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

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,...

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Veröffentlicht in:Scientific reports 2020-08, Vol.10 (1), p.13844, Article 13844
Hauptverfasser: Kim, Hee Kee, Lee, Sun-Yeul, Koike, Nobuya, Kim, Eunju, Wirianto, Marvin, Burish, Mark J., Yagita, Kazuhiro, Lee, Hyun Kyoung, Chen, Zheng, Chung, Jin Mo, Abdi, Salahadin, Yoo, Seung-Hee
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creator Kim, Hee Kee
Lee, Sun-Yeul
Koike, Nobuya
Kim, Eunju
Wirianto, Marvin
Burish, Mark J.
Yagita, Kazuhiro
Lee, Hyun Kyoung
Chen, Zheng
Chung, Jin Mo
Abdi, Salahadin
Yoo, Seung-Hee
description 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.
doi_str_mv 10.1038/s41598-020-70757-w
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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.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/s41598-020-70757-w</identifier><identifier>PMID: 32796949</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/378/1385 ; 631/443/376 ; Animals ; Antineoplastic Agents, Phytogenic - adverse effects ; ARNTL Transcription Factors ; Bioluminescence ; BMAL1 protein ; Cell body ; Chemotherapy ; Circadian rhythm ; Circadian Rhythm - drug effects ; Circadian Rhythm - genetics ; Circadian Rhythm - physiology ; Circadian rhythms ; Core protein ; Daytime ; Disease Models, Animal ; Diurnal ; Dorsal horn ; Dorsal root ganglia ; Fusion protein ; Ganglia, Spinal - physiology ; Gene Expression ; Humanities and Social Sciences ; Hypersensitivity ; In Vitro Techniques ; Mice ; multidisciplinary ; Neuralgia - etiology ; Neuralgia - physiopathology ; Paclitaxel ; Paclitaxel - adverse effects ; Pain ; Pain perception ; Period 2 protein ; Period Circadian Proteins ; Peripheral Nerve Injuries ; Peripheral nerves ; Peripheral neuropathy ; Quality of life ; Rats ; Ribonucleic acid ; RNA ; Satellite cells ; Science ; Science (multidisciplinary) ; Sensory neurons ; Spinal Cord Dorsal Horn - physiology ; Transcriptomics</subject><ispartof>Scientific reports, 2020-08, Vol.10 (1), p.13844, Article 13844</ispartof><rights>The Author(s) 2020</rights><rights>The Author(s) 2020. 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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. 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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.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>32796949</pmid><doi>10.1038/s41598-020-70757-w</doi><oa>free_for_read</oa></addata></record>
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subjects 631/378/1385
631/443/376
Animals
Antineoplastic Agents, Phytogenic - adverse effects
ARNTL Transcription Factors
Bioluminescence
BMAL1 protein
Cell body
Chemotherapy
Circadian rhythm
Circadian Rhythm - drug effects
Circadian Rhythm - genetics
Circadian Rhythm - physiology
Circadian rhythms
Core protein
Daytime
Disease Models, Animal
Diurnal
Dorsal horn
Dorsal root ganglia
Fusion protein
Ganglia, Spinal - physiology
Gene Expression
Humanities and Social Sciences
Hypersensitivity
In Vitro Techniques
Mice
multidisciplinary
Neuralgia - etiology
Neuralgia - physiopathology
Paclitaxel
Paclitaxel - adverse effects
Pain
Pain perception
Period 2 protein
Period Circadian Proteins
Peripheral Nerve Injuries
Peripheral nerves
Peripheral neuropathy
Quality of life
Rats
Ribonucleic acid
RNA
Satellite cells
Science
Science (multidisciplinary)
Sensory neurons
Spinal Cord Dorsal Horn - physiology
Transcriptomics
title Circadian regulation of chemotherapy-induced peripheral neuropathic pain and the underlying transcriptomic landscape
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