Astrocyte-mediated central amygdala microcircuit gates comorbid anxiety
symptoms in chronic pain
Gui-Ying Zan, Song-Yu Yao, Ying-Zhi Deng, Yun-Hao Jiang, Ru-Feng Ye,
Yexiang Chen, Jian-Dong Long, Ying-Jie Cheng, Jing-Rui Chai, Chi Xu, Min
Zhao, Zhi-Qiang Liu, Jing-Gen Liu, Yu-Jun Wang
Neuron. 2025 Oct 2:S0896-6273(25)00670-1. doi: 10.1016/j.neuron.2025.09.
004.

https://www.sciencedirect.com/science/article/pii/S0896627325006701?via%3Dihub

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.