Circadian gene NPAS2 modulates pain sensitization in CFA-induced inflammatory pain model

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.