ArticleThe Journal of clinical investigation2025
Cingulate retinoic acid signaling regulates neuropathic pain and comorbid anxiodepression via extracellular matrix homeostasis.
Article in The Journal of clinical investigation, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- Temporal Transcriptomic Changes in the Cingulate Cortex of Neuropathic Pain Mice.Biomedicines · 2026Article
- Roles and therapeutic prospects of the laminin family in disorders of the nervous system.Journal of translational medicine · 2026Review
- CSF1R T567M mutation induces microglial dysfunction and synaptic impairment in patient iPSC-derived cerebral organoids of CSF1R-related disorder.Cell death discovery · 2026Article
- A neuron-astrocyte signaling axis in the ACC sustains diabetic neuropathic pain.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Shared Mechanisms and Integrated Management of Post-Stroke Pain and Depression: A Comprehensive Review.Pain and therapy · 2026Review
- Synaptic plasticity in affective comorbidities of neuropathic pain: a bibliometric analysis based on WoSCC and PubMed (2003-2025).Frontiers in neurology · 2026Article
- Mechanical cues as immunomodulators in neuroinflammation-driven spinal sensitization: analgesic mechanisms and therapeutic strategies.Frontiers in immunology · 2026Review
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Authors and funding
18 authors.
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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 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.
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