CAP1 mediates chronic inflammatory pain-induced anxiety through cAMP/PKA/NF-κB signaling pathway in the anterior cingulate cortex of male mice.

Authors

Yu-Chen Jin, Qing-Juan Guo, Yu-Xuan Yan, Yong-Li Jiang, Da-Ke Song, Bei-Ning Lu, Cheng Zeng, Jiao Yue, Liu-Kun Yang, Rui-Xia Liu, Kun Zhang, Xu-Bo Li, Ran He, Yu-Jie Lu, Xin-Shang Wang, Shui-Bing Liu

Published in

Brain, behavior, and immunity. Pages 107073. Oct 14, 2026. Epub Oct 14, 2026.

Abstract

A substantial subset of chronic pain patients suffers from comorbid anxiety, and this bidirectional exacerbation poses a major clinical challenge. Current pharmacotherapies have limited efficacy with notable side effects, underscoring the need for new targets. We successfully established a Complete Freund's Adjuvant (CFA) ‑induced chronic inflammatory pain model in male mice, which developed mechanical/thermal hyperalgesia, anxiety‑like behaviors, and Anterior Cingulate Cortex (ACC) synaptic plasticity abnormalities. RNA‑seq identified marked upregulation of ACC Adenylyl Cyclase‑Associated Protein 1 (CAP1). ACC CAP1 overexpression in naive mice selectively reduced mechanical pain and induced anxiety without affecting thermal nociception, whereas ACC CAP1 knockdown in CFA mice reversed anxiety and restored Excitatory/Inhibitory (E/I) balance while leaving pain thresholds unchanged. Mechanistically, CAP1 knockdown suppressed neuroinflammation via the Cyclic Adenosine Monophosphate (cAMP)/ Protein Kinase A (PKA)/Nuclear Factor kappa‑light‑chain‑enhancer of activated B cells (NF‑κB) pathway, as shown by reduced p‑PKA/p‑P65, cAMP, and pro‑inflammatory cytokines (Interleukin‑6, IL‑6; Interleukin‑1 beta, IL‑1β; Tumor Necrosis Factor alpha, TNF‑α). Consistent with this, an NF‑κB agonist completely blocked the anxiolytic effects of CAP1 knockdown, confirming that CAP1 acts through this signaling cascade to promote cytokine release and subsequent synaptic remodeling. Collectively, these findings establish ACC CAP1 as a critical mediator of chronic pain‑induced anxiety in male mice and suggest that targeting CAP1 may represent a promising strategy for precision intervention in pain-related affective disorders.

PMID:
42874881
Bibliographic data and abstract were imported from PubMed on 15 Oct 2026.

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