NS5806 reduces carrageenan‐evoked inflammation by suppressing extracellular signal‐regulated kinase activation in primary sensory neurons and immune cells

Abstract Background The compound NS5806 attenuates neuropathic pain via inhibiting extracellular signal‐regulated kinase (ERK) activation in neuronal somata located at the dorsal root ganglion (DRG) and superficial spinal dorsal horn. NS5806 also reduces the expansion of DRG macrophages and spinal microglia several days after peripheral nerve injury, implying an anti‐inflammatory effect. Methods To test whether NS5806 inhibits inflammation, as a model we intraplantarly injected carrageenan into a hind paw of the rat. To examine whether NS5806 reduces carrageenan‐evoked mechanical allodynia, thermal hyperalgesia, and edema, as well as ERK activation in the nerve fibres, mast cells, and macrophages in the hind paw skin, we used behavioural, immunohistochemical, and cytological methods. Results NS5806 did not impair motor function, affect basal nociception, or cause edema in naive rats. Six hours after carrageenan injection, mechanical allodynia, thermal hyperalgesia, and edema appeared in the rat's ipsilateral hind paw, and all were reduced by intraplantar co‐injection of NS5806. NS5806 suppressed carrageenan‐evoked ERK activation in the peripheral axons and somata of L4 DRG neurons, as well as mast cells and macrophages in the paw skin. NS5806 also reduced carrageenan‐evoked mast cell degranulation and macrophage proliferation. NS5806 and the ERK pathway inhibitor PD98059 had a similar effect in inhibiting the proliferation of cultured RAW264.7 macrophages. Furthermore, all the in vivo anti‐inflammatory effects of NS5806 were similar to those of PD98059. Conclusions Acting like an ERK pathway inhibitor, NS5806 reduces inflammation‐evoked mechanical allodynia, thermal hyperalgesia, and edema by suppressing ERK activation in primary sensory neurons, mast cells, and macrophages. Significance Previous studies show that NS5806 only acts on neurons. This report unveils that NS5806 also acts on immune cells in the skin to exert its anti‐inflammatory effects. Since NS5806 is lipid soluble for skin penetration, it suggests that NS5806 could also be developed into an anti‐inflammatory drug for external use.