Circadian regulation of chemotherapy-induced peripheral neuropathic pain and the underlying transcriptomic landscape.

Abstract

Growing evidence demonstrates circadian rhythms of pain hypersensitivity in various chronic disorders. In chemotherapy-induced peripheral neuropathy (CIPN), agents such as paclitaxel are known to elicit chronic neuropathic pain in cancer patients and seriously compromise their quality of life. Here, we report that the mechanical threshold for allodynia in paclitaxel-treated rats exhibited a robust circadian oscillation, reaching the nadir during the daytime (inactive phase). Using Per2::LucSV circadian reporter mice expressing a PER2::LUC fusion protein, we isolated dorsal root ganglia (DRG), the primary sensory cell body for peripheral nerve injury generated hypersensitivity, and monitored ex vivo reporter bioluminescence. We observed strong circadian reporter rhythms in DRG neurons which are highly entrainable by external cues. Paclitaxel treatment significantly lengthened DRG circadian periods, with little effects on the amplitude of oscillation. We further observed the core protein BMAL1 and PER2 in DRG neurons and satellite cells. Using DRG and dorsal horn (DH; another key structure for CIPN pain response) tissues from vehicle and paclitaxel treated rats, we performed RNA-sequencing and identified diurnal expression of core clock genes as well as clock-controlled genes in both sites. Interestingly, 20.1% and 30.4% of diurnal differentially expressed genes (DEGs) overlapped with paclitaxel-induced DEGs in the DRG and the DH respectively. In contrast, paclitaxel-induced DEGs displayed only a modest overlap between daytime and nighttime (Zeitgeber Time 8 and 20). Furthermore, paclitaxel treatment induced de novo diurnal DEGs, suggesting reciprocal interaction of circadian rhythms and chemotherapy. Our study therefore demonstrates a circadian oscillation of CIPN and its underlying transcriptomic landscape.

• Authors: Hee Kee Kim, Sun-Yeul Lee, Nobuya Koike, Eunju Kim, Marvin Wirianto, Mark J Burish, Kazuhiro Yagita, Hyun Kyoung Lee, Zheng Chen, Jin Mo Chung, Salahadin Abdi, Seung-Hee Yoo
• Journal: Scientific reports (Sci Rep) Vol. 10 Issue 1 Pg. 13844 (08 14 2020) ISSN: 2045-2322 [Electronic] England
• PMID: 32796949 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• ARNTL Transcription Factors
• Antineoplastic Agents, Phytogenic
• Bmal1 protein, mouse
• Per2 protein, mouse
• Period Circadian Proteins
• Paclitaxel

Topics

• ARNTL Transcription Factors
• Animals
• Antineoplastic Agents, Phytogenic (adverse effects)
• Circadian Rhythm (drug effects, genetics, physiology)
• Disease Models, Animal
• Ganglia, Spinal (physiology)
• Gene Expression
• In Vitro Techniques
• Mice
• Neuralgia (etiology, physiopathology)
• Paclitaxel (adverse effects)
• Period Circadian Proteins
• Peripheral Nerve Injuries
• Rats
• Spinal Cord Dorsal Horn (physiology)