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

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.