Cannabinoid Signaling in the Skin: Therapeutic Potential of the "C(ut)annabinoid" System

Abstract

The endocannabinoid system (ECS) has lately been proven to be an important, multifaceted homeostatic regulator, which influences a wide-variety of physiological processes all over the body. Its members, the endocannabinoids (eCBs; e.g., anandamide), the eCB-responsive receptors (e.g., CB₁, CB₂), as well as the complex enzyme and transporter apparatus involved in the metabolism of the ligands were shown to be expressed in several tissues, including the skin. Although the best studied functions over the ECS are related to the central nervous system and to immune processes, experimental efforts over the last two decades have unambiguously confirmed that cutaneous cannabinoid ("c[ut]annabinoid") signaling is deeply involved in the maintenance of skin homeostasis, barrier formation and regeneration, and its dysregulation was implicated to contribute to several highly prevalent diseases and disorders, e.g., atopic dermatitis, psoriasis, scleroderma, acne, hair growth and pigmentation disorders, keratin diseases, various tumors, and itch. The current review aims to give an overview of the available skin-relevant endo- and phytocannabinoid literature with a special emphasis on the putative translational potential, and to highlight promising future research directions as well as existing challenges.

Keywords: acne; atopic dermatitis; cannabinoid; fibrosis; hair growth; inflammation; itch; psoriasis; skin; tumor; wound healing.

Figure 1

Schematic overview of the (endo)cannabinoid system (ECS) and its putative connections to other signaling systems. Depending on how we choose to limit the definition, the number of the putative ligands as well as that of the possible targets increases dramatically; therefore, on the figure, we only summarize the most important ones. Each ligand possesses a unique molecular fingerprint, i.e., the ability to concentration-dependently activate/antagonize/inhibit a selected group of possible targets. Obviously, all these actions are highly context-dependent (e.g., they are influenced by the relative expression of the potential targets in the given tissue, the concentration of the substance), resulting in characteristic, and in some cases even opposing biological responses. Although the classical, lipophilic eCBs definitely require inter- and intracellular carriers, relatively little is known about these transporter systems. Intracellular eCB transporters may include fatty acid binding proteins (FABPs) and heat shock protein 70 (HSP70), whereas FABP4, albumins, HSP70 and extracellular vesicles [61,62] are likely to be involved in their intercellular transport [63]. With respect to FAAH1 and -2 it is important to note that only scarce evidence is available about the expression and functionality of the latter. Intriguingly, FAAH2 is not expressed in mice and rats, but shares substrate spectrum of FAAH1 (however, it has inferior affinity towards AEA and N-acyl taurines). Conventional FAAH-inhibitors can inhibit its activity [48], and its missense polymorphism (A458S) may lead to psychiatric disorders (anxiety, mild learning disability) [64]. Later in the text, except when stated otherwise, by mentioning “FAAH”, we refer to “FAAH1”. 5-HT: 5-hydroxytryptamine (serotonin) receptor; A_2A and A₃: adenosine 2A and 3 receptors; ABDH6 and -12: α/β-hydrolase domain containing 6 and 12; CBC: (−)-cannabichromene; CBD: (−)-cannabidiol; CBDV: (−)-cannabidivarin; CBG: (−)-cannabigerol; CBGV: (−)-cannabigerovarin; CBN: (−)-cannabinol; (−)-cis-PET: (−)-cis-perrottetinene; COX₂: cyclooxygenase-2; DAGL: diacylglycerol lipase; eCB: endocannabinoid; FAAH: fatty acid amide hydrolase; GPR: G protein-coupled receptor; LOX: lipoxygenase; MAGL: monoacylglycerol lipase; NAAA: N-acylethanolamine hydrolyzing acid amidase; NAPE-PLD: N-acylphosphatidylethanolamine-specific phospholipase D; PPAR: peroxisome proliferator-activated receptor; PTPN22: protein tyrosine phosphatase non-receptor type 22; THC: (−)-trans-Δ⁹-tetrahydrocannabinol; THCV: (−)-Δ⁹-tetrahydrocannabivarin; TRP: transient receptor potential.

Figure 2

Examples of the context-dependent complexity of the cannabinoid signaling. (a) Overview of the most important potential targets of the phytocannabinoids (pCBs), which can be concentration-dependently activated/antagonized/inhibited by these molecules. Each pCB can be characterized by a unique molecular fingerprint, and every pCB was found to interact with only a subset of potential targets shown on panel (a). Importantly, the interactions can even result in opposing outcomes (e.g., THC is a partial CB₁ agonist, whereas CBD is a CB₁ antagonist/inverse agonist), making prediction of cellular effects of the pCBs even more difficult. (b) The actual biological response, which develops following the activation of CB₁ receptor depends on several additional factors, including biased agonism [31,32,65,66,67,68,69,70,71,72,73], possible receptor heteromerization [32,74,75,76,77,78,79,80], localization (i.e., cell membrane vs. mitochondria vs. lysosomes [81,82,83]), as well as the composition of the lipid microenvironment of the given membrane [58,84]. Green arrows on panel (b): the most common signaling pathways of CB₁. Note that besides CB₁, biased agonism is well-described in case of CB₂, GPR18, GPR55 and GPR119 as well, whereas CB₂ was proven to heteromerize with, e.g., C-X-C chemokine receptor type 4 chemokine receptor (CXCR4), or GPR55 (for details, see the above references). The question mark indicates that functional heteromerization of CB₁ and GABA_B receptors is questionable. AT₁: angiotensin II receptor type 1; CYP: cytochrome P450 enzymes; D₂: dopamine receptor 2; EMT(s): endocannabinoid membrane transporter(s); ENT1: equilibrative nucleoside transporter 1; GABA_B: γ-aminobutyric acid receptor B; LPA₁: lysophosphatidic acid receptor 1; Na_v: voltage-gated Na⁺ channels; OX₁: orexin 1 receptor; VDAC1: voltage-dependent anion channel 1. The figure was adapted and modified from [31] originally licensed under CC-BY, version 4.0.

Figure 3

Schematic overview of potentially beneficial and detrimental consequences of pharmacological modulation of CB₁ (a) and CB₂ (b), as well as of CBD administration (c). Note that certain effects (e.g., promoting hair growth) can context-dependently be considered to be a beneficial (e.g., in hirsutism) or a detrimental (e.g., in alopecia) outcome. Question marks indicate controversial data, whereas gray background highlight unproven effects, which are only hypothesized based on indirect evidence; thus, systematic studies are invited to unveil if they indeed develop.