Stargazin调节使君子酸受体亚基转运和突触靶向——疼痛治疗的新靶点

背景 使君子酸(α-amino-3 -hydroxy-5 -methy-4-isoxazole propionate,AMPA)受体是中介中枢神经系统兴奋性突触传递的主要受体,参与疼痛信号传递.Stargazin蛋白是一种AMPA受体调节蛋白,在AMPA受体中介的疼痛信号传递中扮演重要角色.目的 对Stargazin蛋白调节AMPA受体亚基在胞浆胞膜中的转运作用及与疼痛的关系作用进行回顾与总结.内容 Stargazin蛋白可调节AMPA受体不同亚基在胞浆胞膜转运,并通过与突触后膜致密蛋白-95 (postsynaptic density-95,PSD-95)的相互作用,促进AMPA受体亚基突触靶向；Stargazin还通过C末端自身磷酸化修饰改变与PSD-95蛋白相互作用的强度,控制AMPA受体的突触靶向.Stargazin通过调节AMPA受体的转运,间接调控AMPA受体中介的疼痛信号传递.趋向 下调Stargazin的表达或干扰其与兴奋性突触后PSD-95蛋白的相互作用,可间接抑制AMPA受体的功能,是未来疼痛治疗研究的新靶点.     

糖皮质激素受体参与阿片耐受机制的研究进展

阿片药物耐受是影响临床应用阿片类药物进行疼痛治疗的主要问题.阿片药物耐受机制复杂,有许多调节因素参与其中.近年的研究提示,糖皮质激素受体在阿片耐受机制的各个环节中均发挥调节作用.如能合理利用糖皮质激素受体的这种调节作用,来找到治疗阿片耐受的突破点,将为难治性疼痛的治疗带来福音.     

组胺受体1和2拮抗药对神经病理性疼痛的疗效

目的 探讨脑室内注射组胺受体拮抗药对神经病理性疼痛大鼠的治疗作用.方法 选择左侧坐骨神经部分结扎致神经病理性疼痛大鼠30只,随机均分为五组.对照组(C组)脑室内注射生理盐水;P1、P2组分别注射组胺受体1拮抗药美吡拉敏1.5 μg和15 μg;R1、R2组注射组胺受体2拮抗药雷尼替丁10μ和100 μg,评价注药后痛阈的改变.结果 与C组相比,R1、R2组雷尼替丁能显著提高大鼠对机械性刺激的痛阈(P<0.05);且R2组对疼痛的治疗效果加强,时间延长.结论 神经病理性疼痛时,采用组胺受体2拮抗药能提高痛阈,缓解疼痛.     

N-甲基-D-天冬氨酸受体参与神经病理性疼痛的机制研究进展

背景 N-甲基-D-天冬氨酸(N- methyl- D- aspartate,NMDA)受体依赖的神经可塑性不仅与学习、记忆等生理学功能有关,而且在慢性痛等伤害性病理学损伤中发挥重要作用.目的 就NMDA受体在神经病理性疼痛的研究进展作简要介绍. 内容 探讨NMDA受体在疼痛传输通路中的表达及作用的相关机制.趋向 为更好地治疗神经病理性疼痛(neuropathic pain,NP)提供理论依据.     

炎症因子参与神经病理性疼痛-抑郁共病的研究进展

背景 神经病理性疼痛与抑郁症共病严重影响了患者的生活质量.近年来研究发现,炎症因子在神经病理性疼痛抑郁共病发病中起重要作用.目的 综述炎症因子参与神经病理性疼痛抑郁共病的研究进展,为该病的有效防治提供参考 内容 神经病理性疼痛与感觉系统的功能障碍相关,它包括触诱发痛、痛觉过敏、自发痛等一系列疼痛症状.抑郁症表现为心境低落和厌恶活动.小胶质细胞激活后,释放的炎症因子如TNF-α、IL-6、IL-1β,通过结合5-羟色胺受体、谷氨酸盐受体、γ-氨基丁酸能受体及激活下丘脑-垂体-肾上腺素轴促进神经病理性疼痛和抑郁症的发生.趋向 炎症因子可能是治疗神经病理性疼痛-抑郁共病的靶标.     

δ-阿片受体抑制阿片诱发痛觉过敏的研究进展

背景 阿片类药物是治疗中、重度疼痛的主要药物,长时间应用可出现阿片诱发的痛觉过敏和耐受,而增加药物剂量可造成更严重的痛觉过敏和耐受,从而形成恶性循环,很大程度上限制了阿片类药物在临床工作中的应用.目的 通过对近年δ-阿片受体在痛觉过敏中所起作用的研究进行总结,帮助读者了解国外相关研究的最新趋势和进展.内容 就δ-阿片受体的结构、分布、生理功能和δ-阿片受体的抗痛觉过敏作用的研究进展进行综述.得出如下结论,通过抑制δ-阿片受体磷酸化、敲除δ-阿片受体编码基因和应用δ-阿片受体拮抗剂等方法,可抑制痛觉过敏和耐受的形成.趋向 随着越来越多的学者对δ-阿片受体抑制痛觉过敏的作用达成共识,δ-阿片受体有望成为临床疼痛治疗的新靶点.     

神经突触中枢神经突触膜相关鸟甘酸激酶锚定蛋白参与疼痛调节的研究进展

背景 中枢神经突触膜相关鸟苷酸激酶(membrane-associated guanylate kinase,MAGUK)蛋白家族包含4种突触相关蛋白:PSD-93、PSD-95、SAP-102、SAP-97,它们参与调节谷氨酸突触信号传递,与学习记忆和疼痛等有关. 目的综述神经突触MAGUK锚定蛋白与疼痛相关受体和分子之间的相互作用及其在疼痛信号调节及传递中的作用. 内容 神经突触MAGUK锚定蛋白可通过与N-甲基-D-天冬氨酸(N-methyl-D-aspartate,NMDA)受体、神经元型一氧化氮合酶(neuronal nitric oxide synthase,nNOS)、使君子酸(α-amino-3-hydroxy-5-methy-4-isoxazole propionate,AMPA)受体以及突触细胞黏附分子(synaptic cell-adhesion molecules,Syn CAM)等相互作用参与调节疼痛信号在突触的传递,影响突触传递强度. 趋向 干扰神经突触MAGUK锚定蛋白与疼痛相关受体和重要分子间的相互作用可影响疼痛信号在突触的传递,是疼痛治疗的新靶点.     

参与伤害性反应的代谢型谷氨酸受体及信号转导机制

代谢型谷氨酸受体(metabotropic glutamate receptors,mGluRs)是一类与G蛋白耦联的谷氨酸受体,在外周和脊髓参与伤害性信号的处理,并通过不同的细胞内信号转导机制,调节各种激酶、受体和离子通道的磷酸化以及转录因子的激活,是治疗疼痛的重要靶位.     

CC类趋化因子亚家族在神经病理性疼痛中的作用机制

背景 现有的药物对慢性疼痛的治疗效果不佳且副作用较大,因而需要寻找新的、安全有效的治疗方法.而最近研究发现,趋化因子及其受体在慢性疼痛的发生发展中起着重要的作用. 目的 综述趋化因子在慢性疼痛尤其是神经病理性疼痛中的作用机制. 内容 就趋化因子家族CC类亚家族参与疼痛调控的相关研究进行综述,阐述其在神经病理性疼痛发生发展中的可能作用机制. 趋向 越来越多的学者发现CC类亚家族参与神经病理性疼痛的发生发展,其有望成为临床上治疗慢性疼痛的一个新靶点.     

糖皮质激素参与疼痛信号调控的研究进展

背景 糖皮质激素用于临床急、慢性疼痛的治疗已有几十年历史,糖皮质激素受体通过多种机制参与了疼痛信号转导过程.目的 更好地了解糖皮质激素是如何通过细胞内信号分子而发挥镇痛作用,指导临床合理应用糖皮质激素.内容 从其抑制炎症反应和疼痛介质的产生,以及作用于一些相关受体,甚至参与阿片耐受机制等方面作一总结.趋向 目前对糖皮质激素的研究尚存在很多争议,研究其具体作用机制仍是基础研究的靶点之一.     

In Vitro Sarcoma Cells Release a Lipophilic Substance That Activates the Pain Transduction System via TRPV1

Background

Despite success in treating many forms of cancer, pain associated with malignancy remains a serious clinical issue with a poorly understood etiology. This study determined if certain sarcoma cell lines produced a soluble factor that activates the TRPV1 ion channel expressed on nociceptive sensory neurons, thereby activating a major pain transduction system.

Materials and Methods

Trigeminal ganglia were harvested from rats and cultured. A rhabdomyosarcoma (CRL1598) and osteosarcoma (CRL 1543) cell line were grown to 75% confluency. Conditioned media (CM) was collected after 24 h of exposure and subjected to reverse phase chromatography. Neuronal activation in the presence of CM was measured using iCGRP RIA and calcium imaging after treatment with vehicle or I-RTX, a potent TRPV1 antagonist. Data were analyzed by ANOVA/Bonferroni or t test.

Results

The rhabdomyosarcoma CM produced a 4-fold increase in iCGRP release compared with control media (P < 0.001). The osteosarcoma cell line CM produced a 7-fold increase in iCGRP release compared with control media (P < 0.001). This evoked iCGRP release was via TRPV1 activation since the effect was blocked by the antagonist I-RTX. The application of rhabdomyosarcoma CM produced about a 4-fold increase in [Ca²⁺]I levels (P < 0.001), and this effect was blocked by pretreatment with the TRPV1 antagonist, I-RTX.

Conclusions

We have shown that certain sarcoma cell lines produce a soluble, lipophilic factor that activates the peripheral nociceptor transduction system via TRPV1 activation, thereby contributing to cancer pain. Further investigations are needed to develop tumor-specific analgesics that do not produce unwanted or harmful side-effects.     

TRPV1在疼痛治疗中的作用及研究进展

TRPV1(transient receptorpotential vanilloid-1,TRPV1)作为一类与痛觉传递有密切联系的膜通道性受体,在介导炎性痛、内脏痛、癌痛甚至痛觉敏化等多种疼痛中均起重要作用.目前对于其生理学特点和调控痛觉的机制研究已取得巨大进展,如辣椒素等TRPV1激动剂、拮抗剂甚至相关药物的研制也有一定成绩,进一步思考如何合理运用RNAi等新型介入技术开发TRPV1在疼痛缓解上的潜在效能必将为临床疼痛的针对性治疗开辟一条新道路.     

Acid‐sensing ion channel 3 or P2X2/3 is involved in the pain‐like behavior under a high bone turnover state in ovariectomized mice

We have recently demonstrated that pathological changes leading to increased bone resorption by osteoclast activation are related to the induction of pain‐like behavior in ovariectomized (OVX) mice. In addition, bisphosphonate and the antagonist of transient receptor potential vanilloid type 1 (TRPV1), an acid‐sensing nociceptor, improved the threshold value of pain‐like behaviors accompanying an improvement in the acidic environment in the bone tissue based on osteoclast inactivation. The aim of this study was to evaluate the effect of (i) an inhibitor of vacuolar H⁺‐ATPase, known as an proton pump, (ii) an antagonist of acid‐sensing ion channel (ASIC) 3, as another acid‐sensing nociceptor, and (iii) the P2X2/3 receptor, as an ATP‐ligand nociceptor, on pain‐like behavior in OVX mice. This inhibitor and antagonists were found to improve the threshold value of pain‐like behavior in OVX mice. These results indicated that the skeletal pain accompanying osteoporosis is possibly associated with the acidic microenvironment and increased ATP level caused by osteoclast activation under a high bone turnover state. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:566–573, 2016.     

Capsaicin: A review of its pharmacology and clinical applications

Capsaicin is a naturally occurring alkaloid derived from chillies that is responsible for its hot pungent taste. It is an odourless fat soluble compound that is rapidly absorbed through the skin. Capsaicin is thought to produce analgesia by depleting substance P in small fibre nociceptor neurons on which Transient Receptor Potential action channel (subfamily V), type 1 (TRPV1) is predominantly located. It binds to the vanilloid receptor TRPV1, which acts as a molecular integrator of chemical and physical painful stimuli.Topically applied capsaicin is useful in alleviating pain associated with diabetic neuropathy and chronic musculoskeletal pain. It is used to increase the bladder capacity and reduce incontinence in patients with bladder hyperactivity. Capsaicin can reduce post-operative nausea and vomiting when applied at acupressure points. It may be used to treat pruritis associated with renal failure and protect the stomach against non-steroidal anti-inflammatory drug induced gastritis. The development of capsaicin analogues and TRPV1 antagonists may provide more effective and better tolerated therapeutic agents in the future. Synthetic agents that are less pungent and target the TRPV1 receptor may prove to be more efficacious and more tolerable than naturally occurring capsaicin for the treatment of pain and inflammatory disease states.     

Autonomous contractile activity in the isolated rat bladder is modulated by a TRPV1 dependent mechanism

AIMS: Resiniferatoxin (RTX), a vanilloid compound and agonist of the transient receptor potential channel 1 (TRPV1), is known for its beneficial effects on neurogenic detrusor overactivity. The mainstream rationale for its use is the desensitization of TRPV1 on sensory bladder afferents. However, recent findings showed that TRPV1 is present in other cell types in the bladder. To eliminate the effects of RTX on spinal and central neural circuits, we investigated autonomous contractility in normal and neurogenic rat bladders after treatment with RTX. METHODS: Female Wistar rats were made paraplegic at vertebral level T8-T9. Animals were intravesically pre-treated with vehicle (ethanol 5%) or RTX (100 nM) and sacrificed after 72 hr. Each bladder was excised and placed in a heated organ bath, where intravesical pressures were measured. Effects on contractile parameters of intravesical volume load, the non-selective muscarinic receptor agonist carbachol (CA) and electrical stimulation (ES) of nerves were studied in both groups. RESULTS: In RTX-treated normal bladders we found shorter contractions with higher amplitude than in control bladders (P < 0.05). In RTX-treated neurogenic bladders the amplitude and duration of autonomous contractions were increased compared with controls (P < 0.05). Furthermore RTX induced an increased response to CA and to ES (P < 0.05). CONCLUSIONS: RTX significantly affected the properties of autonomous bladder contractile activity. This provides evidence for local effects of RTX on bladder contractile activity, which are not mediated by afferent neural pathways and which may contribute to the beneficial effects on detrusor overactivity. TRPV1 and TRPV1(+) cells seem to play an important role in (autonomous) bladder contractility.     

TRPV4 ion channel as important cell sensors

This review provides a summary of the physiological significance of the TRPV4 ion channel. Although TRPV4 was initially characterized as an osmosensor, we found that TRPV4 can also act as a thermosensor or a mechanosensor in brain neurons or epithelial cells in the urinary bladder. Here, we summarize the newly characterized functions of TRPV4, including the research progress that has been made toward our understanding of TRPV4 physiology, and discuss other recent data pertaining to TRPV4. It is thought that TRPV4 may be an important drug target based on its broad expression patterns and important physiological functions. Possible associations between diseases and TRPV4 are also discussed.     

Microinjection of an adenosine A1 agonist into the medial pontine reticular formation increases tail flick latency to thermal stimulation

BACKGROUND: Both pain and the pharmacologic management of pain can cause the undesirable effect of sleep disruption. One goal of basic and clinical neuroscience is to facilitate rational drug development by identifying the brain regions and neurochemical modulators of sleep and pain. Adenosine is thought to be an endogenous sleep promoting substance and adenosinergic compounds can contribute to pain management. In the pontine brain stem adenosine promotes sleep but the effects of pontine adenosine on pain have not been studied. This study tested the hypothesis that an adenosine agonist would cause antinociception when microinjected into pontine reticular formation regions that regulate sleep. METHODS: The tail flick latency (TFL) test quantified the time in seconds for an animal to move its tail away from a thermal stimulus created by a beam of light. TFL measures were used to evaluate the antinociceptive effects of the adenosine A1 receptor agonist N6-p-sulfophenyladenosine (SPA). Pontine microinjection of SPA (0.1 microg/0.25 microl, 0.88 mm) was followed by TFL measures as a function of time after drug delivery and across the sleep-wake cycle. RESULTS: Compared with saline (control), pontine administration of the adenosine agonist significantly increased latency to tail withdrawal (P < 0.0001). The increase in antinociceptive behavior evoked by the adenosine agonist SPA was blocked by pretreatment with the adenosine A1 receptor antagonist 8-cyclopentyl-1, 3-dipropylxanthine (DPCPX, 0.75 ng/0.25 microl, 10 microm). CONCLUSIONS: These preclinical data encourage additional research on the cellular mechanisms by which adenosine in the pontine reticular formation contributes to the supraspinal modulation of pain.     

TRPV1 is involved in stretch-evoked contractile changes in the rat autonomous bladder model: a study with piperine, a new TRPV1 agonist

AIM: Vanilloids like capsaicin and resiniferatoxin (RTX) have been used for more than a decade in the treatment of neurogenic detrusor overactivity. Recently, the vanilloid molecule piperine (PIP) has been shown to have similar pharmacological properties as these drugs. In this study, we looked at PIP-effects on autonomous bladder contractile activity, with particular interest for its selectivity for the transient receptor potential channel 1 (TRPV1) receptor. Additionally, we studied the role of TRPV1 in volume-induced contractile changes using selective and non-selective TRPV1 antagonists. METHODS: The acute and prolonged effects of PIP were studied on rat bladders. Each bladder was excised and placed in a heated organ bath, where intravesical pressures were measured. In acute experiments, PIP was added directly to the bathing solution. For prolonged effects, animals were pre-treated intravesically with vehicle (ethanol 5%) or PIP (10(-4) M) and sacrificed 72 hr later. The effects of selective (capsazepine (CZP)) and non-selective (ruthenium red (RR)) TRPV1 antagonists on volume-evoked contractile parameters were also studied. RESULTS: Acute administration of PIP 10(-4) M significantly increased amplitude of bladder contractions (P < 0.05). These effects were significantly antagonized (P < 0.05) by the TRPV1-selective antagonist CZP (10(-5) M) and the non-selective TRP-antagonist RR (10(-5) M). Intravesical pre-treatment with PIP induced shorter contractions with more periods of non-activity (P < 0.05) compared to controls. Inhibition of TRPV1 with CZP and RR significantly reduced the volume-evoked rise in contractile amplitude in isolated bladders (P < 0.05). CONCLUSION: We found evidence for acute and prolonged effects of PIP on bladder contractility, which seem to be mediated through TRPV1. Furthermore, we found evidence for involvement of TRPV1 in afferent signaling of mechanical stimuli.     

The role of the transient receptor potential (TRP) superfamily of cation-selective channels in the management of the overactive bladder

? The pathophysiology of lower urinary tract symptoms (LUTS), detrusor overactivity (DO), and the overactive bladder (OAB) syndrome is multifactorial and remains poorly understood. ? The transient receptor potential (TRP) channel superfamily has been shown to be involved in nociception and mechanosensory transduction in various organ systems, and studies of the LUT have indicated that several TRP channels, including TRPV1, TRPV2, TRPV4, TRPM8, and TRPA1, are expressed in the bladder, and may act as sensors of stretch and/or chemical irritation. ? However, the roles of these individual channels for normal LUT function and in LUTS/DO/OAB, have not been established. ? TRPV1 is the channel best investigated. It is widely distributed in LUT structures, but despite extensive information on morphology and function in animal models, the role of this channel in normal human bladder function is still controversial. Conversely, its role in the pathophysiology and treatment of particularly neurogenic DO is well established. ? TRPV1 is co-expressed with TRPA1, and TRPA1 is known to be present on capsaicin-sensitive primary sensory neurones. Activation of this channel can induce DO in animal models. ? TRPV4 is a Ca(2+)-permeable stretch-activated cation channel, involved in stretch-induced ATP release, and TRPV4-deficient mice exhibit abnormal frequencies of voiding and non-voiding contractions in cystometric experiments. ? TRPM8 is a cool receptor expressed in the urothelium and suburothelial sensory fibres. It has been implicated in the bladder-cooling reflex and in idiopathic DO. ? The occurrence of other members of the TRP superfamily in the LUT has been reported, but information on their effects on LUT functions is scarce. There seem to be several links between activation of different members of the TRP superfamily and LUTS/DO/OAB, and further exploration of the involvement of these channels in LUT function, normally and in dysfunction, may be rewarding.