| RRC ID |
86399
|
| 著者 |
Yasukochi S, Yamakawa W, Taniguchi M, Itoyama S, Tsuruta A, Kusunose N, Yamauchi T, Nakamura R, Matsunaga N, Ohdo S, Koyanagi S.
|
| タイトル |
The Circadian Clock Component REV-ERB Is an Analgesic Target for Cancer-Induced Tactile Pain Hypersensitivity.
|
| ジャーナル |
J Neurosci
|
| Abstract |
Neuropathic pain is one of the most intractable pain conditions associated with tumor growth compressing and damaging nerves. A troublesome hallmark symptom of neuropathic pain is hypersensitivity to innocuous stimuli, known as "tactile allodynia," which is often refractory to currently available analgesics. Diurnal variations in pain hypersensitivity are common in patients with cancer, but the underlying mechanisms are enigmatic. Herein, we report that spinal expression of lipocalin-2 (LCN2) enhances pain sensitivity of NCTC2472 fibrosarcoma-implanted male mice during specific stages of the diurnal cycle. As the tumor grew, interleukin-6 (IL-6) levels increased in the spinal cord of the mice. Increased IL-6 levels stimulated LCN2 expression in spinal microglia, but this expression was periodically repressed by the circadian clock components REV-ERBα and REV-ERBβ. Notably, intraspinal dorsal horn injection of lentiviral vectors expressing REV-ERBα or REV-ERBβ in tumor-bearing mice alleviated tactile allodynia. Furthermore, intrathecal injection of SR9009, a synthetic agonist of REV-ERBs, also attenuated cancer-induced pain hypersensitivity, accompanied by suppressing spinal LCN2 expression. These results suggest that temporal elevation of LCN2 expression decreases the threshold of tactile pain hypersensitivity induced by tumor growth. We propose that the circadian clock component of REV-ERBs is an effective target for alleviation of cancer-induced tactile allodynia, identifying a new class of analgesic agents.
|
| 巻・号 |
45(22)
|
| 公開日 |
2025-5-28
|
| DOI |
10.1523/JNEUROSCI.1969-24.2025
|
| PII |
JNEUROSCI.1969-24.2025
|
| PMID |
40268481
|
| PMC |
PMC12121715
|
| MeSH |
Analgesics* / pharmacology
Analgesics* / therapeutic use
Animals
Cancer Pain* / drug therapy
Cancer Pain* / metabolism
Cell Line, Tumor
Circadian Clocks* / drug effects
Circadian Clocks* / physiology
Hyperalgesia* / drug therapy
Hyperalgesia* / etiology
Hyperalgesia* / metabolism
Lipocalin-2 / metabolism
Male
Mice
Mice, Inbred C57BL
Nuclear Receptor Subfamily 1, Group D, Member 1* / agonists
Nuclear Receptor Subfamily 1, Group D, Member 1* / genetics
Nuclear Receptor Subfamily 1, Group D, Member 1* / metabolism
Pyrrolidines / pharmacology
Receptors, Cytoplasmic and Nuclear
Repressor Proteins
Spinal Cord / metabolism
Thiophenes / pharmacology
Thiophenes / therapeutic use
|
| IF |
5.674
|
| リソース情報 |
| ヒト・動物細胞 |
MG6(RCB2403) |
