Targeting Central Sensitisation in Rheumatoid Arthritis: Exploring NCX3 as a Novel Therapeutic Strategy

Rheumatoid arthritis (RA) is a chronic autoimmune disease marked by persistent joint inflammation, leading to progressive tissue damage and severe pain. Despite advances in antirheumatic treatments, effective pain management remains inadequate for 40-52% of patients. The phenomenon is thought to be exacerbated—and potentially driven—by central sensitisation, where the central nervous system amplifies peripheral nociceptive signals, intensifying pain perception. My research aims to mechanistically dissect central sensitisation in RA, evaluating the sodium-calcium exchanger NCX3 as a potential therapeutic target. NCX3, identified through a genome-wide association study and validated in mouse models, regulates intracellular Ca2+ levels in spinal neurons and is highly likely to be a crucial modulator of pain in RA. The project will employ cutting-edge in vivo Ca2+ imaging techniques in an RA mouse model to directly interrogate central sensitisation in spinal cord projection neurons. We will compare activity between NCX3-ablated and wild-type mice, and test whether over-expressing NCX3 can improve pain behaviours. Finally, we will examine NCX3 gene expression in human and mouse spinal cord under painful inflammatory conditions. The results I obtain will fill crucial gaps in our mechanistic understanding of RA pain and validate a novel drug target, against which compounds are already being developed.