Opioid receptors in skin – link between stress and skin disease?

Abstract

Opioid peptides and its receptors are highly conserved and crucial for survival in stress situations. Besides their well‐known role in antinociception, they control cell differentiation and proliferation and influence apoptosis in various tissues. We are first to discover their presence in skin and to establish their functions in modulation of chronic itch and wound healing.µ‐Opioid receptor is a key player in induction of chronic itch. This could be confirmed using µ‐opiate receptor knockout mice experiments and clinical studies on patients with chronic itch. We have induced a dry skin dermatitis as a model for chronic itching on knockout and wild type mice. µ‐Opioid receptor knockout mice revealed significant less scratching behavior, less epidermal hypertrophy and different density and quality of epidermal nerve endings compared to the wild type mice. In addition, topically applied opioid receptor antagonists relieved significantly chronic pruritus in a double‐blind, placebo‐controlled, cross‐over study in 40 patients with atopic dermatitis.Several findings suggest that the δ‐opioid receptor and its endogenous ligands (enkephalins) are important in cell differentiation and proliferation. We proved the existence of a functional active δ‐opioid receptor in different skin cells using RT‐PCR, Western blot analysis and migration assays. In addition, δ‐opioid receptor knockout mice revealed a phenotype of thinner epidermis and higher expression of cell differentiation marker cytokeratin 10 (CK 10) compared to wild‐type mice. In a burn wound model, δ‐opioid receptor knockout mice showed significant wound healing delay and a severe epidermal hypertrophy at the wound margin. This can be explained by a change of cell differentiation and migration due to the absence of a functional active δ‐opioid receptor.In summary, these experiments proved that the skin and the nervous system interact with each other in a bi‐directional way, i.e. nervous system releases neuropeptides in stress situations affecting skin homeostasis and sensations and vice versa.Therefore, the opioid receptor system is an excellent model to study the connection between psychological stress and aggravation of different skin diseases.