Differential Changes in the Peptidergic and the Non-Peptidergic Skin Innervation in Rat Models for Inflammation, Dry Skin Itch, and Dermatitis

Abstract

Skin innervation is a dynamic process that may lead to changes in nerve fiber density during pathological conditions. We have investigated changes in epidermal nerve fiber density in three different rat models that selectively produce chronic itch (the dry skin model), or itch and inflammation (the dermatitis model), or chronic inflammation without itch (the CFA model). In the epidermis, we identified peptidergic fibers-that is, immunoreactive (IR) for calcitonin gene-related peptide or substance P—and non-peptidergic fibers—that is, IR for P2X3. The overall density of nerve fibers was determined using IR for the protein gene product 9.5. In all three models, the density of epidermal peptidergic nerve fibers increased up to five times when compared with a sham-treated control group. In contrast, the density of epidermal non-peptidergic fibers was not increased, except for a small but significant increase in the dry skin model. Chronic inflammation showed an increased density of peptidergic fibers without itch, indicating that increased nerve fiber density is not invariably associated with itch. The finding that different types of skin pathology induced differential changes in nerve fiber density may be used as a diagnostic tool in humans, through skin biopsies, to identify different types of pathology and to monitor the effect of therapies.

Mechanisms and Management of Itch in Dry Skin

“…Substance P (SP) and calcitonin generelated peptide (CGRP) are neuropeptides produced by sensory nerves in the dermis to communicate with different cell populations in the different layers of the skin, which in turn stimulate nerve fibres. An increase in the elongated epidermal peripheral nerve fibres consist of SP/CGRP-containing C-fibres, which usually represent epidermal peptidergic nerve fibres, has been reported in the AEW model (39,40).…”

Role of neurturin in spontaneous itch and increased nonpeptidergic intraepidermal fiber density in a mouse model of psoriasis

“…Ablation of the peptidergic or non-peptidergic subset of fibers produces modality-specific deficits in response to heat and mechanical stimuli, respectively [8; 40]. Enhanced intraepidermal nonpeptidergic nerve density has been reported previously in animal models of dry skin itch [25; 34]. …”

Antipruritic Effects of Janus Kinase Inhibitor Tofacitinib in a Mouse Model of Psoriasis

“…Epidermal hyper innervation by itch-signaling fibers is considered to be one cause of chronic itch (16), and increased epidermal nerve density has been frequently reported in humans with chronic itch conditions including psoriasis (16)(17)(18)(19)(20). In line with this, intraepidermal nonpeptidergic nerve density is increased in animal models of dry skin itch and psoriatic itch (21)(22)(23). In contrast, conflicting results have been reported for epidermal nerve density in human with chronic itch.…”