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.

Previously we have demonstrated that brain-derived neurotrophic factor (BDNF) contributes to spinal long-term potentiation (LTP) and pain hypersensitivity through activation of GluN2B-containing N-methyl-D-aspartate (GluN2B-NMDA) receptors in rats following spinal nerve ligation (SNL). However, the molecular mechanisms by which BDNF impacts upon GluN2B-NMDA receptors and spinal LTP still remain unclear. In this study, we first documented that Fyn kinase-mediated phosphorylation of GluN2B subunit at tyrosine 1472 (pGluN2B) was involved in BDNF-induced spinal LTP and pain hypersensitivity in intact rats. Second, we revealed a co-localization of Fyn and GluN2B-NMDA receptor in cultured dorsal horn neurons, implying that Fyn is a possible intermediate kinase linking BDNF/TrkB signaling with GluN2B-NMDA receptors in the spinal dorsal horn. Furthermore, we discovered that both SNL surgery and intrathecal active Fyn could induce an increased expression of dorsal horn pGluN2B, as well as pain hypersensitivity in response to von Frey filaments stimuli; and more importantly, all these actions were effectively abrogated by pre-treatment with either PP2 or ifenprodil to respectively inhibit Fyn kinase and GluN2B-NMDA receptors activity. Moreover, we found that intrathecal administration of BDNF scavenger TrkB-Fc prior to SNL surgery, could prevent the nerve injury-induced increase of both pFyn and pGluN2B expression, and also inhibit the mechanical allodynia in neuropathic rats. Collectively, these results suggest that Fyn kinase-mediated pGluN2B is critical for BDNF-induced spinal LTP and pain hypersensitivity in SNL rats. Therefore, the BDNF-Fyn-GluN2B signaling cascade in the spinal dorsal horn may constitute a key mechanism underlying central sensitization and neuropathic pain development after peripheral nerve injury.

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