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The molecular mechanism and physiological role of silent nociceptor activation

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Title:The molecular mechanism and physiological role of silent nociceptor activation
Creators Name:Nees, T.A. and Wang, N. and Adamek, P. and Verkest, C. and Schaefer, I. and Virnich, J. and Balkaya, S. and Prato, V. and Morelli, C. and Zeitzschel, N. and Begay, V. and Lee, Y.J. and Lewin, G.R. and Heppenstall, P.A. and Taberner, F.J. and Lechner, S.G.
Abstract:Silent nociceptors are sensory afferents that are insensitive to noxious mechanical stimuli under normal conditions but become sensitized to such stimuli during inflammation. Using RNA-sequencing and quantitative RT-PCR we demonstrate that inflammation selectively upregulates the expression of the transmembrane protein TMEM100 in silent nociceptors and electrophysiology revealed that over-expression of TMEM100 is required and sufficient to un-silence silent nociceptors. Moreover, we show that mice lacking TMEM100 do not develop secondary hyperalgesia, i.e. pain hypersensitivity that spreads beyond the site of inflammation, in a mouse model of knee joint inflammation and that AAV-mediated overexpression of TMEM100 in articular afferents in the absence of inflammation is sufficient to induce secondary hyperalgesia in remote skin regions without causing knee joint pain. Thus, our work identifies TMEM100 as a key regulator of silent nociceptor un-silencing and reveals a physiological role for this hitherto enigmatic afferent subclass in triggering spatially remote secondary hyperalgesia during inflammation.
Publisher:Cold Spring Harbor Laboratory Press
Article Number:2022.04.07.486730
Date:19 October 2022
Official Publication:https://doi.org/10.1101/2022.04.07.486730

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