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ResearchIn-Press PreviewCell biologyNeuroscience Open Access | 10.1172/JCI190539

Cingulate retinoic acid signaling regulates neuropathic pain and comorbid anxiodepression via extracellular matrix homeostasis

Zhen-Zhen Li,1 Wan-Neng Liu,1 Ke-Xin Liu,1 Zhi-Wei Dou,1 Rui Zhao,2 Yun Chen,1 Meng-Meng Wang,1 Tao-Zhi Wang,3 Fei Wang,1 Wen-Juan Han,1 Wen-Guang Chu,1 Xing-Xing Zheng,1 Rou-Gang Xie,1 Hua Yuan,2 Xiao-Fan Jiang,4 Xiao-Long Sun,2 Ceng Luo,1 and Shengxi Wu1

1Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, China

2Department of Rehabilitation Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China

3Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China

4Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China

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1Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, China

2Department of Rehabilitation Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China

3Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China

4Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China

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1Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, China

2Department of Rehabilitation Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China

3Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China

4Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China

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1Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, China

2Department of Rehabilitation Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China

3Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China

4Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China

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1Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, China

2Department of Rehabilitation Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China

3Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China

4Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China

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1Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, China

2Department of Rehabilitation Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China

3Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China

4Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China

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1Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, China

2Department of Rehabilitation Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China

3Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China

4Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China

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1Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, China

2Department of Rehabilitation Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China

3Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China

4Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China

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1Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, China

2Department of Rehabilitation Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China

3Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China

4Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China

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1Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, China

2Department of Rehabilitation Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China

3Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China

4Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China

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1Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, China

2Department of Rehabilitation Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China

3Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China

4Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China

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1Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, China

2Department of Rehabilitation Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China

3Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China

4Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China

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1Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, China

2Department of Rehabilitation Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China

3Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China

4Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China

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1Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, China

2Department of Rehabilitation Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China

3Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China

4Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China

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1Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, China

2Department of Rehabilitation Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China

3Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China

4Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China

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1Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, China

2Department of Rehabilitation Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China

3Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China

4Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China

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1Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, China

2Department of Rehabilitation Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China

3Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China

4Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China

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1Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, China

2Department of Rehabilitation Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China

3Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China

4Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China

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Published July 1, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI190539.
Copyright © 2025, Li et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published July 1, 2025 - Version history
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Abstract

Neuropathic pain is often comorbid with affective disorders. Synaptic plasticity in anterior cingulate cortex (ACC) is assumed to be a crucial interface for pain perception and emotion. Laminin β1 (LAMB1), a key element of extracellular matrix (ECM) in ACC was recently revealed to convey extracellular alterations to intracellular synaptic plasticity and underlie neuropathic pain and aversive emotion. However, it remains elusive what triggers activity-dependent changes of LAMB1 and ECM remodeling after nerve injury. Here, we uncovered a key role of retinoic acid (RA)/RARB signaling in neuropathic pain and associated anxiodepression via regulation of ECM homeostasis. We showed that nerve injury reduced RA level in the serum and ACC in mice and human, which brought about downregulation of its corresponding receptor, RARB. Overexpressing RARB relieved pain hypersensitivity and comorbid anxiodepression, while silencing RARB exacerbated pain sensitivity and induced anxiodepression. Further mechanistic analysis revealed that RARB maintained ECM homeostasis via transcriptional regulation of LAMB1, reversing abnormal synaptic plasticity and eventually improved neuropathic pain and aversive emotion. Taken together with our previous study, we revealed an intracellular-extracellular-intracellular feedforward regulatory network in modulating pain plasticity. Moreover, we identified cingulate RA/RARB signaling as a promising therapeutic target for treatment of neuropathic pain and associated anxiodepression.

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  • Version 1 (July 1, 2025): In-Press Preview
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