Li Xiao-Jie, Wu Shuo, Liu Zi-Han, Liu An-An, Peng Hui-Sheng, Wang Yu-Jun, Chen Ye-Xiang, Liu Jing-Gen, Xu Chi
School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
Department of Neurobiology and Acupuncture Research, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, The Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310061, China.
Acta Pharmacol Sin. 2025 Jun;46(6):1567-1579. doi: 10.1038/s41401-025-01496-9. Epub 2025 Feb 19.
Research shows that chronic pain may induce depression-like behaviors through impairing adult hippocampal neurogenesis (AHN) in the ventral dentate gyrus (DG), whereas restoration of AHN may effectively alleviate depression. The C-X-C motif chemokine receptor 2 (CXCR2) is a chemokine receptor involved in various neural activities of the hippocampus including AHN. In this study we investigated the role of CXCR2 of neural stem cells (NSCs) in the ventral DG in regulating both AHN and depression-like behaviors of mice with chronic neuropathic pain. Chronic neuropathic pain was induced in mice by the spared nerve injury (SNI) surgery; mechanical allodynia and depression-like behaviors were monitored, then mouse DG was collected for analysis. We observed that chronic neuropathic pain significantly decreased the number of immature neurons in the ventral DG by inhibiting the neuronal differentiation of NSCs; specific overexpression of CXCR2 in NSCs by injecting the adeno-associated virus (AAV) into the DG restored adult neurogenesis accompanied by alleviated depression-like behaviors in SNI mice. In contrast, the knockdown of CXCR2 in hippocampal NSCs of naive mice was sufficient to inhibit adult neurogenesis, inducing depression-like behaviors. Moreover, we found that the Wnt3a/β-catenin pathway was downregulated in the ventral DG of SNI mice, which was restored after CXCR2 overexpression or infusing a CXCR2 agonist CXCL1 into the ventral DG. We conclude that CXCR2 expressed in hippocampal NSCs is crucial for regulating adult neurogenesis and chronic pain-induced depression-like behavior, thus representing a new target for the treatment of chronic pain comorbid depression.
研究表明，慢性疼痛可能通过损害腹侧齿状回（DG）的成年海马神经发生（AHN）诱导类似抑郁的行为，而恢复AHN可有效缓解抑郁。C-X-C基序趋化因子受体2（CXCR2）是一种趋化因子受体，参与海马的各种神经活动，包括AHN。在本研究中，我们研究了腹侧DG神经干细胞（NSC）中的CXCR2在调节慢性神经性疼痛小鼠的AHN和类似抑郁行为中的作用。通过保留神经损伤（SNI）手术诱导小鼠产生慢性神经性疼痛；监测机械性异常性疼痛和类似抑郁的行为，然后收集小鼠DG进行分析。我们观察到，慢性神经性疼痛通过抑制NSC的神经元分化显著减少了腹侧DG中未成熟神经元的数量；通过向DG注射腺相关病毒（AAV）使NSC中CXCR2特异性过表达可恢复成年神经发生，并减轻SNI小鼠的类似抑郁行为。相反，在未处理小鼠的海马NSC中敲低CXCR2足以抑制成年神经发生，诱导类似抑郁的行为。此外，我们发现Wnt3a/β-连环蛋白通路在SNI小鼠的腹侧DG中下调，在CXCR2过表达或向腹侧DG注入CXCR2激动剂CXCL1后恢复。我们得出结论，海马NSC中表达的CXCR2对调节成年神经发生和慢性疼痛诱导的类似抑郁行为至关重要，因此代表了治疗慢性疼痛合并抑郁症的新靶点。
