Astrocyte inhibition and PV interneuron activation: key mechanisms in electroacupuncture's effect on pain-anxiety comorbidity.

Background: Evidence indicates that the interplay between pain and anxiety poses clinical challenges for the evaluation and management of chronic pain, yet effective therapies for these comorbidities are limited. This study aimed to elucidate the effects and mechanisms of electroacupuncture (EA) on pain-anxiety comorbidities.

Methods: Mice injected with Complete Freund's adjuvant (CFA) in the ipsilateral hind paw developed persistent inflammatory pain and anxiety-like behaviors, as assessed by the von Frey, open field, elevated plus maze, and novelty-suppressed feeding tests. EA was administered 12-17d after CFA injection with once daily. rAAV virus and chemogenetics were used to manipulate parvalbumin (PV) interneurons and astrocytes excitation in the anterior cingulate cortex (ACC). Immunofluorescence, morphological analysis, patch clamp and in vivo fiber Ca²⁺ imaging were used to examine the activation of PV interneurons and astrocytes. The effect of EPCPX (antagonist of A1R) and chemogenetics activated astrocytes on EA analgesia were observed in a subset of mice prior to EA.

Results: EA administration alleviated pain and anxiety-like behaviors in CFA mice, activated PV interneurons, and inhibited astrocytes activation in the ACC. Furthermore, both PV interneurons activation and astrocyte inhibition in the ACC elicited effects similar to those elicited by EA on pain and anxiety. Chemogenetic activation of ACC astrocytes reversed the effects of EA. Additionally, astrocyte activation in the ACC suppressed PV interneurons and induced pain-anxiety like behaviors in mice. Adenosine A1 receptors, crucial for mediating the interaction between astrocytes and PV interneurons in the ACC, were also found to be involved in the effects of EA on pain-anxiety comorbidity.

Conclusions: These findings reveal that EA alleviates the pain and anxiety comorbidity through a potential mechanism involving the activation of PV interneurons, which are modulated by the inhibition of astrocytes in the ACC, thus providing a promising therapeutic strategy for persistent pain and concurrent anxiety.