Dorsal horn neurons release extracellular ATP in a VNUT-dependent manner that underlies neuropathic pain.
Dorsal horn neurons release extracellular ATP in a VNUT-dependent manner that underlies neuropathic pain.
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DOI：
10.1038/ncomms12529
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发表时间：
2016-08-12
影响因子：
16.6
通讯作者：
Inoue K
中科院分区：
文献类型：
--
作者：
Masuda T;Ozono Y;Mikuriya S;Kohro Y;Tozaki-Saitoh H;Iwatsuki K;Uneyama H;Ichikawa R;Salter MW;Tsuda M;Inoue K
细胞外ATP激活脊髓嘌呤能受体是周围神经损伤（PNI）后神经性超敏反应的必要条件。然而，PNI后脊髓内负责释放ATP的细胞类型尚不清楚。本研究显示PNI增加脊髓中囊泡核苷酸转运蛋白（VNUT）的表达。脊髓内细胞外ATP含量（[ATP]e）在PNI后增加，这种增加被胞外抑制剂抑制。缺乏VNUT的小鼠没有表现出pni诱导的[ATP]e的增加，并且过敏反应减弱。这些表型在脊髓背角（SDH）神经元中特异性缺失VNUT的小鼠中重现，但在初级感觉神经元、小胶质细胞或星形胶质细胞中缺乏VNUT的小鼠中没有重现。相反，VNUT缺失小鼠SDH神经元中的异位VNUT表达恢复了pni诱导的[ATP]e和疼痛的增加。因此，VNUT对于SDH神经元的胞外ATP释放是必需的，这有助于神经性疼痛。嘌呤能受体在背角细胞外ATP的激活有助于神经性疼痛，但哪种细胞类型在这种情况下释放ATP尚不清楚。作者在一个神经性疼痛的小鼠模型中表明，ATP是由背角神经元释放的，这一过程需要囊状核苷酸转运体VNUT。
Activation of purinergic receptors in the spinal cord by extracellular ATP is essential for neuropathic hypersensitivity after peripheral nerve injury (PNI). However, the cell type responsible for releasing ATP within the spinal cord after PNI is unknown. Here we show that PNI increases expression of vesicular nucleotide transporter (VNUT) in the spinal cord. Extracellular ATP content ([ATP]e) within the spinal cord was increased after PNI, and this increase was suppressed by exocytotic inhibitors. Mice lacking VNUT did not show PNI-induced increase in [ATP]e and had attenuated hypersensitivity. These phenotypes were recapitulated in mice with specific deletion of VNUT in spinal dorsal horn (SDH) neurons, but not in mice lacking VNUT in primary sensory neurons, microglia or astrocytes. Conversely, ectopic VNUT expression in SDH neurons of VNUT-deficient mice restored PNI-induced increase in [ATP]e and pain. Thus, VNUT is necessary for exocytotic ATP release from SDH neurons which contributes to neuropathic pain. Purinergic receptor activation by extracellular ATP in the dorsal horn contributes to neuropathic pain, but which cell types release ATP in this context is not known. The authors show in a mouse model of neuropathic pain that ATP is released by dorsal horn neurons, a process requiring the vesicular nucleotide transporter, VNUT.