Fang Yuanyuan, Sui Xiaokai, Zheng Danhao, Sun Jiahui, Chen Ting, Jia Junke, Yao Jing, Wang Jie, Chen Chang, Zhang Zongze
Department of Anaesthesiology, Zhongnan Hospital, Wuhan University, Wuhan, China.
State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Center for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences-Wuhan National Laboratory for Optoelectronics, Wuhan, Hubei Province, China.
Brain Res Bull. 2025 Jul 29;230:111488. doi: 10.1016/j.brainresbull.2025.111488.
The comorbidity of chronic pain and anxiety exerts a profound impact on neurological functions. This study aims to investigate the alterations in brain metabolism and functional connectivity that arise from the interaction between chronic pain and anxiety in rats. Furthermore, the potential therapeutic effects of esketamine on these alterations are examined.
Twelve-week-old male rats underwent spared nerve injury (SNI) surgery to establish a model of chronic pain with anxiety. Pain intensity was assessed regularly with pain thresholds responding to mechanical and thermal stimuli after surgery. Anxiety-like behaviors were evaluated on day 32 post-SNI using open field test (OFT) and elevated plus maze test (EPM). Commencing on day 29 post-SNI, they received intraperitoneal administration of esketamine at 6 mg/kg once daily for three consecutive days. Additional cohorts were used for functional magnetic resonance imaging (fMRI), nuclear magnetic resonance (NMR) spectroscopy, and brain c-Fos immunostaining on post-surgery day 32.
Esketamine significantly alleviated SNI-induced hyperalgesia and anxiety-like behaviors, leading to reduced sensitivity to mechanical and thermal pain and a longer duration spent in the central area of the OFT, and longer time spent in the open arms of the EPM. Additionally, SNI rats showed an increased C enrichment of Glx in the cerebral cortex, striatum and thalamus, while esketamine reduced Glx enrichment in the cerebral cortex, indicating decreased cortical glutamate dynamics. Esketamine negated the increased functional connectivity between the right primary somatosensory cortex (S1) and the basolateral amygdala (BLA) induced by chronic pain and anxiety. Consistently, esketamine significantly decreased neuronal activation labelled with c-Fos cells in the S1 and BLA following acute pain stimulation.
Esketamine alleviates SNI-induced hyperalgesia and anxiety, potentially by reducing the heightened functional connectivity between the S1 and the BLA associated with pain and anxiety, while also normalizing glutamate metabolism in the brain. These findings suggest that esketamine may be a promising therapeutic option for managing pain and anxiety related to chronic pain conditions.
慢性疼痛与焦虑的共病对神经功能有深远影响。本研究旨在探究大鼠慢性疼痛与焦虑相互作用所引起的脑代谢和功能连接的改变。此外，还研究了艾氯胺酮对这些改变的潜在治疗作用。
12周龄雄性大鼠接受保留神经损伤（SNI）手术以建立伴有焦虑的慢性疼痛模型。术后定期通过对机械和热刺激的疼痛阈值评估疼痛强度。在SNI术后第32天使用旷场试验（OFT）和高架十字迷宫试验（EPM）评估焦虑样行为。从SNI术后第29天开始，它们连续三天每天接受一次腹腔注射6mg/kg的艾氯胺酮。在术后第32天，另外的大鼠队列用于功能磁共振成像（fMRI）、核磁共振（NMR）波谱分析和脑c-Fos免疫染色。
艾氯胺酮显著减轻了SNI诱导的痛觉过敏和焦虑样行为，导致对机械和热痛的敏感性降低，在OFT中央区域停留的时间延长，以及在EPM开放臂停留的时间延长。此外，SNI大鼠大脑皮层、纹状体和丘脑的Glx中C富集增加，而艾氯胺酮降低了大脑皮层中Glx的富集，表明皮层谷氨酸动力学降低。艾氯胺酮消除了慢性疼痛和焦虑诱导的右侧初级体感皮层（S1）与基底外侧杏仁核（BLA）之间功能连接的增加。一致地，艾氯胺酮显著降低了急性疼痛刺激后S1和BLA中c-Fos细胞标记的神经元激活。
艾氯胺酮减轻了SNI诱导的痛觉过敏和焦虑，可能是通过降低与疼痛和焦虑相关的S1和BLA之间增强的功能连接，同时使大脑中的谷氨酸代谢正常化。这些发现表明，艾氯胺酮可能是治疗与慢性疼痛相关的疼痛和焦虑的有前景的治疗选择。
