The cannabinoids mechanism of action: an overview / Mecanismo de ação dos canabinoides: visão geral

ABSTRACT BACKGROUND AND OBJECTIVES: The discovery of the psychoactive agent of Cannabis sativa (tetrahydrocannabinol - THC) in the second half of the 20th century originated the research that later came to identify dozens of other substances from this plant, including cannabinoids, terpenes and flavonoids. Ensuing description of their interaction sites in animals and humans, together with endogenous ligands, transport proteins as well as synthesis and degradation enzymes, revealed what came to be known as the endocannabinoid system. Several receptors participate in this system. CONTENTS: The first receptors to be discovered were called CB1 and CB2, both are G protein-coupled (GPCR). It is noteworthy that CB1 receptors are among the most abundant and widely distributed GPCR in the mammalian brain, with marked expression in basal ganglia, cerebellum and hippocampus, for instance; on the other hand, they are scarce in areas of the brainstem related to breathing control. In light of the multiplicity of pharmacological effects of cannabinoids, concomitant with the lack of more clarifying studies on their mechanisms of action despite the great interest in research on their therapeutic application, it is necessary to deepen the knowledge in this area. CONCLUSION: Considering the literature research conducted for the composition of this article, it is possible to conclude that cannabinoids have a broad spectrum of action mechanisms in the human body, and that more robust clinical studies are needed to better understand their broad therapeutic potential.

RESUMO JUSTIFICATIVA E OBJETIVOS: A descoberta do princípio psicoativo da Cannabis sativa (tetrahidrocanabinol - THC) na segunda metade do século XX inaugurou pesquisas que posteriormente vieram a identificar dezenas de outras substâncias a partir dessa planta, incluindo canabinoides, terpenos e flavonoides. A subsequente descrição dos sítios de interação dessas substâncias em animais e humanos, assim como seus ligantes endógenos, proteínas de transporte e enzimas de síntese e degradação, revelou o que veio a ser conhecido como sistema endocanabinoide. Diversos receptores participam deste sistema. CONTEÚDO: Os primeiros receptores a serem descobertos foram denominados CB1 e CB2, ambos são acoplados à proteína G (GPCR). É importante ressaltar que os receptores CB1 estão entre os GPCRs mais abundantes e amplamente distribuídos do encéfalo de mamíferos, com marcada expressão, por exemplo, em gânglios da base, cerebelo e hipocampo; em contrapartida, são escassos em áreas do tronco cerebral relacionadas ao controle da respiração. Diante da multiplicidade de efeitos farmacológicos dos canabinoides, concomitante à falta de estudos mais esclarecedores sobre seus mecanismos de ação apesar do grande interesse na pesquisa de sua aplicação terapêutica, é preciso aprofundar o conhecimento nessa área. CONCLUSÃO: Considerando as pesquisas bibliográficas realizadas para a composição deste artigo, é possível concluir que os canabinoides possuem um amplo espectro de mecanismos de ação no organismo humano, e que mais estudos clínicos robustos são necessários para que seja possível entender melhor o seu amplo potencial terapêutico.

Selective Cannabinoid Receptor-1 Agonists Regulate Mast Cell Activation in an Oxazolone-Induced Atopic Dermatitis Model

BACKGROUND: Many inflammatory mediators, including various cytokines (e.g. interleukins and tumor necrosis factor [TNF]), inflammatory proteases, and histamine are released following mast cell activation. However, the endogenous modulators for mast cell activation and the underlying mechanism have yet to be elucidated. Endogenous cannabinoids such as palmitoylethanolamide (PEA) and N-arachidonoylethanolamine (anandamide or AEA), were found in peripheral tissues and have been proposed to possess autacoid activity, implying that cannabinoids may downregulate mast cell activation and local inflammation. OBJECTIVE: In order to investigate the effect of cannabinoid receptor-1 (CB1R) agonists on mast cell activation, AEA-derived compounds were newly synthesized and evaluated for their effect on mast cell activation. METHODS: The effects of selected compounds on FcepsilonRI-induced histamine and beta-hexosaminidase release were evaluated in a rat basophilic leukemia cell line (RBL-2H3). To further investigate the inhibitory effects of CB1R agonist in vivo, an oxazolone-induced atopic dermatitis mouse model was exploited. RESULTS: We found that CB1R inhibited the release of inflammatory mediators without causing cytotoxicity in RBL-2H3 cells and that CB1R agonists markedly and dose-dependently suppressed mast cell proliferation indicating that CB1R plays an important role in modulating antigen-dependent immunoglobulin E (IgE)-mediated mast cell activation. We also found that topical application of CB1R agonists suppressed the recruitment of mast cells into the skin and reduced the level of blood histamine. CONCLUSION: Our results indicate that CB1R agonists down-regulate mast cell activation and may be used for relieving inflammatory symptoms mediated by mast cell activation, such as atopic dermatitis, psoriasis, and contact dermatitis.