Molecular characteristics of painful neuromas

Human peripheral nerves have a remarkable ability to regenerate after damage. However, when re-growing axons fail to meet their target organ, they can transform into painful neuromas. Animals across the tree of life, from nematodes to fish, all show axonal regeneration, but the formation of neuromas is a more recent evolutionary development, appearing in birds and mammals. In humans, these painful neuromas commonly occur when nerve injuries are not addressed surgically or after amputations. Kyle Eberlin and colleagues used specific molecular markers to compare ten neuromas they surgically excised to six healthy nerves collected from lower legs that were being amputated for unrelated reasons. Axonal components of the neuromas were disorganized in structure, demonstrated high levels of markers for regenerative capacity, and showed an abundance of sympathetic nerve fibers. Calcitonin gene-related peptide (CGRP), a neuropeptide involved in pain perception, was expressed in 84% of axons, versus 3% in healthy nerves. Neuromas also showed increased expression of the mechanosensitive channel Piezo2 and upregulation of the low-threshold sodium channel Nav1.3, both signs that the nerves were highly excitable and sensitive to touch. According to the authors, any of these differences from healthy nerves could potentially be targets for novel therapeutic interventions.