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
Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Department of Neurobiology and Acupuncture Research, The Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China.
Department of Acupuncture and Moxibustion, the First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China.
CNS Neurosci Ther. 2024 Apr;30(4):e14520. doi: 10.1111/cns.14520. Epub 2023 Nov 29.
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.
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.
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 (rACC-DRN neurons) but not rACC CaMKII neurons projecting to DRN GABAergic neurons (rACC-DRN neurons). This is supported by the findings that chemogenetic activation of the rACC-DRN circuit alleviates anxiety-like behaviors in rats with chronic pain, whereas neither chemogenetic inhibition nor chemogenetic activation of the rACC-DRN 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 rACC-DRN circuit blocked the therapeutic effects of EA on chronic pain-induced anxiety-like behaviors.
Our data suggest that the reversal of rACC-DRN circuit dysfunction may be a mechanism underlying the therapeutic effect of EA on chronic pain-induced anxiety-like behaviors.
慢性疼痛引发的负面情绪是一个严重的临床问题。电针是一种经临床验证的用于管理与疼痛相关负面情绪的安全有效方法。然而，电针治疗对负面情绪影响的神经回路机制仍不清楚。
通过足底注射完全弗氏佐剂（CFA）建立慢性炎症性疼痛诱导焦虑样行为的大鼠模型。利用腺相关病毒（AAV）示踪技术来识别从喙前部扣带回皮质（rACC）到中缝背核（DRN）的兴奋性突触传递。采用化学遗传学方法，我们研究了rACC-DRN神经回路在慢性疼痛诱导的焦虑样行为中的作用，并探究电针是否能逆转慢性疼痛诱导的rACC-DRN神经回路功能障碍及焦虑样行为。
我们发现，化学遗传学激活rACC-DRN神经回路可减轻CFA诱导的焦虑样行为，而化学遗传学抑制rACC-DRN神经回路则导致短期CFA诱导的焦虑样行为。进一步研究表明，CFA诱导的焦虑样行为的发生归因于投射至DRN 5-羟色胺能神经元的rACC CaMKII神经元（rACC-DRN神经元）功能障碍，而非投射至DRN γ-氨基丁酸能神经元的rACC CaMKII神经元（rACC-DRN神经元）功能障碍。这一观点得到以下研究结果的支持：化学遗传学激活rACC-DRN神经回路可减轻慢性疼痛大鼠的焦虑样行为，而化学遗传学抑制或激活rACC-DRN神经回路均未改变CFA慢性疼痛诱发的大鼠焦虑样行为。更重要的是，我们发现电针可逆转慢性疼痛诱导的rACC CaMKII神经元和DRN 5-羟色胺能神经元活性变化，且化学遗传学抑制rACC-DRN神经回路可阻断电针对慢性疼痛诱导的焦虑样行为的治疗效果。
我们的数据表明，rACC-DRN神经回路功能障碍的逆转可能是电针治疗慢性疼痛诱导的焦虑样行为的潜在机制。
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