Dong Jiaqi, Wei Jingyi, Tong Hongwei, Shi Xiaohua, Yuan Menghui, Cao Yiwei, El-Magd Mohammed A, Chen Qiang, Zhang Hongxin, Yuan Peng, Mu Jiao
Department of Hematology, Xi'an Central Hospital, Xi'an, Shaanxi, China.
Department of Nuclear Medicine, Tangdu Hospital, Air Force Medical University, Xi'an, Shaanxi, China.
Mol Pain. 2025 Jan-Dec;21:17448069251351045. doi: 10.1177/17448069251351045. Epub 2025 Jun 6.
Pain, particularly chronic pain, is a major reason patients seek physical therapy. Inflammation plays a crucial role in both the development and persistence of chronic pain. Neuronal PAS domain protein 2 (NPAS2), a core circadian transcriptional regulator, has been implicated in modulating pain-related stress responses. In this study, we first examined NPAS2 expression in nociceptive-sensitized mice following complete Freund's adjuvant (CFA) administration. We then systematically investigated the effects of CFA on astrocyte activation and inflammatory factor release in NPAS2 knockout (KO) mice. Our results demonstrated that NPAS2 deletion did not alter baseline pain thresholds under normal physiological conditions. However, in CFA-injected mice, NPAS2 KO significantly lowered mechanical and thermal pain thresholds in 50% of subjects, leading to enhanced nociceptive sensitization. This effect may be attributed to the promotion of astrocyte activation and the upregulation of pro-inflammatory cytokines, including IL-1β, IL-6, TNF-α, and NF-κB. These findings highlight NPAS2 as a potential prognostic biomarker for pain chronification and a promising therapeutic target for biologically tailored pain interventions.
疼痛，尤其是慢性疼痛，是患者寻求物理治疗的主要原因。炎症在慢性疼痛的发生和持续过程中起着关键作用。神经元PAS结构域蛋白2（NPAS2）是一种核心昼夜节律转录调节因子，与调节疼痛相关应激反应有关。在本研究中，我们首先检测了完全弗氏佐剂（CFA）给药后伤害性致敏小鼠中NPAS2的表达。然后，我们系统地研究了CFA对NPAS2基因敲除（KO）小鼠星形胶质细胞活化和炎症因子释放的影响。我们的结果表明，在正常生理条件下，NPAS2缺失不会改变基线疼痛阈值。然而，在注射CFA的小鼠中，50%的NPAS2基因敲除小鼠的机械性和热痛阈值显著降低，导致伤害性致敏增强。这种效应可能归因于星形胶质细胞活化的促进和促炎细胞因子的上调，包括白细胞介素-1β、白细胞介素-6、肿瘤坏死因子-α和核因子-κB。这些发现突出了NPAS2作为疼痛慢性化潜在预后生物标志物以及生物定制疼痛干预有前景的治疗靶点的作用。
