anesthesia by a variety of agents. 相似文献
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Wood PL 《IDrugs : the investigational drugs journal》2005,8(3):229-235
Advances in our basic understanding of inhibitory and excitatory amino acid neurotransmission have provided the foundation for directed drug discovery programs to modulate inhibitory GABAergic and excitatory N-methyl-D-aspartate (NMDA) receptor-mediated synapses. Gamma-Amino butyric acid (GABA(A)) and NMDA receptors are complex ion channels formed by multiple protein subunits that act as binding sites for transmitter amino acids and as allosteric regulatory binding sites to regulate ion channel activity. In the case of the NMDA receptor complex, one such allosteric site binds the obligatory glycine and/or d-serine co-agonist. Historical data from preclinical and clinical studies of GABAergic agents have clearly demonstrated that direct receptor modulators lack sufficient therapeutic indices to warrant clinical utility. However, pharmacological modulation of allosteric sites of the GABA multimeric receptor has resulted in the clinical development of safe and efficacious agents, exemplified by the benzodiazepines. Research has also revealed a similar outcome for the NMDA receptor, with allosteric modulators demonstrating improved safety profiles in the modulation of excitatory amino acid (EAA) transmission compared with direct NMDA receptor antagonists. First-generation EAA drugs were low affinity channel blockers of the NMDA multimeric receptor complex and included the anesthetic agent ketamine and the Alzheimer's drug memantine. As predicted by preclinical studies, direct NMDA receptor antagonists (eg, selfotel (Novartis AG) and high-affinity channel blockers (eg, dizocilpine) failed in the clinic as a result of narrow therapeutic indices. More recent efforts have focused on glycine/d-serine co-agonist function. These approaches include partial glycine agonists, in their agonist dose-range, for cognitive improvement and for treating schizophrenia. Such partial glycine agonists are also being advanced for the treatment of neuropathic pain in the antagonist dose range. An alternate approach to partial glycine agonists is to inhibit the uptake carrier(s) for glycine (ie, GlyT-1 and GlyT-2), thereby potentiating the lifetime of synaptic glycine. A number of glycine uptake inhibitors have been reported and their preclinical profiles support investigation into their utility in treating schizophrenia. 相似文献
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Cheng Wang Natalya Sadovova Charlotte Hotchkiss Xin Fu Andrew C Scallet Tucker A Patterson Joseph Hanig Merle G Paule William Slikker 《Toxicological sciences》2006,91(1):192-201
Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, is used as a general pediatric anesthetic. Recent data suggest that anesthetic drugs may cause neurodegeneration during development. The purpose of this study was to determine the robustness of ketamine-induced developmental neurotoxicity using rhesus monkey frontal cortical cultures and also to determine if dysregulation of NMDA receptor subunits promotes ketamine-induced cell death. Frontal cortical cells collected from the neonatal monkey were incubated for 24 h with 1, 10, or 20 microM ketamine alone or with ketamine plus either NR1 antisense oligonucleotides or the nuclear factor kB translocation inhibitor, SN-50. Ketamine caused a marked reduction in the neuronal marker polysialic acid neural cell adhesion molecule and mitochondrial metabolism, as well as an increase in DNA fragmentation and release of lactate dehydrogenase. Ketamine-induced effects were blocked by NR1 antisenses and SN-50. These data suggest that NR1 antisenses and SN-50 offer neuroprotection from the enhanced degeneration induced by ketamine in vitro. 相似文献
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Xuan Zhang Merle G. Paule Cheng Wang William Slikker Jr 《Journal of applied toxicology : JAT》2013,33(9):861-868
Advances in pediatric and obstetric surgery have resulted in an increase in the complexity, duration and number of anesthetic procedures. Currently, the general anesthetics that are used most often have either NMDA receptor blocking or GABA receptor activating properties. It has been reported that prolonged exposure of the developing brain to a clinically relevant concentration of anesthetics that have NMDA antagonist or GABA‐mimetic properties, and/or their combinations, resulted in an extensive abnormal pattern of neuroapoptosis, and subsequent cognitive deficits in animals. Molecular imaging using positron emission tomography (PET) is a leading modality for obtaining non‐ or minimally invasive in vivo measurements of multiple biological processes in various organs. The development of microPET imaging applications has provided the ability to collect sensitive and quantitative three‐dimensional molecular information from the living brains of a variety of animals. The main aim of this review was to describe molecular imaging approaches that have been used in the study of pediatric anesthetic‐induced neuronal toxicity. Published 2013. This article is a US Government work and is in the public domain in the USA. 相似文献
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Lindsley CW Shipe WD Wolkenberg SE Theberge CR Williams DL Sur C Kinney GG 《Current topics in medicinal chemistry》2006,6(8):771-785
This article describes recent progress towards validation of the N-methyl-D-aspartate (NMDA) receptor hypofunction hypothesis of schizophrenia in preclinical models. Schizophrenia, a complex disease characterized by positive, negative and cognitive symptoms, affects 1% of the world population and requires lifelong, daily maintenance therapy. For the last several decades, thinking in this field has been dominated by the hypothesis that hyperfunction of dopamine pathways played a key role in schizophrenia. However, the therapeutic agents developed from this hypothesis have a slow onset of action and tend to improve only the positive symptoms of the disease. The NMDA receptor antagonist PCP has been shown to induce the positive, negative and cognitive symptoms of schizophrenia in healthy patients and cause a resurgence of symptoms in stable patients. These observations led to the NMDA receptor hypofunction hypothesis as an alternative theory for the underlying cause of schizophrenia. According to this hypothesis, any agent that can potentiate NMDA receptor currents has the potential to ameliorate the symptoms of schizophrenia. To date, NMDA receptor currents can be modulated by either direct action on modulatory sites on the NMDA receptor (i.e., the glycine co-agonist binding site) or indirectly by activation of G-protein coupled receptors (GPCRs) known to potentiate NMDA receptor function (i.e., mGluR5). This review will discuss the NMDA receptor hypofunction hypothesis, the NMDA receptor as an emerging target for the development of novel antipsychotic agents and progress towards in vivo target validation with GlyT1 inhibitors and mGluR5 positive allosteric modulators. Other potential targets for modulating NMDA receptor currents (polyamine sites, muscarinic receptors, etc...) will also be addressed briefly. 相似文献
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The NMDA receptor is an important target for drug development, with agents from many different classes acting on this receptor. While the severe side effects associated with complete NMDA receptor blockade have limited clinical usefulness of most antagonists, the understanding of the multiple forms of NMDA receptors provides an opportunity for development of subtype specific agents with potentially fewer side effects. Different NMDA receptor subtypes are assembled from combinations of NR1 and NR2 subunits with each subunit conveying distinct properties. The NRI subunit is the glycine binding subunit and exists as 8 splice variants of a single gene. The glutamate binding subunit is the NR2 subunit, which is generated as the product of four distinct genes, and provides most of the structural basis for heterogeneity in NMDA receptors. Pharmacological heterogeneity results from differences in the structure of ligand binding regions, as well as structural differences between subtypes in a modulatory region called the LIVBP-like domain. This region in NR1 and NR2B controls the action of NR2B-selective drugs like ifenprodil, while this domain in receptors containing the NR2A subunit controls the action of NR2A-selective drugs such as zinc. This suggests that NMDA receptor subtype selective drugs can be created, and further understanding of subtype specific mechanisms ultimately may allow successful use of NMDA receptor antagonists as therapeutic agents. 相似文献
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In recent years great progress has been made in understanding the function of ionotropic and metabotropic glutamate receptors; their pharmacology and potential therapeutic applications. It should be stressed that there are already N-methyl-D-aspartate (NMDA) antagonists in clinical use, such as memantine, which proves the feasibility of their therapeutic potential. It seems unlikely that competitive NMDA receptor antagonists and high-affinity channel blockers will find therapeutic use due to limiting side-effects, whereas agents acting at the glycineB site, NMDA receptor subtype-selective agents and moderate-affinity channel blockers are far more promising. This is supported by the fact that there are several glycineB antagonists, NMDA moderate-affinity channel blockers and NR2B-selective agents under development. Positive and negative modulators of AMPA receptors such as the AMPAkines and 2,3-benzodiazepines also show more promise than e.g. competitive antagonists. Great progress has also been made in the field of metabotropic glutamate receptors since the discovery of novel, allosteric modulatory sites for these receptors. Selective agents acting at these transmembrane sites have been developed that are more drug-like and have a much better access to the central nervous system than their competitive counterparts. The chapter will critically review preclinical and scarce clinical experience in the development of new ionotropic and metabotropic glutamate receptor modulators according to the following scheme: rational, preclinical findings in animal models and finally clinical experience, where available. 相似文献