每周论文更新----2 Sep 2016

zhouxuelong0258

本周推送两篇文献，分别来自Neuron杂志和PNAS杂志。文章的题目分别为：Coupled Activation of Primary Sensory Neurons Contributes to Chronic Pain和A novel orvinol analog, BU08028, as a safe opioid analgesic without abuse liability in primates.

第一篇

Coupled Activation of Primary Sensory Neurons Contributes to Chronic Pain

共激活初级感觉神经元参与慢性疼痛的产生

Kim Y, Anderson M, Park K, Zheng Q, Agarwal A, Gong C, Gong C, Young LA, He S, LaVinka P C, Zhou F, Bergles D, Hanani M, Guan Y, Spray DC, Dong X

Neuron. 2016 Aug 24.

PMID: 27568517.

Abstract

Primary sensory neurons in the DRG play an essential role in initiating pain by detecting painful stimuli in the periphery. Tissue injury can sensitize DRG neurons, causing heightened pain sensitivity, often leading to chronic pain. Despite the functional importance, how DRG neurons function at a population level is unclear due to the lack of suitable tools. Here we developed an imaging technique that allowed us to simultaneously monitor the activities of >1,600 neurons/DRG in live mice and discovered a striking neuronal coupling phenomenon that adjacent neurons tend to activate together following tissue injury. This coupled activation occurs among various neurons and is mediated by an injury-induced upregulation of gap junctions in glial cells surrounding DRG neurons. Blocking gap junctions attenuated neuronal coupling and mechanical hyperalgesia. Therefore, neuronal coupling represents a new form of neuronal plasticity in the DRG and contributes to pain hypersensitivity by "hijacking" neighboring neurons through gap junctions.

                               
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全文链接：http://linkinghub.elsevier.com/retrieve/pii/S0896-6273(16)30460-3

本篇文章来自John Hopkins的董欣中（Dong Xingzhong）教授。大家都知道研究痒的陈宙锋教授，来自华盛顿大学医学院。其实，研究痒的贡献较大的还有一位，就是董欣中教授。自去年被评为HHMI研究员以后，似乎好像钱多了研究方向也变了，开始做疼痛相关的神经元成像研究了。当然，之前我们也有讲过神经元成像确实是近些年甚至未来一段时间内的研究热点和重点。本篇文章就是该实验室出的第一篇疼痛神经元成像研究。

神经元可塑性，或者说是外周敏化以及中枢敏化是慢性疼痛痛觉过敏产生的重要机制。当外周伤害性刺激持续存在的情况下，初级感觉神经元（DRG）或者脊髓背角神经元内的离子通道、受体、细胞信号转导通路以及基因表达都发生一系列的异常适应性变化，这些异常适应性变化最终会导致神经元的敏化。从这个定义上来看，无论是可塑性或者是外周敏化和中枢敏化，似乎对象都是对单个神经元变化而言。那这就有一个问题，如果上升到神经元集群（population）的层面，慢性疼痛对神经元集群有没有影响？是不是能够引起更大集群的神经元开始放电？如果是，为什么会引起增大的神经元集群放电呢？本篇文章，作者利用在体神经元钙成像技术（之前在7月29号讲过双光子钙成像，有兴趣可以回去看看）发现慢性疼痛能够引起DRG内神经元的共激活（邻近的神经元也被激活），发生神经元集群的激活现象。背后的机制可能是包绕神经元的胶质细胞上缝隙连接的表达上调导致的，而干预这种缝隙连接能够很好的减轻慢性疼痛。从而在神经元群层面阐述了外周神经元可塑性的变化对痛觉过敏现象的影响。

第二篇

A novel orvinol analog, BU08028, as a safe opioid analgesic without abuse liability in primates.

苔黑酚类似物BU0828可以作为阿片类镇痛药安全的用于灵长类动物

Ding H, Czoty PW, Kiguchi N, Cami-Kobeci G, Sukhtankar DD, Nader MA, Husbands SM, Ko M-C

Proc Natl Acad Sci U S A. 2016 Aug 29.

PMID: 27573832

Abstract

Despite the critical need, no previous research has substantiated safe opioid analgesics without abuse liability in primates. Recent advances in medicinal chemistry have led to the development of ligands with mixed mu opioid peptide (MOP)/nociceptin-orphanin FQ peptide (NOP) receptor agonist activity to achieve this objective. BU08028 is a novel orvinol analog that displays a similar binding profile to buprenorphine with improved affinity and efficacy at NOP receptors. The aim of this preclinical study was to establish the functional profile of BU08028 in monkeys using clinically used MOP receptor agonists for side-by-side comparisons in various well-honed behavioral and physiological assays. Systemic BU08028 (0.001-0.01 mg/kg) produced potent long-lasting (i.e., >24 h) antinociceptive and antiallodynic effects, which were blocked by MOP or NOP receptor antagonists. More importantly, the reinforcing strength of BU08028 was significantly lower than that of cocaine, remifentanil, or buprenorphine in monkeys responding under a progressive-ratio schedule of drug self-administration. Unlike MOP receptor agonists, BU08028 at antinociceptive doses and ～10- to 30-fold higher doses did not cause respiratory depression or cardiovascular adverse events as measured by telemetry devices. After repeated administration, the monkeys developed acute physical dependence on morphine, as manifested by precipitated withdrawal signs, such as increased respiratory rate, heart rate, and blood pressure. In contrast, monkeys did not show physical dependence on BU08028. These in vivo findings in primates not only document the efficacy and tolerability profile of bifunctional MOP/NOP receptor agonists, but also provide a means of translating such ligands into therapies as safe and potentially abuse-free opioid analgesics.

                               
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全文链接：http://www.pnas.org/cgi/pmidlookup?view=long&pmid=27573832

这是一篇纯的药理学研究，找到理想的药物以后对其进行效能和不良反应的评估，基础意义不大，但是实用性很高。

总结：同7月29日那一期一样，我们认为疼痛传导通路的神经成像研究是一个很好的方向，理论意义很大。

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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