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

## TL;DR

This study shows that Na+/K+-ATPase α1 interacts with P2X3 receptors to influence bone cancer pain, offering a new therapeutic target for managing chronic pain in cancer patients.

## Contribution

The study reveals a novel regulatory mechanism involving Na+/K+-ATPase α1 and P2X3 receptors in bone cancer pain.

## Key findings

- Conditional knockout of NKAα1 in TRPV1+ neurons increases P2X3R-dependent Ca2+ influx and neuronal hyperexcitability.
- NKAα1 knockout enhances CCL5 release, leading to spinal glial activation and worsened pain hypersensitivity in BCP mice.
- DR5-12D antibody stabilizes NKAα1 and reduces pain hypersensitivity in BCP models.

## 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.