每周论文更新----9 Sep 2016

zhouxuelong0258

每周论文更新----9 Sep 2016
周伯通博士

本周推送两篇文章，分别来自Nature和Gut杂志。文章的题目分别为：The TRPM2 ion channel is required for sensitivity to warmth和Stress activates pronociceptive endogenous opioid signalling in DRG neurons during chronic colitis.

首先，第一篇

The TRPM2 ion channel is required for sensitivity to warmth

TRPM2离子通道对于躯体感知温度是必须的Tan CH, McNaughton PA.

Nature. 2016 Aug 25

PMID: 27533035

Abstract

Thermally activated ion channels are known to detect the entire thermal range from extreme heat (TRPV2), painful heat (TRPV1, TRPM3 and ANO1), non-painful warmth (TRPV3 and TRPV4) and non-painful coolness (TRPM8) through to painful cold (TRPA1). Genetic deletion of each of these ion channels, however, has only modest effects on thermal behaviour in mice, with the exception of TRPM8, the deletion of which has marked effects on the perception of moderate coolness in the range 10-25 °C. The molecular mechanism responsible for detecting non-painfulwarmth, in particular, is unresolved. Here we used calcium imaging to identify a population of thermally sensitive somatosensory neurons which do not express any of the known thermally activated TRP channels. We then used a combination of calcium imaging, electrophysiology and RNA sequencing to show that the ion channel generating heat sensitivity in these neurons is TRPM2. Autonomic neurons, usually thought of as exclusively motor, also express TRPM2 and respond directly to heat. Mice in which TRPM2 had been genetically deleted showed a striking deficit in their sensation of non-noxious warm temperatures, consistent with the idea that TRPM2 initiates a 'warm' signal which drives cool-seeking behaviour.

                               
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全文链接：http://www.nature.com/nature/jou ... ll/nature19074.html

这篇文章是八月底出来的，思考了一下，觉得还是应该推送给大家，毕竟热和痛不分家。现在已知的感受冷热的离子通道已经有很多种了，TRVP家族的TRVP1-3、然后还有TRAP1及TRPM3，以及感受冷的TRPM8等。似乎在这方面的研究已经没什么好再探讨的了，毕竟积累很多了。但是新技术的进步必然能带来新的发现。该文的作者通过高敏感的钙离子成像技术发现了一类新的温敏神经元（由于视频文件较大，传不上来，有兴趣可以去官网看看，很有意思），然后经过高通量的转录组测序（RNA-sequencing）后鉴定出热敏感离子通道TRPM2。这种离子通道能够感知热感范围在23-38摄氏度的温度觉，但对于43摄氏度之上的热痛觉（烫）的感知能力较弱。正常的野生型小鼠在两个分别是23摄氏度和38摄氏度的箱子里，倾向于钻到23摄氏度的箱子进行“避暑”，但是敲除了Trpm2的小鼠则不知道往23摄氏度的箱子跑了。从这篇文章也可以看出我们之前一直在说的神经元尤其是大规模的神经元成像技术的重要性，它的广泛应用可能带给我们很多新的发现。

其次，第二篇

Stress activates pronociceptive endogenous opioid signalling in DRG neurons during chronic colitis.

应激通过激活DRG神经元上的促伤害性内源性阿片肽系统引起慢性结肠炎

Guerrero-Alba R, Valdez Morales EE, Jimenez-Vargas JN, Lopez Lopez C, Jaramillo Polanco J, Okamoto T, Nasser Y, Bunnett NW, Lomax AE, Vanner SJ.

Gut. 2016 Sep 2

PMID: 27590998

Abstract

AIMS AND BACKGROUND:Psychological stress accompanies chronic inflammatory diseases such as IBD, and stress hormones can exacerbate pain signalling. In contrast, the endogenous opioid system has an important analgesic action during chronic inflammation. This study examined the interaction of these pathways.

METHODS:Mouse nociceptive dorsal root ganglia (DRG) neurons were incubated with supernatants from segments of inflamed colon collected from patients with chronic UC and mice with dextran sodium sulfate (cDSS)-induced chronic colitis. Stress effects were studied by adding stresshormones (epinephrine and corticosterone) to dissociated neurons or by exposing cDSS mice to water avoidance stress. Changes in excitability of colonic DRG nociceptors were measured using patch clamp and Ca2+ imaging techniques.RESULTS:Supernatants from patients with chronic UC and from colons of mice with chronic colitis caused a naloxone-sensitive inhibition of neuronal excitability and capsaicin-evoked Ca2+ responses. Stress hormones decreased signalling induced by human and mouse supernatants. This effect resulted from stress hormones signalling directly to DRG neurons and indirectly through signalling to the immune system, leading to decreased opioid levels and increased acute inflammation. The net effect of stress was a change endogenous opioid signalling in DRG neuronsfrom an inhibitory to an excitatory effect. This switch was associated with a change in G protein-coupled receptor excitatory signalling to a pathway sensitive to inhibitors of protein kinase A-protein, phospholipase C-protein and G protein βϒ subunits.CONCLUSIONS:Stress hormones block the inhibitory actions of endogenous opioids and can change the effect of opioid signalling in DRG neurons to excitation. Targeting these pathways may prevent heavy opioid use in IBD.

                               
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全文链接：http://gut.bmj.com/content/early ... nl-2016-311456.long

这篇文章来自加拿大，加拿大是做内脏痛比较多的国家，可能是因为他们有好几个内脏痛的大牛，比如Fernando Cervero等。很多内脏痛的模型都是他们制作的。国内做的比较好的内脏痛是苏州大学的徐广银教授，其文章也刊登在Gestroenterology和Gut上过，而且手握一项内脏痛的国家自然科学基因的重大项目。其实很多人都有一个关于内脏痛的基本问题，那就是内脏痛到底跟躯体疼痛的区别？内脏痛的研究是滞后于躯体疼痛的，同时也可以看到大量内脏痛的研究复制了躯体疼痛的内容，比如外周敏化、中枢敏化等。它们之间的区别到现在探讨的也不是很清楚。不管怎么样，疼痛研究学者能够对消化内科疾病提出自己的观点是非常有意义的。肠易激综合征以及本研究使用的慢性结肠炎模型，在临床都是非常常见的门诊消化内科病人的症状，这类疾病在内科书上往往以炎症以及慢性应激来解释的。但是，近些年，从疼痛的角度来看，其实这类疾病主要还是肠道的高敏感性。本来可以容纳一定体积内容物的肠道，现在由于肠道高敏不能容纳，进而表现出了腹痛的症状。本文从应激和肠道高敏感性这两个方面综合探讨了慢性结肠炎内脏痛发生的可能机制，即是因为原来在躯体腾痛中起镇痛的内源性阿片系统由于应激的作用，现在在慢性结肠炎中起着促进疼痛形成的作用。因此，靶向的干预内源性阿片系统可能用来治疗慢性内脏痛。

总结：本周的两篇文章到没有什么特别可说之处。这里推荐大家阅读本周Nature Neuroscience杂志发表的两篇综述：Technologies for imaging neural activity in large volumes以及Improving data quality in neuronal population recordings。神经科学有一个最基本的问题是如何的去大规模的解读大脑或者中枢神经系统的神经电信号。有人说我们现在有脑电技术，我们可以通过脑电图描记技术观察整个大脑脑电信号；又或者我们有电生理技术，我们可以通过胞外记录或者全细胞记录来捕捉大脑神经元信号。但是，其实这两类技术对于神经科学研究的贡献都非常的小。首先脑电技术太宽泛，分辨率很低，即使现在最先进的微阵列也做不到一个电极记录一个神经元，只能记录一群神经元。而电生理技术，范围太小，一个电极进去后只能记录到该电极附近的单个或多个神经元，就好比一个电视屏幕，我只看到电视屏幕里的几个雪花点，于是想推断整个电视在播放什么是完全不可能的，甚至是错误的。Stanford的人机结合或者脑机接口技术在全世界做的比较好，但是现在依然不能够完全解码大脑神经元信号，进而用机械完全精确的代替人的肢体，这主要还是因为大规模神经解码的困难。最近一些年发展起来的的神经元钙成像技术以及高分辨显微拍照技术从不同的方向为我们大规模准确记录大脑信号，为解读大脑信号内容提供可能。相信，神经科学可能因为该技术的发展进入一个快发展阶段。

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麻醉杨洋洋

很好 有启发～