Innervation of the human epidermis. A historical review

Skin biopsy represents an attractive technique to evaluate the extensive innervation of human epidermis, as demonstrated by the immunoreactivity of the intra-epidermal nerve fibers to the marker protein gene product 9.5. Intra-epidermal nerve fibers can be reliably quantified, and their density correlates with both the presence and the severity of sensory neuropathy. The first description of nerve fibers within human epidermis was published by Paul Langerhans. However, the limitations imposed by the relatively insensitive staining methods led several investigators working during the following century to deny or minimize their existence. The author reviews the assumptions and the striking discrepancies emerging from the wide literature on cutaneous sensory terminations since the late nineteenth century and highlights the new developments emerging from the most recent works.