Painful neuromas exhibit axonal phenotypic shift via nociceptive and mechanosensitive marker up-regulation

Neuropathic pain encompasses a spectrum of conditions that significantly impact quality of life. In case of nerve injuries, when regenerating axons fail to reach their target organs, they can form painful neuromas, yet the mechanisms underlying their formation remain unclear. In this exploratory study, we analyzed the neural components of painful neuromas by examining the expression patterns of key nociceptor markers. Neural components within neuromas exhibited up-regulated growth-associated protein 43, indicating their regenerative potential. Calcitonin gene-related peptide was expressed in 84% of axons, versus 3% in healthy nerves, suggesting a phenotypic shift toward a nociceptive profile. We also observed increased expression of the mechanosensitive channel Piezo2 in 78% of axons and up-regulation of the low-threshold sodium channel Nav1.3, consistent with heightened mechanosensitivity and hyperexcitability. These observations identify candidate molecular alterations in painful neuromas and may provide a guide for future development of targeted therapies for neuroma-related pain.