A neural circuit associated with anxiety‐like behaviors induced by chronic inflammatory pain and the anxiolytic effects of electroacupuncture

• Published in: CNS neuroscience & therapeutics Vol. 30; no. 4; pp. e14520 - n/a
• Main Authors: Wu, Zemin, Shen, Zui, Xu, Yingling, Chen, Shaozong, Xiao, Siqi, Ye, Jiayu, Zhang, Haiyan, Ma, Xinyi, Zhu, Yichen, Zhu, Xixiao, Jiang, Yongliang, Fang, Junfan, Liu, Boyi, He, Xiaofen, Gao, Shuzhong, Shao, Xiaomei, Liu, Jinggen, Fang, Jianqiao
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.04.2024; John Wiley and Sons Inc
• Subjects: Acupuncture; Animals; Anti-Anxiety Agents - pharmacology; Anxiety; Anxiety - drug therapy; anxiety‐like behavior; Behavior; Ca2+/calmodulin-dependent protein kinase II; Calcium-Calmodulin-Dependent Protein Kinase Type 2; chronic inflammatory pain; Chronic pain; Chronic Pain - chemically induced; Chronic Pain - therapy; Comorbidity; Cortex (cingulate); Dorsal raphe nucleus; Electroacupuncture; Emotional disorders; Emotions; Freund's adjuvant; gamma-Aminobutyric Acid - pharmacology; Inflammation; Life sciences; Mood disorders; Neurons; Original; Raphe nuclei; Rats; rostral anterior cingulate cortex; Serotonergic Neurons; Serotonin; Synaptic transmission; Viruses; γ-Aminobutyric acid; United States > US; China; dorsal raphe nucleus; anxiety‐like behavior; rostral anterior cingulate cortex; chronic inflammatory pain; electroacupuncture; serotonergic neurons
• ISSN: 1755-5930; 1755-5949
• DOI: 10.1111/cns.14520

Aims Negative emotions induced by chronic pain are a serious clinical problem. Electroacupuncture (EA) is a clinically proven safe and effective method to manage pain‐related negative emotions. However, the circuit mechanisms underlying the effect of EA treatment on negative emotions remain unclear. Methods Plantar injection of complete Freund's adjuvant (CFA) was performed to establish a rat model of chronic inflammatory pain‐induced anxiety‐like behaviors. Adeno‐associated virus (AAV) tracing was used to identify excitatory synaptic transmission from the rostral anterior cingulate cortex (rACC) to the dorsal raphe nucleus (DRN). Employing chemogenetic approaches, we examined the role of the rACC‐DRN circuit in chronic pain‐induced anxiety‐like behaviors and investigated whether EA could reverse chronic pain‐induced dysfunctions of the rACC‐DRN circuit and anxiety‐like behaviors. Results We found that chemogenetic activation of the rACC‐DRN circuit alleviated CFA‐induced anxiety‐like behaviors, while chemogenetic inhibition of the rACC‐DRN circuit resulted in short‐term CFA‐induced anxiety‐like behaviors. Further research revealed that the development of CFA‐induced anxiety‐like behaviors was attributed to the dysfunction of rACC CaMKII neurons projecting to DRN serotonergic neurons (rACCCaMKII‐DRN5‐HT neurons) but not rACC CaMKII neurons projecting to DRN GABAergic neurons (rACCCaMKII‐DRNGABA neurons). This is supported by the findings that chemogenetic activation of the rACCCaMKII‐DRN5‐HT circuit alleviates anxiety‐like behaviors in rats with chronic pain, whereas neither chemogenetic inhibition nor chemogenetic activation of the rACCCaMKII‐DRNGABA circuit altered CFA chronic pain‐evoked anxiety‐like behaviors in rats. More importantly, we found that EA could reverse chronic pain‐induced changes in the activity of rACC CaMKII neurons and DRN 5‐HTergic neurons and that chemogenetic inhibition of the rACCCaMKII‐DRN5‐HT circuit blocked the therapeutic effects of EA on chronic pain‐induced anxiety‐like behaviors. Conclusions Our data suggest that the reversal of rACCCaMKII‐DRN5‐HT circuit dysfunction may be a mechanism underlying the therapeutic effect of EA on chronic pain‐induced anxiety‐like behaviors. Chronic inflammatory pain induces anxiety‐like behaviors, and electroacupuncture ameliorates negative emotions by intervening rACCCaMKII‐DRN5‐HT neural circuit but not the rACCCaMKII‐DRNGABA circuit.