Cingulate retinoic acid signaling regulates neuropathic pain and comorbid anxiodepression via extracellular matrix homeostasis
Zhen-Zhen Li, Wan-Neng Liu, Ke-Xin Liu, Zhi-Wei Dou, Rui Zhao, Yun Chen, Meng-Meng Wang, Tao-Zhi Wang, Fei Wang, Wen-Juan Han, Wen-Guang Chu, Xing-Xing Zheng, Rou-Gang Xie, Hua Yuan, Xiao-Fan Jiang, Xiao-Long Sun, Ceng Luo, Sheng-Xi Wu
Zhen-Zhen Li, Wan-Neng Liu, Ke-Xin Liu, Zhi-Wei Dou, Rui Zhao, Yun Chen, Meng-Meng Wang, Tao-Zhi Wang, Fei Wang, Wen-Juan Han, Wen-Guang Chu, Xing-Xing Zheng, Rou-Gang Xie, Hua Yuan, Xiao-Fan Jiang, Xiao-Long Sun, Ceng Luo, Sheng-Xi Wu
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Research Article Cell biology Neuroscience

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

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 1 (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)/RA receptor β (RARB) signaling in neuropathic pain and associated anxiodepression via regulation of ECM homeostasis. We showed that nerve injury reduced RA levels in the serum and ACC in mice and humans, which brought about downregulation of RA’s 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 improving neuropathic pain and aversive emotion. Taken together with our previous study, we revealed an intracellular-extracellular-intracellular feed-forward 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.

Authors

Zhen-Zhen Li, Wan-Neng Liu, Ke-Xin Liu, Zhi-Wei Dou, Rui Zhao, Yun Chen, Meng-Meng Wang, Tao-Zhi Wang, Fei Wang, Wen-Juan Han, Wen-Guang Chu, Xing-Xing Zheng, Rou-Gang Xie, Hua Yuan, Xiao-Fan Jiang, Xiao-Long Sun, Ceng Luo, Sheng-Xi Wu

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Figure 7

RA levels are decreased in chronic pain comorbid with anxiodepression.

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RA levels are decreased in chronic pain comorbid with anxiodepression. (...
(A) A table summarizing the patient information. The groups met the following conditions: healthy volunteers: NRS < 3, GAD7 ≤ 4, HAMA ≤ 6, HAMD ≤ 8, PHQ-9 ≤ 4; chronic pain: NRS ≥ 3, GAD7 ≤ 4, HAMA ≤ 6, HAMD ≤ 8, PHQ-9 ≤ 4; chronic pain comorbid with anxiety: NRS ≥ 3, GAD7 > 4 and/or HAMA > 6, HAMD ≤ 8, PHQ-9 ≤ 4; chronic pain comorbid with depression: NRS ≥ 3, GAD7 ≤ 4, HAMA ≤ 6, HAM > 8, and/or PHQ-9 > 4; and chronic pain comorbid with anxiodepression: NRS ≥ 3, GAD7 > 4 and/or HAMA > 6, HAMD > 8 and/or PHQ9 > 4. (B) ELISA of RA level in serum from patients (n = 2–22). (C and D) ELISA of RA level in serum (C) (n = 5–6) and the ACC (D) (n = 4–8) after SNI surgery. (E) Schematic diagram showing construction of AAV2/9 expressing RARE–TK promoter–EGFP. TK, thymidine kinase. (F) Fluorescence images of GFP expression in 293FT cells transfected with AAV-RARE plasmid after RA treatment. Scale bars: 20 μm. (G) Immunoblots and quantitative summary of GFP expression in 293FT cells transfected with AAV-RARE plasmid after RA (5 μM) treatment (n = 3). Veh, vehicle. (H and I) Immunofluorescence (H) and quantitative summary (I) of GFP and RARB expression in ACC from SNI-treated mice expressing AAV-RARE (n = 4). Scale bars: 30 μm. (J) Luciferase activity of vehicle and RA addition in the transfection of Rarb-Luc (n = 6–12). *P < 0.05, **P < 0.01. Statistical analysis was performed by Kruskal-Wallis H test (B, D, and J), 1-way ANOVA (C), 2-tailed unpaired t test (G and I for RARB density), and Mann-Whitney U test (I for GFP density).