Na+/K+-ATPase Modulates Purinergic P2X3 Receptor Function to Drive Bone Cancer Pain

Abstract

Bone cancer pain (BCP) is one of the most common types of chronic pain in cancer patients, with a prevalence of up to 75%. However, the pathological mechanism and therapeutic approaches are limited. Here, we demonstrated that Na⁺/K⁺-ATPase α1 (NKAα1) is a critical regulator of nociception through interaction with purinergic P2X3 receptor (P2X3R) in the dorsal root ganglion (DRG). Conditional knockout of NKAα1 in transient receptor potential vanilloid 1-positive (TRPV1⁺) neurons led to an increase in P2X3R-dependent Ca²⁺ influx and neuronal hyperexcitability and also promoted pain hypersensitivity in BCP model mice. In addition, NKAα1 knockout in TRPV1⁺ neurons further enhanced C-C motif chemokine ligand 5 release, thereby exacerbating spinal glial cell activation and pain hypersensitivity in BCP mice. DR5-12D, a monoclonal antibody to stabilize the expression of NKAα1, markedly inhibited the hyperexcitability of DRG nociceptors and ameliorated pain hypersensitivity in BCP mice. Overall, NKAα1 modulates P2X3R-dependent Ca²⁺ influx and the excitability of DRG nociceptors, thereby providing valuable theoretical guidance for the treatment of BCP.