Flavonoid chronotherapy normalizes circadian dynamics and sleep architecture in mice with painful nerve injury
- 1University of Helsinki
Abstract
Neuropathic pain (NP) is linked to disrupted sleep and circadian abnormalities upon painful peripheral nerve injury. By performing spared nerve injury (SNI) in circadian reporter PER2::LUC mice, we characterized the real-time changes in rhythmicity of the core clock gene Per2 in the pain-regulating dorsal root ganglia (DRG), and the sleep-wake cycle using wireless EEG/EMG under NP conditions. We further evaluated whether the clock-resynchronizing flavonoids, nobiletin (2 mg/kg/day) and tangeretin (1.8 mg/kg/day), administered continuously via osmotic minipumps for two weeks, could restore circadian dynamics and alleviate pain-related behaviour. Both flavonoids alleviated SNI-induced dynamic hypersensitivity in PER2::LUC mice on post-surgical day 14. SNI increased the amplitude of Per2 rhythms in the DRGs, which was restored to pre-surgical levels by administration of flavonoids. In addition, tangeretin showed sleep-restoring properties upon SNI by alleviating disturbances in NREM sleep and wakefulness. These results support targeting circadian disruption as a potential chronotherapeutic approach to alleviate NP.
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BibTeX
@misc{launonen2026flavonoid,
title = {{Flavonoid chronotherapy normalizes circadian dynamics and sleep architecture in mice with painful nerve injury}},
author = {H. Launonen and W. Dai and M. Wen and N. Milicevic and M.-K. Koskinen and A. Pertovaara and E. Kalso and H.-K. Wigren and V. Palada},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.26.761906},
url = {https://www.biorxiv.org/content/10.64898/2026.10.26.761906v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Flavonoid chronotherapy normalizes circadian dynamics and sleep architecture in mice with painful nerve injury
AU - H. Launonen
AU - W. Dai
AU - M. Wen
AU - N. Milicevic
AU - M.-K. Koskinen
AU - A. Pertovaara
AU - E. Kalso
AU - H.-K. Wigren
AU - V. Palada
PY - 2026
DA - 2026/10/26
PB - bioRxiv
DO - 10.64898/2026.10.26.761906
UR - https://www.biorxiv.org/content/10.64898/2026.10.26.761906v1
AB - Neuropathic pain (NP) is linked to disrupted sleep and circadian abnormalities upon painful peripheral nerve injury. By performing spared nerve injury (SNI) in circadian reporter PER2::LUC mice, we characterized the real-time changes in rhythmicity of the core clock gene Per2 in the pain-regulating dorsal root ganglia (DRG), and the sleep-wake cycle using wireless EEG/EMG under NP conditions. We further evaluated whether the clock-resynchronizing flavonoids, nobiletin (2 mg/kg/day) and tangeretin (1.8 mg/kg/day), administered continuously via osmotic minipumps for two weeks, could restore circadian dynamics and alleviate pain-related behaviour. Both flavonoids alleviated SNI-induced dynamic hypersensitivity in PER2::LUC mice on post-surgical day 14. SNI increased the amplitude of Per2 rhythms in the DRGs, which was restored to pre-surgical levels by administration of flavonoids. In addition, tangeretin showed sleep-restoring properties upon SNI by alleviating disturbances in NREM sleep and wakefulness. These results support targeting circadian disruption as a potential chronotherapeutic approach to alleviate NP.
ER -