Netrin-1 Contributes to Myelinated Afferent Fiber Sprouting and Neuropathic Pain
Netrin-1 Contributes to Myelinated Afferent Fiber Sprouting and Neuropathic Pain
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Netrin-1 有助于有髓传入纤维发芽和神经性疼痛。
DOI：
10.1007/s12035-015-9482-x
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发表时间：
2016-10-01
影响因子：
5.1
通讯作者：
Li, Man
中科院分区：
文献类型：
--
作者：
Wu, Cai-Hua;Yuan, Xiao-Cui;Li, Man
Netrin - 1是一种神经导向分子，与脊髓神经元和皮质神经元的发育有关。在成年脊髓中，UNC5H（Netrin - 1的排斥性受体）而非结直肠癌缺失蛋白（DCC，Netrin - 1的吸引性受体）构成了Netrin - 1信号转导的主要方式，它可能参与轴突排斥并抑制神经突生长。脊髓背角有髓传入纤维的异常出芽可导致与带状疱疹后神经痛（PHN，带状疱疹）及其他神经性疼痛相关的机械性痛觉超敏。然而，Netrin - 1是否参与有髓传入纤维的出芽及机械性痛觉超敏仍不清楚。在一种超强效瞬时受体电位香草酸亚型1（TRPV1）激动剂树胶脂毒素（RTX）诱导的带状疱疹后神经痛样模型中，RTX处理6周可增加脊髓背角神经元（包括神经激肽1阳性投射神经元）中Netrin - 1的表达。在人神经母细胞瘤SH - SY5Y细胞中，我们发现TRPV1拮抗剂辣椒平可拮抗RTX诱导的Netrin - 1上调。RTX处理后，UNC5H2表达逐渐降低，而DCC表达显著增加。在脊髓背角沉默Netrin - 1可显著减轻RTX诱导的机械性痛觉超敏以及有髓纤维向脊髓Ⅱ层的出芽。我们的结果表明，RTX处理通过激活TRPV1受体上调Netrin - 1的表达，并通过增加DCC表达将富含UNC5H2的脊髓背角转变为有利于生长的环境，从而增强有髓传入神经的出芽。Netrin - 1可能成为减少带状疱疹后神经痛及其他神经性疼痛状况下初级传入神经出芽和机械性痛觉超敏的靶点。
Netrin-1 is a neuronal guidance molecule implicated in the development of spinal cord neurons and cortical neurons. In the adult spinal cord, UNC5H (repulsive receptor of netrin-1), but not deleted in colorectal cancer (DCC) (attractive receptor of netrin-1), constitutes a major mode of netrin-1 signal transduction, which may be involved in axon repulsion and inhibits neurite outgrowth. Abnormal sprouting of myelinated afferent fibers in the spinal dorsal horn can cause mechanical allodynia associated with postherpetic neuralgia (PHN, Shingles) and other neuropathic pains. However, whether netrin-1 participates in sprouting of myelinated afferent fibers and mechanical allodynia remains unknown. In an ultropotent TRPV1 agonist resiniferatoxin (RTX)-induced PHN-like model, RTX treatment for 6 weeks increased netrin-1 expression in dorsal horn neurons, including NK-1-positive projection neurons. In human neuroblastoma SH-SY5Y cells, we found that TRPV1 antagonist capsazepine antagonized RTX-induced upregulation of netrin-1. After RTX treatment, UNC5H2 expression was gradually decreased, whereas DCC expression was significantly increased. Silencing netrin-1 in the spinal dorsal horn significantly attenuated RTX-induced mechanical allodynia and sprouting of myelinated fibers into the spinal lamina II. Our results suggest that RTX treatment upregulates netrin-1 expression through activation of TRPV1 receptors and change UNC5H2-rich spinal dorsal horn into a growth-permissive environment by increasing DCC expression, thus enhancing the sprouting of myelinated afferent nerves. Netrin-1 may be targeted for reducing primary afferent sprouting and mechanical allodynia in PHN and other neuropathic pain conditions.