每周论文更新----14 Oct 2016

zhouxuelong0258

每周论文更新----14 Oct 2016

周伯通博士

本周推送两篇文章，分别来自Nature Communications和Cell Reports杂志。文章的题目分别为："Inhibition of TRPV1 channels by a naturally occurring omega-9 fatty acid reduces pain and itch" 和 "Hypofunctional TrkA accounts for the absence of pain sensitization in the African Naked Mole-Rat"。

第一篇

Inhibition of TRPV1 channels by a naturally occurring omega-9 fatty acid reduces pain and itch

omega-9脂肪酸能够抑制TRPV1离子通道进而缓解疼痛和痒

Morales-Lázaro SL, Llorente I, Sierra-Ramírez F, López-Romero AE, Ortíz-Rentería M, Serrano-Flores B, Simon SA, Islas LD, Rosenbaum T.

Nat Commun. 2016 Oct 10

PMID: 27721373

Abstract

The transient receptor potential vanilloid 1 (TRPV1) ion channel is mainly found in primary nociceptive afferents whose activity has been linked to pathophysiological conditions including pain, itch and inflammation. Consequently, it is important to identify naturallyoccurring antagonists of this channel. Here we show that a naturally occurring monounsaturated fatty acid, oleic acid, inhibits TRPV1activity, and also pain and itch responses in mice by interacting with the vanilloid (capsaicin)-binding pocket and promoting the stabilization of a closed state conformation. Moreover, we report an itch-inducing molecule, cyclic phosphatidic acid, that activatesTRPV1 and whose pruritic activity, as well as that of histamine, occurs through the activation of this ion channel. These findings provide insights into the molecular basis of oleic acid inhibition of TRPV1 and also into a way of reducing the pathophysiological effects resulting from its activation.

                               
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全文链接：http://dx.doi.org/10.1038/ncomms13092

第二篇

Hypofunctional TrkA Accounts for the Absence of Pain Sensitization in the African Naked Mole-Rat

TrkA功能的降低介导了非洲裸鼹鼠的疼痛感知缺失Omerbašić D, Smith ES, Moroni M, Homfeld J, Eigenbrod O, Bennett NC, Reznick J, Faulkes CG, Selbach M, Lewin GR.

Cell Rep. 2016 Oct 11

PMID: 27732851

Abstract

The naked mole-rat is a subterranean rodent lacking several pain behaviors found in humans, rats, and mice. For example, nerve growth factor (NGF), an important mediator of pain sensitization, fails to produce thermal hyperalgesia in naked mole-rats. Thesensitization of capsaicin-sensitive TRPV1 ion channels is necessary for NGF-induced hyperalgesia, but naked mole-rats have fully functional TRPV1 channels. We show that exposing isolated naked mole-rat nociceptors to NGF does not sensitize TRPV1. However, the naked mole-rat NGF receptor TrkA displays a reduced ability to engage signal transduction pathways that sensitize TRPV1. Between one- and three-amino-acid substitutions in the kinase domain of the naked mole-rat TrkA are sufficient to render the receptorhypofunctional, and this is associated with the absence of heat hyperalgesia. Our data suggest that evolution has selected for a TrkAvariant that abolishes a robust nociceptive behavior in this species but is still compatible with species fitness.

                               
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全文链接：http://www.cell.com/cell-reports/fulltext/S2211-1247(16)31274-8

总结：

第一篇文章得益于近几年来结构生物学的发展，疼痛相关蛋白质结构的解析使得疼痛药物的开发进展很快。我们前期推送的“Structure-based discovery of opioid analgesics with reduced side effects”也属于这一范畴的文章。已知的疼痛相关蛋白质结构的有TRPV1和G蛋白偶联受体（阿片受体）等，通过在结构层面的设计可能会为疼痛药物的研发开启一个新的方向。同样，这方面也是疼痛基础研究一个比较好的切入点。

第二篇文章是基于新颖疼痛模型的一篇文章。在曹君利教授发表的“疼痛基础研究的困惑和挑战”一文中，就明确提到疼痛基础研究中疼痛模型的问题。现在所有使用的疼痛模型不能全部的模拟人类疼痛，这可能是疼痛基础研究进展缓慢的一个很重要的原因。如果能开发或者找到一个比较贴近于自然状态的疼痛模型尤其是人类自身的疼痛模型将对于疼痛基础研究有着重要的启示作用。比如，基于家族性的遗传性红斑性肢痛的发现就对疼痛相关的Nav1.7的鉴定起到了重要的作用。这方面的工作耶鲁的Waxman或者伦敦大学学院的Wood教授做的很好，可以去看看。

这里是服务疼痛基础研究科研人员的微信号“疼痛研究论坛”。我们：

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