Up-regulation of LCN2 in the anterior cingulate cortex contributes to neural injury-induced chronic pain

Xiang-Jie Song; Chen-Ling Yang; Danyang Chen; Yumeng Yang; Yu Mao; Peng Cao; Aijun Jiang; Wei Wang; Zhi Zhang; Wenjuan Tao

doi:10.3389/fncel.2023.1140769

Up-regulation of LCN2 in the anterior cingulate cortex contributes to neural injury-induced chronic pain

Front Cell Neurosci. 2023 Jun 8:17:1140769. doi: 10.3389/fncel.2023.1140769. eCollection 2023.

Authors

Xiang-Jie Song^#¹, Chen-Ling Yang^#^{2

3}, Danyang Chen¹, Yumeng Yang^{2

3}, Yu Mao¹, Peng Cao⁴, Aijun Jiang⁵, Wei Wang⁵, Zhi Zhang¹, Wenjuan Tao^{2

3}

Affiliations

¹ 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.
² Key Laboratory of Oral Diseases Research of Anhui Province, College and Hospital of Stomatology, Anhui Medical University, Hefei, China.
³ Department of Physiology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China.
⁴ Department of Neurology, Stroke Center, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
⁵ Department of Endocrinology and Laboratory for Diabetes, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.

^# Contributed equally.

Abstract

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, in vivo 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^Glu) 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^Glu neuronal hyperactivity in SNI 2W mice. In addition, administering purified recombinant LCN2 protein in the ACC could induce pain sensitization by inducing ACC^Glu neuronal hyperactivity in naïve mice. This study provides a mechanism by which LCN2-mediated hyperactivity of ACC^Glu neurons contributes to pain sensitization, and reveals a new potential target for treating chronic pain.

Keywords: ACC; LCN2; chemogenetics; chronic pain; in vivo 2P calcium imaging; neuronal hyperactivity.

Grants and funding

This work was supported by the National Key Research and Development Program of China (STI2030-Major Projects 2021ZD0203100), the National Natural Science Foundation of China (grants: 32025017, 32121002, 82101300, 82101301, and 32271176), the CAS Project for Young Scientists in Basic Research (YSBR-013), and the Innovative Research Team of High-level Local Universities in Shanghai (SHSMU-ZDCX20211902).