The endocannabinoid system of the skin in health and disease: novel perspectives and therapeutic opportunities

Abstract

The newly discovered endocannabinoid system (ECS; comprising the endogenous lipid mediators endocannabinoids present in virtually all tissues, their G-protein-coupled cannabinoid receptors, biosynthetic pathways and metabolizing enzymes) has been implicated in multiple regulatory functions both in health and disease. Recent studies have intriguingly suggested the existence of a functional ECS in the skin and implicated it in various biological processes (e.g. proliferation, growth, differentiation, apoptosis and cytokine, mediator or hormone production of various cell types of the skin and appendages, such as the hair follicle and sebaceous gland). It seems that the main physiological function of the cutaneous ECS is to constitutively control the proper and well-balanced proliferation, differentiation and survival, as well as immune competence and/or tolerance, of skin cells. The disruption of this delicate balance might facilitate the development of multiple pathological conditions and diseases of the skin (e.g. acne, seborrhea, allergic dermatitis, itch and pain, psoriasis, hair growth disorders, systemic sclerosis and cancer).

Figure 1

Functions of the cutaneous ECS. Prototypic endocannabinoids such as anandamide (N-arachidonoylethanolamine; AEA) and 2-arachidonoylglycerol (2-AG) are produced locally in various cellular compartments of the skin (i.e. epidermis, sebaceous gland, hair follicle) (green arrows). These endocannabinoids, via binding to cannabinoid receptor subtypes 1 and/or 2 (CB₁/CB₂), constitutively control the proper and well-balanced cutaneous functions (e.g. sensation, growth, survival, immune competence and/or tolerance) (red arrows). For example, activation of CB₁ and CB₂ on epidermal keratinocytes by locally produced endocannabinoids results in the suppression of cellular proliferation, differentiation and the release of inflammatory mediators as well as the induction of apoptosis. Likewise, endocannabinoids, via CB₁/CB₂, inhibit inflammatory responses of resident and infiltrating immune cells. Furthermore, activation of CB₁ in the hair follicle by AEA attenuates hair shaft elongation and intrafollicular proliferation, whereas it stimulates apoptosis and the development of catagen regression. On another member of the pilosebaceous unit (i.e. on the sebaceous gland-derived sebocytes), locally released endocannabinoids markedly enhance lipid production and apoptosis via CB₂. Finally, skin-derived endocannabinoids inhibit various sensory phenomena (e.g. pain and itch) via CB₁ expressed on sensory afferent nerves.

Figure 2

ECS-targeted approaches in skin diseases. Modulations of the fine-tuned tone of the cutaneous endocannabinoid system (ECS) could have therapeutic values in the management of a large variety of human skin diseases. For example, suppression of the skin ECS tone (using e.g. CB antagonists and/or agents that attenuate the local production of endocannabinoids) could be used in the therapy of certain hair growth (e.g. forms of alopecia, effluvium) and sebaceous gland disorders (e.g. acne, seborrhea). Conversely, augmentation of the tone of the cutaneous ECS (using e.g. CB agonists and/or agents that stimulate the local production of endocannabinoids) could be beneficial in the treatment of various benign and malignant skin tumors, hyperproliferative skin diseases (e.g. psoriasis), excessive hair growth (e.g. hirsutism), different forms of dermatitis, dry skin conditions and sensory phenomena (e.g. pain, itch).