The mRNA Translation Inhibitor Vioprolide A Prevents Inflammatory Pain-Like Behaviour With Limited Action on Already Established Pain-Like Behaviour in Mice.

BACKGROUND: Accumulating evidence indicates that pharmacological inhibition of the translational machinery is a therapeutic strategy for various diseases. However, whether inhibitors of mRNA translation might be suitable for pain therapy remains poorly understood. Here, we tested the potential analgesic effects of the natural product vioprolide A, which targets nucleolar protein 14 (NOP14) that is essential for ribosome biogenesis, in mouse models of pain. METHODS: We assessed the antinociceptive effects of vioprolide A in C57BL/6 mice using four different models: zymosan-induced peritonitis, zymosan-induced paw inflammation, complete Freund's adjuvant-induced paw inflammation and spared nerve injury. Plasma and brain levels of vioprolide A were determined in a pharmacokinetic study. Immunostaining and western blot experiments were performed to investigate the distribution and expression of NOP14 in dorsal root ganglia. RESULTS: Pretreatment with vioprolide A alleviated the visceral inflammatory hypersensitivity during zymosan-induced peritonitis, and it attenuated the somatic inflammatory hypersensitivity during zymosan-induced paw inflammation in a dose-dependent manner. However, treatment with vioprolide A did not affect established hypersensitivities. Pharmacokinetic measurements revealed that vioprolide A was not brain-penetrant and exhibited a short plasma half-life, which however seems to be sufficient to exert long-lasting antinociceptive effects. Tissue stainings revealed that NOP14 is expressed in a population of sensory neurons. CONCLUSIONS: Our findings imply that vioprolide A may alleviate inflammatory nociceptive behaviours, but highlight that these effects may be limited to specific types of pain and treatment strategies. SIGNIFICANCE STATEMENT: The inhibitor of mRNA translation, vioprolide A, produced robust antinociception in distinct murine models of pain. This study provides evidence supporting further investigation of mRNA translation inhibitors, which attenuate pain by a novel mechanism of action that is not shared by established analgesics.