Hypothalamic clock governs circadian pain.

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 (SCNVIP) activates a signaling pathway involving the paraventricular nucleus (PVN) and the ventrolateral periaqueductal gray (vlPAG), ultimately increasing nociceptive sensitivity. At night (active phase), reduced SCNVIP 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.