2. Academic Validation
  3. Astrocyte-mediated central amygdala microcircuit gates comorbid anxiety symptoms in chronic pain

Astrocyte-mediated central amygdala microcircuit gates comorbid anxiety symptoms in chronic pain

  • Neuron. 2025 Oct 2:S0896-6273(25)00670-1. doi: 10.1016/j.neuron.2025.09.004.
Gui-Ying Zan 1,  Song-Yu Yao 2,  Ying-Zhi Deng 3,  Yun-Hao Jiang 4,  Ru-Feng Ye 5,  Yexiang Chen 5,  Jian-Dong Long 3,  Ying-Jie Cheng 6,  Jing-Rui Chai 3,  Chi Xu 5,  Min Zhao 6,  Zhi-Qiang Liu 7,  Jing-Gen Liu 8,  Yu-Jun Wang 9
Affiliations

Affiliations

  • 1 CAS Key Laboratory of Receptor Research and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 555 Zuchongzhi Road, Shanghai 201203, China; Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China. Electronic address: zanguiying@126.com.
  • 2 CAS Key Laboratory of Receptor Research and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 555 Zuchongzhi Road, Shanghai 201203, China; Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Key Laboratory of Acupuncture and Neurobiology of Zhejiang Province, Hangzhou 310053, China.
  • 3 CAS Key Laboratory of Receptor Research and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 555 Zuchongzhi Road, Shanghai 201203, China.
  • 4 School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China.
  • 5 Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Key Laboratory of Acupuncture and Neurobiology of Zhejiang Province, Hangzhou 310053, China.
  • 6 Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
  • 7 Department of Anesthesiology, The Obstetrics & Gynecology Hospital of Fudan University, Shanghai 200090, China.
  • 8 CAS Key Laboratory of Receptor Research and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 555 Zuchongzhi Road, Shanghai 201203, China; Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Key Laboratory of Acupuncture and Neurobiology of Zhejiang Province, Hangzhou 310053, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, China. Electronic address: jgliu@simm.ac.cn.
  • 9 CAS Key Laboratory of Receptor Research and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 555 Zuchongzhi Road, Shanghai 201203, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, China. Electronic address: yjwang@simm.ac.cn.
PMID: 41043420 DOI: 10.1016/j.neuron.2025.09.004
Abstract

Comorbid anxiety symptoms are prominent affective components of chronic pain, yet the central mechanisms underlying these symptoms remain elusive. The central amygdala (CeA) regulates nociceptive processing and associated anxiety in chronic pain. However, the specific microcircuits and cell types within the CeA that regulate pain-related anxiety have not been fully elucidated. In this study, we discovered a microcircuit in the CeA wherein dynorphinergic neurons of the lateral subdivision of the central amygdala (CeL) project to the medial subdivision (CeM), activation of which gates anxiogenic effects associated with chronic pain. Dynorphin-mediated activation of CeM astroglial kappa opioid receptors (KORs), dependent upon corticotropin-releasing factor (CRF) receptor 2 signaling, enhanced CeM neuron excitability by promoting N-methyl-D-aspartate receptor (NMDAR) activation, likely via releasing gliotransmitter D-serine. Behaviorally, KOR-mediated bidirectional communication between CeA peptidergic neurons and astrocytes modulates the anxiogenic effect of chronic pain. Our findings reveal a neuroglial microcircuit underlying pain-associated anxiety and suggest potential targets for therapeutic intervention.

Keywords

CeL(Pdyn)-CeM projections; D-serine; astrocyte; chronic-pain-related anxiety; kappa opioid receptor.

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