Papers of the Week

Rheumatoid arthritis-associated pain is poorly managed, often persisting when joint inflammation is pharmacologically controlled. Comparably, in the mouse K/BxN serum-transfer model of inflammatory arthritis, hind-paw nociceptive hypersensitivity occurs with ankle joint swelling (5 days post-immunisation) persisting after swelling has resolved (25 days post-immunisation). In this study, lipid mediator profiling of lumbar dorsal root ganglia (DRG), the site of sensory neuron cell bodies innervating the ankle joints, 5 days and 25 days after serum transfer demonstrated a shift in specialised pro-resolving lipid mediator (SPM) profiles. Persistent nociception without joint swelling was associated with low concentrations of the SPM Maresin-1 (MaR1) and high macrophage numbers in DRG. MaR1 application to cultured DRG neurons inhibited both capsaicin-induced increase of intracellular calcium ions and release of calcitonin gene-related peptide (CGRP) in a dose-dependent manner. Furthermore, in peritoneal macrophages challenged with lipopolysaccharide, MaR1 reduced pro-inflammatory cytokine expression. Systemic MaR1 administration caused sustained reversal of nociceptive hypersensitivity and reduced inflammatory macrophage numbers in DRG. Unlike gabapentin, which was used as positive control, systemic MaR1 did not display acute anti-hyperalgesic action. Therefore, these data suggest that MaR1 effects observed following K/BxN serum transfer relate to modulation of macrophage recruitment, more likely than to direct actions on sensory neurons. Our study highlights that, in DRG, aberrant pro-resolution mechanisms play a key role in arthritis joint pain dissociated from joint swelling, opening novel approaches for RA pain treatment.