Abstract:
:Cancer-associated pain is debilitating. Understanding the mechanisms that cause it can inform drug development that may improve quality of life in patients. Here, we found that the reduced abundance of potassium channels called TRESK in dorsal root ganglion (DRG) neurons sensitized nociceptive sensory neurons and cancer-associated pain. Overexpressing TRESK in DRG neurons suppressed tumor-induced neuronal hyperexcitability and pain hypersensitivity in bone metastasis model rats, whereas knocking down TRESK increased neuronal hyperexcitability and pain hypersensitivity in normal rats. Mechanistically, tumor-associated production of vascular endothelial growth factor (VEGF) activated the receptor VEGFR2 on DRGs, which increased the abundance of the calcineurin inhibitor DSCR1, which, in turn, decreased calcineurin-mediated activation of the transcription factor NFAT, thereby reducing the transcription of the gene encoding TRESK. Intrathecal application of exogenous calcineurin to tumor-bearing rats rescued TRESK abundance and abrogated both DRG hyperexcitability and pain hypersensitivity, whereas either inhibition or knockdown of calcineurin in normal rats reduced TRESK abundance and increased DRG excitability and pain sensitivity. These findings identify a potentially targetable mechanism that may cause bone metastasis-associated pain in cancer patients.
journal_name
Sci Signaljournal_title
Science signalingauthors
Yang Y,Li S,Jin ZR,Jing HB,Zhao HY,Liu BH,Liang YJ,Liu LY,Cai J,Wan Y,Xing GGdoi
10.1126/scisignal.aao5150subject
Has Abstractpub_date
2018-10-16 00:00:00issue
552eissn
1945-0877issn
1937-9145pii
11/552/eaao5150journal_volume
11pub_type
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