Institute of Neuroscience and State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Biology.
J Neurosci. 2020 Jan 8;40(2):297-310. doi: 10.1523/JNEUROSCI.1414-19.2019. Epub 2019 Nov 19.
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 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. 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.
胰腺炎相关蛋白（PAPs）在内脏疾病中具有多种功能。先前的研究表明，在未受伤的大鼠背根神经节（DRG）中，PAP-I 的表达水平较低，但在外周神经损伤后表达增加。然而，其在神经病理性疼痛中的作用尚不清楚。我们发现，在 spared nerve injury 模型大鼠的 DRG 神经元中，PAP-I 的表达持续上调，并向脊髓背角转运，作为一种促炎因子发挥作用。鞘内给予 PAP-I 可增强感觉性痛觉过敏，而通过基因敲除或抗体应用导致 PAP-I 缺乏则可减轻 spared nerve injury 后的维持期触觉过敏。此外，PAP-I 通过激活参与神经病理性疼痛的 C-C 趋化因子受体 2（CCR2）来发挥作用的脊髓小胶质细胞。抑制小胶质细胞激活或 C-C 趋化因子受体 2 均可消除 PAP-I 诱导的痛觉过敏。因此，PAP-I 介导外周神经损伤后的神经元-小胶质细胞串扰，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性疼痛状态，其维持机制在很大程度上尚不清楚。在这里，我们揭示了在外周神经损伤后，PAP-I 可以被转运到脊髓背角，并且在神经病理性疼痛的进展中至关重要。重要的是，我们证明了 PAP-I 主要通过 CCR2-p38 MAPK 通路激活脊髓小胶质细胞来发挥作用。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为明显，这表明小胶质细胞也参与了神经病理性疼痛的维持期。
