A sensory subpopulation depends on vesicular glutamate transporter 2 for mechanical pain, and together with substance P, inflammatory pain
A sensory subpopulation depends on vesicular glutamate transporter 2 for mechanical pain, and together with substance P, inflammatory pain
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DOI：
10.1073/pnas.1013602108
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发表时间：
2011-04-05
影响因子：
11.1
通讯作者：
Kullander, Klas
中科院分区：
文献类型：
--
作者：
Lagerstrom, Malin C.;Rogoz, Katarzyna;Kullander, Klas
切除或功能受损的感觉神经元组为躯体感觉系统中外周模态特异性布线提供了重要的见解。炎性痛觉过敏、冷痛和有害的机械感觉都依赖于Na(v)1.8阳性感觉神经元。快速作用的神经递质（如谷氨酸）和缓慢释放的神经肽（如P物质）的释放有助于对外界刺激的多样化反应。本研究表明，Na(v)1.8（Cre）阳性神经元中Vglut2的缺失会损害机械性疼痛和ngf诱导的热痛觉过敏，而触觉诱发的感觉、热痛、福尔马林诱发的慢性神经性疼痛则是正常的。然而，当Vglut2(f/f)；Na(v)1.8（Cre）小鼠在福尔马林试验前注射SP拮抗剂，第二阶段疼痛反应几乎完全消失，而对照组小鼠疼痛反应不受影响。我们的研究结果表明，源自Na(v)1.8阳性神经元的vglut2依赖信号是机械性疼痛的主要感知机制，与SP一起，炎症性疼痛。这些数据定义了与特定模式相关的主要传入事件集，并提供了有用的遗传工具，用于分析由功能不同的神经元群和递质激活的途径。
Ablating or functionally compromising sets of sensory neurons has provided important insights into peripheral modality-specific wiring in the somatosensory system. Inflammatory hyperalgesia, cold pain, and noxious mechanosensation have all been shown to depend upon Na(v)1.8-positive sensory neurons. The release of fast-acting neurotransmitters, such as glutamate, and more slowly released neuropeptides, such as substance P (SP), contribute to the diversified responses to external stimuli. Here we show that deleting Vglut2 in Na(v)1.8(Cre)-positive neurons compromised mechanical pain and NGF-induced thermal hyperalgesia, whereas tactile-evoked sensation, thermal, formalin-evoked, and chronic neuropathic pain were normal. However, when Vglut2(f/f); Na(v)1.8(Cre) mice were injected with a SP antagonist before the formalin test, the second phase pain response was nearly completely abolished, whereas in control mice, the pain response was unaffected. Our results suggest that VGLUT2-dependent signaling originating from Na(v)1.8-positive neurons is a principal sensing mechanism for mechanical pain and, together with SP, inflammatory pain. These data define sets of primary afferents associated with specific modalities and provide useful genetic tools with which to analyze the pathways that are activated by functionally distinct neuronal populations and transmitters.