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Latest publication 09/01/2025

The mRNA Translation Inhibitor Vioprolide A Prevents Inflammatory Pain-Like Beha

The finding that vioprolide prevented hypersensitivity but did not affect established hypersensitivity might also be related to mRNA translation...

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    [title] => The mRNA Translation Inhibitor Vioprolide A Prevents Inflammatory Pain-Like Beha
    [paragraph] => The mRNA Translation Inhibitor Vioprolide A Prevents Inflammatory Pain-Like Behaviour With Limited Action on Already Established Pain-Like Behaviour in Mice
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Authors
Patrick Engel, Tilman Gross, Gesine Wack, Rekia Sinderwald, Luisa Burgers, Robert Fürst, Achim Schmidtko

 Lab

Journal
European Journal of Pain
Abstract
The finding that vioprolide prevented hypersensitivity but did not affect established hypersensitivity might also be related to mRNA translation mechanisms that differ before and after the pain conditions are installed. Before the onset of persistent pain, translational control in nociceptive neurons governs acute responses to noxious cues through a variety of mechanisms. It can be modulated by activation of various membrane receptors, such as tyrosine receptor kinases (TrkA and TrkB), metabotropic glutamate receptors, NMDA receptors and insulin-like receptors (Khoutorsky and Price2018), which, however, are distinct with respect to functional effects on translation (induction or repression). For example, the primary ligand for the TrkA receptor, nerve growth factor (NGF), is a potent activator of signalling through the mammalian/mechanistic target of rapamycin (mTOR) pathway in sensory neurons (Melemedjian et al.2010). It has been shown that mTOR signalling regulates the rate of mRNA translation via phosphorylation of 4E-binding protein, which promotes the assembly of the eIF4F complex, ribosome recruitment to the mRNA and initiation of translation of ‘eiF4E-sensitive’ mRNAs (Khoutorsky et al.2015; Thoreen et al.2012). Another mTOR effector in sensory neurons is ribosomal protein S6 kinase 1 (S6K1), which mediates translation of c-Fos and modulates the rapid response to inflammatory mediators (de la Pena et al.2021). Furthermore, it has been recently found that metabotropic glutamate receptor 5 regulates pain signalling in sensory neurons through activation of elongation factor 2 kinase (eEF2K), which is capable of inducing the integrated stress response through ribosome-dependent activation of the eIF2α kinase, GCN2, thereby suppressing global protein synthesis, but enabling the preferential translation of brain-derived neurotrophic factor (BDNF) (Smith et al.2025). Other mechanisms regulating translation initiation include phosphorylation of eukaryotic initiation factor 2α (Barragan-Iglesias et al.2019; de la Pena et al.2023; Khoutorsky et al.2016; Yousuf et al.2023), regulation of the length of the poly(A) tail of mRNA (Barragan-Iglesias et al.2018; Bogen et al.2012; Ferrari, Bogen, Chu, and Levine2013) or microRNAs-mediated effects (Zhao et al.2010). During persistent pain, translational regulation shifts significantly. For example, in a mouse model of paclitaxel-induced neuropathic pain, translating ribosome affinity purification (TRAP) sequencing revealed 160 genes (79 upregulated and 81 downregulated) with persistently altered mRNA translation in NaV1.8-positive nociceptors (Sankaranarayanan et al.2025), and ribosome profiling indicated that mRNA translation of 404 genes (371 increased and 33 decreased) was altered in DRGs (de la Pena et al.2025) after the paclitaxel treatment. Moreover, it seems possible that these changes are not limited to cell bodies: increased local translation in axons has been suggested to support production of proteins at injury sites, thereby contributing to nociceptive signalling (Khoutorsky and Price2018). However, the functional significance of local translation in axons during persistent pain remains poorly understood. Our observation that the vioprolide target NOP14 is localised to the nucleus of DRG neurons (Figure5), corresponding to its anticipated function in nucleolar processing of pre-18S ribosomal RNA and nuclear export of 40S pre-ribosomal subunit to the cytoplasm (Dragon et al.2002; Milkereit et al.2003), supports the hypothesis that vioprolide A could mainly affect somatic protein synthesis rather than protein synthesis in axons. On the other hand, it cannot be excluded that an inhibition of ribosome biogenesis might manifest with deficits in both somatic and axonal protein synthesis. Further studies are required to elucidate how vioprolide A affects mRNA translation mechanisms that are important under conditions before persistent pain has developed.
Keywords/Topics
peritonitis
BIOSEB Instruments Used:
Dynamic Weight Bearing 2.0 (BIO-DWB-DUAL)
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