The psychoactive cannabinoids from Cannabis sativa L. and the arachidonic acid-derived endocannabinoids are nonselective natural ligands for cannabinoid receptor type 1 (CB1) and CB2 receptors. Although the CB1 receptor is responsible for the psychomodulatory effects, activation of the CB2 receptor is a potential therapeutic strategy for the treatment of inflammation, pain, atherosclerosis, and osteoporosis. Here, we report that the widespread plant volatile (E) Cannabis ͉ CB2 cannabinoid receptor ͉ foodstuff ͉ inflammation ͉ natural product P lant essential oils are typically composed of volatile aromatic terpenes and phenylpropanoids. These lipophilic volatiles freely cross cellular membranes and serve various ecological roles, like plant-insect interactions (1, 2). The sesquiterpene (E)-␤-caryophyllene [(E)-BCP] (Fig. 1) is a major plant volatile found in large amounts in the essential oils of many different spice and food plants, such as oregano (Origanum vulgare L.), cinnamon (Cinnamomum spp.) and black pepper (Piper nigrum L.) (3-5). In nature, (E)-BCP is usually found together with small quantities of its isomers (Z)-␤-caryophyllene [(Z)-BCP or isocaryophyllene] and ␣-humulene (formerly ␣-caryophyllene) or in a mixture with its oxidation product, BCP oxide (Fig. 1). Because of its weak aromatic taste, (E)-BCP is commercially used as a food additive and in cosmetics (6). (E)-BCP is also a major component (up to 35%) in the essential oil of Cannabis sativa L (7). Although Cannabis contains Ͼ400 different secondary metabolites, including Ͼ65 cannabinoid-like natural products, only ⌬ 9 -tetrahydrocannabinol (THC), ⌬ 8 -tetrahydrocannabinol, and cannabinol have been reported to activate cannabinoid receptor types 1 (CB 1 ) and 2 (CB 2 ) (8). Here, we show that the essential oil component (E)-BCP selectively binds to the CP55,940 binding site (i.e., THC binding site) in the CB 2 receptor, leading to cellular activation and antiinflammatory effects. CB 1 and CB 2 cannabinoid receptors are GTP-binding protein (G protein) coupled receptors that were first cloned in the early 1990s (9, 10). Although the CB 1 receptor is expressed in the central nervous system and in the periphery, the CB 2 receptor is primarily found in peripheral tissues (11). In vivo, CB receptors are activated by arachidonic acid-derived endocannabinoids, such as 2-arachidonoyl ethanolamine (anandamide or AEA) and 2-arachidonoylglycerol (2-AG) (12, 13). In addition to a wide range of primarily CB 1 receptor-mediated physiological effects on the central nervous system, different cannabinoid ligands have been reported to modulate immune responses (14). In particular, CB 2 receptor ligands have been shown to inhibit inflammation and edema formation (15), exhibit analgesic effects (16), and play a protective role in hepatic ischemia-reperfusion injury (17). In the gastrointestinal tract, CB 2 receptor agonists have been shown to prevent experimental colitis by reducing inflammation (18). Moreover, the CB 2 receptor has been described as a potential ...

The mammalian brain is one of the organs with the highest energy demands, and mitochondria are key determinants of its functions. Here we show that the type-1 cannabinoid receptor (CB(1)) is present at the membranes of mouse neuronal mitochondria (mtCB(1)), where it directly controls cellular respiration and energy production. Through activation of mtCB(1) receptors, exogenous cannabinoids and in situ endocannabinoids decreased cyclic AMP concentration, protein kinase A activity, complex I enzymatic activity and respiration in neuronal mitochondria. In addition, intracellular CB(1) receptors and mitochondrial mechanisms contributed to endocannabinoid-dependent depolarization-induced suppression of inhibition in the hippocampus. Thus, mtCB(1) receptors directly modulate neuronal energy metabolism, revealing a new mechanism of action of G protein-coupled receptor signaling in the brain.

The cannabinoid CB2 receptor (CB2R) represents a promising therapeutic target for various forms of tissue injury and inflammatory diseases. Although numerous compounds have been developed and widely used to target CB2R, their selectivity, molecular mode of action and pharmacokinetic properties have been poorly characterized. Here we report the most extensive characterization of the molecular pharmacology of the most widely used CB2R ligands to date. In a collaborative effort between multiple academic and industry laboratories, we identify marked differences in the ability of certain agonists to activate distinct signalling pathways and to cause off-target effects. We reach a consensus that HU910, HU308 and JWH133 are the recommended selective CB2R agonists to study the role of CB2R in biological and disease processes. We believe that our unique approach would be highly suitable for the characterization of other therapeutic targets in drug discovery research.

Plant volatiles typically occur as a complex mixture of low-molecular weight lipophilic compounds derived from different biosynthetic pathways, and are seemingly produced as part of a defense strategy against biotic and abiotic stress, as well as contributing to various physiological functions of the producer organism. The biochemistry and molecular biology of plant volatiles is complex, and involves the interplay of several biochemical pathways and hundreds of genes. All plants are able to store and emit volatile organic compounds (VOCs), but the process shows remarkable genotypic variation and phenotypic plasticity. From a physiological standpoint, plant volatiles are involved in three critical processes, namely plant–plant interaction, the signaling between symbiotic organisms, and the attraction of pollinating insects. Their role in these ‘‘housekeeping’’ activities underlies agricultural applications that range from the search for sustainable methods for pest control to the production of flavors and fragrances. On the other hand, there is also growing evidence that VOCs are endowed with a range of biological activities in mammals, and that they represent a substantially under-exploited and still largely untapped source of novel drugs and drug leads. This review summarizes recent major developments in the study of biosynthesis, ecological functions and medicinal applications of plant VOCs.

The widespread plant volatile beta-caryophyllene (BCP) was recently identified as a natural selective agonist of the peripherally expressed cannabinoid receptor 2 (CB₂). It is found in relatively high concentrations in many spices and food plants. A number of studies have shown that CB₂ is critically involved in the modulation of inflammatory and neuropathic pain responses. In this study, we have investigated the analgesic effects of BCP in animal models of inflammatory and neuropathic pain. We demonstrate that orally administered BCP reduced inflammatory (late phase) pain responses in the formalin test in a CB₂ receptor-dependent manner, while it had no effect on acute (early phase) responses. In a neuropathic pain model the chronic oral administration of BCP attenuated thermal hyperalgesia and mechanical allodynia, and reduced spinal neuroinflammation. Importantly, we found no signs of tolerance to the anti-hyperalgesic effects of BCP after prolonged treatment. Oral BCP was more effective than the subcutaneously injected synthetic CB₂ agonist JWH-133. Thus, the natural plant product BCP may be highly effective in the treatment of long lasting, debilitating pain states. Our results have important implications for the role of dietary factors in the development and modulation of chronic pain conditions.