Pirt promotes substance P release in cancer-induced bone pain.

INTRODUCTION

Cancer-induced bone pain (CIBP) is a major clinical challenge due to its intricate, poorly understood pathogenesis. Sensitized tumor-innervating nerves interacting with cancer cells drive CIBP, and substance P (SP) released by these nerves is a key mediator of pathological processes. However, the mechanisms regulating SP release in CIBP remain unclear.

OBJECTIVES

To explore Pirt's involvement in CIBP and its role in regulating SP release.

METHODS

Molecular and behavioral experiments were performed using Pirt knockout (Pirt-KO) and wild-type (WT) mice in a CIBP model. Pain-related behaviors and SP were assessed, with Pirt expression and localization analyzed in dorsal root ganglia (DRG) and spinal cord.

RESULTS

Pirt-KO mice exhibited attenuated heat allodynia, mechanical allodynia, and spontaneous pain vs WT mice. Substance P level in tissues and SP release from DRG neurons was significantly reduced in Pirt-KO mice. All DRG SP-positive neurons expressed Pirt, and Pirt - green fluorescent protein (GFP) terminals projected to spinal lamina I/II, colocalizing with SP-positive terminals.

CONCLUSION

Pirt plays a crucial role in promoting SP release in CIBP, shedding light on the molecular mechanisms underlying CIBP and providing a potential therapeutic target.