Song Xiang-Jie, Yang Chen-Ling, Chen Danyang, Yang Yumeng, Mao Yu, Cao Peng, Jiang Aijun, Wang Wei, Zhang Zhi, Tao Wenjuan
Hefei National Research Center for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
Key Laboratory of Oral Diseases Research of Anhui Province, College and Hospital of Stomatology, Anhui Medical University, Hefei, China.
Front Cell Neurosci. 2023 Jun 8;17:1140769. doi: 10.3389/fncel.2023.1140769. eCollection 2023.
Chronic pain caused by disease or injury affects more than 30% of the general population. The molecular and cellular mechanisms underpinning the development of chronic pain remain unclear, resulting in scant effective treatments. Here, we combined electrophysiological recording, two-photon (2P) calcium imaging, fiber photometry, Western blotting, and chemogenetic methods to define a role for the secreted pro-inflammatory factor, Lipocalin-2 (LCN2), in chronic pain development in mice with spared nerve injury (SNI). We found that LCN2 expression was upregulated in the anterior cingulate cortex (ACC) at 14 days after SNI, resulting in hyperactivity of ACC glutamatergic neurons (ACC) and pain sensitization. By contrast, suppressing LCN2 protein levels in the ACC with viral constructs or exogenous application of neutralizing antibodies leads to significant attenuation of chronic pain by preventing ACC neuronal hyperactivity in SNI 2W mice. In addition, administering purified recombinant LCN2 protein in the ACC could induce pain sensitization by inducing ACC neuronal hyperactivity in naïve mice. This study provides a mechanism by which LCN2-mediated hyperactivity of ACC neurons contributes to pain sensitization, and reveals a new potential target for treating chronic pain.
由疾病或损伤引起的慢性疼痛影响着超过30%的普通人群。慢性疼痛发生发展的分子和细胞机制仍不清楚，导致有效治疗方法匮乏。在此，我们结合电生理记录、双光子（2P）钙成像、光纤光度测定、蛋白质免疫印迹和化学遗传学方法，以确定分泌型促炎因子Lipocalin-2（LCN2）在 spared nerve injury（SNI）小鼠慢性疼痛发生发展中的作用。我们发现，在SNI后14天，前扣带回皮质（ACC）中LCN2的表达上调，导致ACC谷氨酸能神经元（ACC）活性亢进和疼痛敏化。相比之下，用病毒构建体抑制ACC中的LCN2蛋白水平或外源性应用中和抗体，可通过防止SNI 2W小鼠的ACC神经元活性亢进，显著减轻慢性疼痛。此外，在ACC中给予纯化的重组LCN2蛋白，可通过诱导未处理小鼠的ACC神经元活性亢进而诱导疼痛敏化。本研究提供了一种机制，即LCN2介导的ACC神经元活性亢进促成疼痛敏化，并揭示了一个治疗慢性疼痛的新潜在靶点。
