title: Inhibition of basal and ultraviolet B-induced melanogenesis by cannabinoid CB(1) receptors: a keratinocyte-dependent effect.
abstract: Ultraviolet radiation is the major environmental insult to the skin and stimulates the synthesis of melanin in melanocytes, which then distribute it to the neighboring keratinocytes where it confers photo-protection. Skin color results from the paracrine interaction between these two cell types. Recent studies suggest that endocannabinoids are potential mediators in the skin. Here, we investigated whether cannabinoid drugs play a role in melanogenesis and if ultraviolet radiation modifies the cutaneous endocannabinoid system. We used human melanotic melanoma cell line (SK-mel-1) in monoculture or co-culture with human keratinocytes (HaCat). Endocannabinoid levels, cannabinoid receptors expression, and melanin content were evaluated under basal conditions and after ultraviolet-B irradiation (311 nm). We provide evidence that human melanoma cells (SK-mel-1) express CB(1) receptors, and when in co-culture with keratinocytes (HaCat), the selective CB(1) receptor agonist arachidonyl-2-chloroethylamide (ACEA 1 and 10 μM) inhibited (by 33.4 and 37.3%, respectively) basal melanogenesis. In addition, ultraviolet-B-induced melanogenesis in co-cultures was abolished by ACEA 10 μM. Both ACEA inhibitory effects were reversed by AM251 (1 μM), a selective CB(1) antagonist. Furthermore, ultraviolet-B radiation increased endocannabinoids levels only in keratinocytes, whereas CB(1) cannabinoid receptor expression was up-regulated only in melanoma cells. Our results collectively suggest that ultraviolet radiation activates paracrine CB(1)-mediated endocannabinoid signaling to negatively regulate melanin synthesis. The endocannabinoid system in the skin may be a possible target for future therapies in pigmentary disorders.
authors.affiliation: Institute of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, Portugal. smagina@med.up.pt
authors.forename: Sofia
authors.initials: S
authors.lastname: Magina
authors.forename: Carina
authors.initials: C
authors.lastname: Esteves-Pinto
authors.forename: Eduardo
authors.initials: E
authors.lastname: Moura
authors.forename: Maria Paula
authors.initials: MP
authors.lastname: Serrão
authors.forename: Daniel
authors.initials: D
authors.lastname: Moura
authors.forename: Stefania
authors.initials: S
authors.lastname: Petrosino
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
authors.forename: Maria Augusta
authors.initials: MA
authors.lastname: Vieira-Coelho
mesh_terms: D001095:Arachidonic Acids / Q000494:pharmacology; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000528:radiation effects; D008543:Melanins / Q000235:genetics / Q000378:metabolism*; D008544:Melanocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000528:radiation effects; D019899:Paracrine Communication; D010859:Pigmentation Disorders / Q000188:drug therapy*; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012867:Skin / Q000473:pathology; D014466:Ultraviolet Rays
chemical_list: D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D008543:Melanins; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C119325:arachidonyl-2-chloroethylamide; C103505:AM 251