Abstract

Nearly 30 years after the discovery of the psychoactive ingredient of Cannabis sativa, Δ⁹-tetrahydrocannabinol (THC) in 1964, the endogenous counterparts of THC were discovered and were collectively termed endocannabinoids (eCBs). To date, among several members of the eCB family N-arachidonoylethanolamine (anandamide, AEA) and 2-arachidonoylglycerol (2-AG) are widely recognized as the most bioactive substances, able to bind to and activate G protein-coupled type-1 (CB₁) and type-2 (CB₂) cannabinoid receptors, as well as other non-CB₁/non-CB₂ receptor targets. In addition, an ensemble of proteins that synthesize, transport and degrade eCBs have been identified in the last 20 years, altogether forming the so-called eCB system. eCBs control basic biological processes spanning from cell choice between survival and death, progenitor/stem cell proliferation and differentiation, and neurotransmission to reproductive events, energy balance and immune response. Unsurprisingly, in the last two decades eCBs have emerged as key regulators of human pathophysiology at multiple levels. Here, a modern view of the biochemistry and pharmacology of the eCB system will be presented, in order to put in a better perspective the impact of eCB signaling on human health and disease, both centrally and peripherally. In particular, it will be shown that eCBs regulate bone elongation and remodeling, as well as inflammation and adaptive/innate immunity. Moreover, unprecedented results on AEA and 2-AG alterations in human patients with systemic lupus erythematosus will be presented, that may help to better understand the role of lipid signaling in this disease.