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Abstract

Mechanically silent nociceptors, or mechanically insensitive afferents, do not typically respond to noxious mechanical stimuli. However, they become sensitized during inflammatory conditions. Despite their significant presence among joint-innervating nociceptive fibers and their abundance in organs such as the colon, bladder, and skin, the physiological role and molecular mechanism underpinning their activation have remained elusive since their discovery over thirty years ago. In this doctoral thesis, it was elucidated that silent nociceptors constitute up to forty percent of all nociceptive afferents innervating the mouse knee joint. Notably, the infrapatellar fat pad exhibits particularly dense innervation by these afferents. Through RNA-sequencing and quantitative RT-PCR, data revealed that nerve growth factor-associated inflammation, as seen in conditions like osteoarthritis, selectively enhances the expression of the transmembrane protein TMEM100 within silent nociceptors. Electrophysiological analyses employing the mechano-clamp technique verified that TMEM100 overexpression is indispensable for the activation of these nociceptors. Significantly, TMEM100-deficient mice did not manifest secondary mechanical hypersensitivity in a model of knee joint monoarthritis. This secondary hypersensitivity represents pain that radiates beyond the immediate inflammation site and is intricately linked with the progression from acute to chronic pain. Supporting this notion, in experiments where TMEM100 was overexpressed in articular afferents without any inflammatory stimulus, mechanical hypersensitivity was observed in distant skin regions without inducing local knee joint pain. Consequently, these findings postulate that in the context of inflammatory knee joint pain, primary and secondary hypersensitivities are mediated by distinct primary sensory afferent subpopulations. The functionally obscure mechanically silent nociceptors predominantly mediate secondary hyperalgesia, with TMEM100 emerging as a pivotal regulatory protein in this activation cascade.