We evaluated the influence of skin innervation on the epidermis in mice. The rich innervation of skin was demonstrated by immunocytochemistry with protein gene product 9.5, a ubiquitin carboxy hydrolase. Protein gene product-immunoreactive nerve fibers were in the epidermis, subepidermal plexus, dermal nerve trunks, and nerve terminals around sweat glands. Effects of denervation on the plantar surface of the hind foot was assessed by comparing the thickness of the epidermis, which was innervated by the sciatic nerve. Within 48 h after sectioning of the sciatic nerve, protein gene product (+)-nerves in the territory of the sciatic nerve were completely degenerated. There was a significant thinning of the denervated epidermis 72 h post-transection (30.5+/-1.1 vs 41.4+/-2.9 microm, 74+/-4% of the control side). The reduction in epidermal thickness persisted when skin remained denervated (69-75% of the control side). Incorporation of bromodeoxyuridine was reduced 24 h after denervation (71+/-6% of the control side). Reduction in bromodeoxyuridine-incorporation was most pronounced within 48 h after denervation (19+/-6% of the control side). Therefore, the reduction in bromodeoxyuridine-labeling followed a similar temporal course as the thinning of the epidermis (25-50%). Both epidermal thinning and reduced bromodeoxyuridine-labeling were reversed by epidermal reinnervation three months after denervation. Patterns of keratinocyte differentiation and programmed cell death were unaffected by skin denervation. These findings are consistent with the notion that skin innervation exerts influence on the proliferation of keratinocytes and the thickness of the epidermis, and offers a new look at the interaction between nociceptive nerves and their innervated targets.