Long‐Term Effects of Neonatal Capsaicin Treatment on Intraepidermal Nerve Fibers and Keratinocyte Proliferation in Rat Glabrous Skin

Abstract

Innervation is required to preserve several aspects of skin homeostasis. Previous studies in rodents have shown that sciatic nerve transection leads to epidermal thinning and reduced keratinocyte proliferation. As the sciatic nerve is composed of sensory and motor axons, it is not clear whether skin alterations reflect motor or sensory disturbances. In this study, we used neonatal capsaicin treatment to evaluate whether sensory chemical denervation affects keratinocyte proliferation at 1, 3, and 6 months of age. Using design-based stereological methods, we estimated the total length of intraepidermal nerve fibers (IENF) that were of peptidergic type and the number of bromodeoxyuridine-labeled (BrdU þ ) nuclei in the hind paw glabrous epidermis of control and capsaicin-treated rats. We found that the treatment decreased the total fiber length of IENF immunoreactive for both protein gene product 9.5 (PGP þ ) and of IENF immunoreactive for calcitonin gene-related peptide (CGRP þ ). The length of PGP þ fibers decreased by 83%, 81%, and 77% and that of CGRP þ fibers decreased by 48%, 58%, and 58% at 1, 3, and 6 months, respectively. Double-immunofluorescence staining for neural beta III tubulin and CGRP revealed that the majority of the remaining fibers in the epidermis after capsaicin treatment were of peptidergic type. The number of BrdU þ nuclei was similar in both groups. Our findings suggest that IENF present after capsaicin treatment are sufficient to maintain epidermal replacement. Anat Rec, 294:173-184, 2011. V V C 2010 Wiley-Liss, Inc.

Cellular infiltrates in skin and sural nerve of patients with polyneuropathies

“…A potential mechanism may involve the fine balance between skin innervation and cellular integrity. Skin cells regulate cutaneous innervation, and normal cutaneous innervation is essential for cellular integrity of the skin . We know of no firm evidence on the potential mechanisms that may operate in involving low‐grade immune cell invasion associated with cutaneous nerve fiber damage.…”

Modulatory Role of Sensory Innervation on Hair Follicle Stem Cell Progeny during Wound Healing of the Rat Skin

“…However, the fact that capsaicin-treated rodents develop cornea and skin lesions even when self-grooming and scratching behaviors are prevented suggests other possibilities [3], [28], [29], [30]. Recently, we proposed that in conditions of high cell demand and partial denervation some epithelia are not able to generate the number of cells that are required for epithelial expansion [31].The results of the present work point in that direction revealing that sensory nerves are involved in the beginning of the process of reepithelialization. Accordingly, the epidermal proliferation around the excisional wound was impaired during the first 47 h postwounding in the capsaicin-treated rats.…”

“…Therefore, it is likely that substances released from nonpeptidergic terminals also mediate nerve-eptihelial interactions. In fact, nonpeptidergic fibers have been described as the predominant type of fibers in several epithelial tissues of the rat, making them a putative source of signals to keratinocytes that need to be identified (see below) [7] , [31] . Another intriguing question about the role of noceffectors during wound healing is whether a similar mechanism operates in glabrous skin which completely lacks hair follicles.…”

“…To reduce sensory innervation we used the neonatal capsaicin treatment as previously described [31] . Within 24–36 h after birth, hypothermia-anaesthetized rat pups were injected subcutaneously in the back skin with either a single dose of capsaicin (50 mg/kg) or vehicle alone (10% Tween-80 and 10% ethanol (v/v) in 0.9% NaCl).…”

“…The total number of immunoreactive BrdU cells was estimated with the stereological probe of the optical fractionator [31] . Data were obtained with a Nikon Labophot-2 microscope equipped with 10× and 100× (oil immersion, 1.4 NA) objectives, a motorized x-y-z stage control, and interfaced with StereoInvestigator Software 9 (MBF Bioscience, Williston, USA).…”