Decreased abundance of TRESK two-pore domain potassium channels in sensory neurons underlies the pain associated with bone metastasis

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.

TRESK background K+ channel deletion selectively uncovers enhanced mechanical and cold sensitivity

“…Another study reported similar results in TG neurons but, surprisingly, lumbar DRG neurons from the same TRESK KO mice were not found to be hyperexcitable (Guo et al 2019). Although we did not differentiate between IB4 + and IB4 − neurons in this study, our data support previous findings of enhanced excitability of nociceptive sensory neurons (small DRGs) either after TRESK deletion or after a significant decrease in its expression (Dobler et al 2007;Tulleuda et al 2011;Yang et al 2018;Weir et al 2019). These effects have been also found after a decreased TRESK expression in a functional TRESK[G339R] knockout mice (Dobler et al 2007;Kollert et al 2015), after sciatic nerve axotomy (Tulleuda et al 2011) or in a model of cancer-associated pain (Yang et al 2018).…”

“…Although we did not differentiate between IB4 + and IB4 − neurons in this study, our data support previous findings of enhanced excitability of nociceptive sensory neurons (small DRGs) either after TRESK deletion or after a significant decrease in its expression (Dobler et al 2007;Tulleuda et al 2011;Yang et al 2018;Weir et al 2019). These effects have been also found after a decreased TRESK expression in a functional TRESK[G339R] knockout mice (Dobler et al 2007;Kollert et al 2015), after sciatic nerve axotomy (Tulleuda et al 2011) or in a model of cancer-associated pain (Yang et al 2018). This is in agreement with the neuronal activation observed by compounds blocking TRESK Tulleuda et al 2011;Castellanos et al 2018) or with the decreased excitability when overexpressing the channel (Guo & Cao, 2014;Yang et al 2018), indicating that the regulation of TRESK expression is an important factor to control sensory neuron excitability.…”

“…) or in a model of cancer‐associated pain (Yang et al . ). This is in agreement with the neuronal activation observed by compounds blocking TRESK (Bautista et al .…”

“…; Yang et al . ). Likewise, trigeminal expression of a mutated form of TRESK linked to migraine results in facial mechanical allodynia (Royal et al .…”

“…) or with the decreased excitability when overexpressing the channel (Guo & Cao, ; Yang et al . ), indicating that the regulation of TRESK expression is an important factor to control sensory neuron excitability.…”