Beta-caryophyllene is a dietary cannabinoid

The psychoactive cannabinoids from Cannabis sativa L. and the arachidonic acid-derived endocannabinoids are nonselective natural ligands for cannabinoid receptor type 1 ([CB.sub.1]) and [CB.sub.2] receptors. Although the [CB.sub.1] receptor is responsible for the psychomodulatory effects, activation of the [CB.sub.2] receptor is a potential therapeutic strategy for the treatment of inflammation, pain, atherosclerosis, and osteoporosis. Here, we report that the widespread plant volatile (E)-[beta]-caryophyllene [(E)-BCP] selectively binds to the [CB.sub.2] receptor ([K.sub.i] = 155 [+ or -] 4 nM) and that it is a functional [CB.sub.2] agonist. Intriguingly, (E)-BCP is a common constituent of the essential oils of numerous spice and food plants and a major component in Cannabis. Molecular docking simulations have identified a putative binding site of (E)-BCP in the [CB.sub.2] receptor, showing ligand [pi]-[pi] stacking interactions with residues F117 and W258. Upon binding to the [CB.sub.2] receptor, (E)-BCP inhibits adenylate cylcase, leads to intracellular calcium transients and weakly activates the mitogen-activated kinases Erk1/2 and p38 in primary human monocytes. (E)-BCP (500 nM) inhibits lipopolysaccharide (LPS)-induced proinflammatory cytokine expression in peripheral blood and attenuates LPS-stimulated Erk1/2 and JNK1/2 phosphorylation in monocytes. Furthermore, peroral (E)-BCP at 5 mg/kg strongly reduces the carrageenan-induced inflammatory response in wild-type mice but not in mice lacking [CB.sub.2] receptors, providing evidence that this natural product exerts cannabimimetic effects in vivo. These results identify (E)-BCP as a functional nonpsychoactive [CB.sub.2] receptor ligand in foodstuff and as a macrocyclic antiinflammatory cannabinoid in Cannabis. Cannabis | CB2 cannabinoid receptor | foodstuff | inflammation | natural product