Sensory innervation of the skin subserves protective sensations for th
e body to prevent thermal and noxious injuries. Neurophysiologically,
they belong to the categories of A delta and C fibers, usually with ca
liber less than one mu m in diameter. Morphological demonstration of t
he terminals of these nerves in the epidermis has been recognized rece
ntly by sensitive immunocytochemistry and an axonal marker, the protei
n gene product 9.5 (PGP). PGP is a ubiquitin C-terminal hydrolase, whi
ch is abundantly present in the nervous system, and particularly enric
hed in the unmyelinated nerves. Sensory nerves positive for PGP arise
from the dorsal root ganglion, pass through the dermis, parallel the e
pidermis-dermis border, penetrate the basement membrane, move vertical
ly and upwards in the epidermis with tortuous course and knobby appear
ance, and finally terminate at the granular layers of the epidermis. I
n rodents, denervation of the skin results in degeneration of epiderma
l nerves within 48 h of nerve transection, and thinning of the epiderm
is. In humans, application of this technique to evaluate disorders of
the peripheral nervous system makes study of the degeneration of senso
ry nerve terminals possible. Patients with sensory neuropathy had fewe
r epidermal nerves than normal subjects, consistent with the notion of
distal axonopathy. This approach has the potential to evaluate human
sensory neuropathy in temporal and spatial domains. In addition, the i
nfluences of epidermal denervation open a new field to explore the int
eractions between sensory nerves and keratinocytes.