Nerve Injury-Induced Neuronal PAP-I Maintains Neuropathic Pain by Activating Spinal Microglia
Nerve Injury-Induced Neuronal PAP-I Maintains Neuropathic Pain by Activating Spinal Microglia
复制标题
神经损伤诱导的神经元 PAP-I 通过激活脊髓小胶质细胞维持神经病理性疼痛
DOI：
10.1523/jneurosci.1414-19.2019
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发表时间：
2020-01-08
影响因子：
5.3
通讯作者：
Zhang, Xu
中科院分区：
文献类型：
--
作者：
Li, Jiayin;Shi, Haixiang;Zhang, Xu
胰腺炎相关蛋白（PAPs）在内脏疾病中具有多种功能。以往的研究表明，PAP-I在未处理大鼠的DRG中表达水平较低，但在周围神经损伤后重新表达。然而，其在神经性疼痛中的作用仍然未知。我们发现，在大鼠备用神经损伤模型的DRG神经元中，PAP-I表达持续上调，并向脊髓背角转运，作为促炎因子发挥作用。鞘内注射PAP-I增强感觉痛觉过敏，而PAP-I基因敲除或抗体应用的缺陷减轻了保留神经损伤后维持阶段的触觉异常性疼痛。此外，PAP-I通过参与神经病理性疼痛的C-C趋化因子受体2型激活脊髓小胶质细胞发挥作用。抑制小胶质细胞活化或C-C趋化因子受体2型消除PAP-I诱导的痛觉过敏。因此，PAP-I介导周围神经损伤后神经元-小胶质细胞的串扰，并有助于维持神经病理性疼痛。神经病理性疼痛是一种适应不良的疼痛状态，其维持机制尚不清楚。在这里，我们发现，周围神经损伤后，PAP-I可以被运送到脊髓背角，并在神经病理性疼痛的进展至关重要。重要的是，我们证明PAP-I主要通过CCR 2-p38 MAPK通路激活脊髓小胶质细胞发挥作用。此外，我们证实PAP-I的促炎作用在神经病理性疼痛建立后更加突出，从而表明小胶质细胞也参与了神经病理性疼痛的维持阶段。
Pancreatitis-associated proteins (PAPs) display multiple functions in visceral diseases. Previous studies showed that the expression level of PAP-I was low in the DRG of naive rats but was de novo expressed after peripheral nerve injury. However, its role in neuropathic pain remains unknown. We found that PAP-I expression was continuously upregulated in the DRG neurons from rat spared nerve injury models, and transported toward the spinal dorsal horn to act as a proinflammatory factor. Intrathecal delivery of PAP-I enhanced sensory hyperalgesia, whereas PAP-I deficiency by either gene knockout or antibody application alleviated tactile allodynia at the maintenance phase after spared nerve injury. Furthermore, PAP-I functioned by activating the spinal microglia via C-C chemokine receptor Type 2 that participated in neuropathic pain. Inhibition of either microglial activation or C-C chemokine receptor Type 2 abolished the PAP-I-induced hyperalgesia. Thus, PAP-I mediates the neuron-microglial crosstalk after peripheral nerve injury and contributes to the maintenance of neuropathic pain. SIGNIFICANCE STATEMENT Neuropathic pain is maladaptive pain condition, and the maintaining mechanism is largely unclear. Here we reveal that, after peripheral nerve injury, PAP-I can be transported to the spinal dorsal horn and is crucial in the progression of neuropathic pain. Importantly, we prove that PAP-I mainly functions through activating the spinal microglia via the CCR2-p38 MAPK pathway. Furthermore, we confirm that the proinflammatory effect of PAP-I is more prominent after the establishment of neuropathic pain, thus indicating that microglia also participate in the maintenance phase of neuropathic pain.