Role of TMEM100 in mechanically insensitive nociceptor un-silencing

Silent nociceptors remained enigmatic ever since they were first described decades ago. Here, Nees. et al. show that inflammation-induced upregulation of TMEM100 unsilences silent nociceptors, which triggers secondary mechanical pain hypersensitivity. Mechanically 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 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 in mice. Moreover, we show that mice lacking TMEM100 do not develop secondary mechanical hypersensitivity-i.e., pain hypersensitivity that spreads beyond the site of inflammation-during knee joint inflammation and that AAV-mediated overexpression of TMEM100 in articular afferents in the absence of inflammation is sufficient to induce mechanical hypersensitivity 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 mechanical hypersensitivity during inflammation.

Automated summary

In this study, Nees. et al. found that inflammation-induced upregulation of TMEM100 can sensitize silent nociceptors, leading to secondary mechanical pain hypersensitivity. They showed that TMEM100 expression is increased in silent nociceptors during inflammation, and over-expression of TMEM100 is sufficient to un-silence silent nociceptors in mice. Furthermore, they demonstrated that TMEM100 is essential for the development of secondary mechanical hypersensitivity during knee joint inflammation, and its overexpression can induce mechanical hypersensitivity in remote skin regions without causing knee joint pain. This work identifies TMEM100 as a key regulator of silent nociceptor un-silencing and uncovers its role in triggering spatially remote secondary mechanical hypersensitivity during inflammation.