Hypothalamic clock governs circadian pain.

Wei, Hong-Rui; Lou, Qianqian; Li, Le-Xian; Tang, Lan; Wu, Run-Jie; Li, Hong-Yu; Jiang, Ai-Jun; Yang, Xin-Lu et al. · Science · 2026

basic_science · Level V

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Abstract

Chronic pain exhibits circadian rhythms in humans, but the mechanisms underlying such rhythmicity remain unclear. Here, we found daily oscillations in the nociceptive thresholds in a mouse model of neuropathic pain, driven by a rhythmic circuit from the master clock in the hypothalamus to the descending analgesia system. In the daytime (resting phase), higher vasoactive intestinal peptide (VIP) neuronal activity in suprachiasmatic nucleus (SCN<sup>VIP</sup>) activates a signaling pathway involving the paraventricular nucleus (PVN) and the ventrolateral periaqueductal gray (vlPAG), ultimately increasing nociceptive sensitivity. At night (active phase), reduced SCN<sup>VIP</sup> neuronal activity decreases pain sensitivity through this polysynaptic circuit. This study identified a circuit for regulating pain rhythmicity that might be targeted to improve chronic pain management.

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