The endocannabinoid 2-arachidonoylglycerol (2-AG) is a lipid mediator involved in various physiological processes. In response to neural activity, 2-AG is synthesized post-synaptically, then activates pre-synaptic cannabinoid CB1 receptors (CB1Rs) in a retrograde manner, resulting in transient and longlasting reduction of neurotransmitter release. The signalling competence of 2-AG is tightly regulated by the balanced action between ‘on demand’ biosynthesis and degradation. We review recent research on monoacylglycerol lipase (MAGL), ABHD6 and ABHD12, three serine hydrolases that together account for approx. 99% of brain 2-AG hydrolase activity. MAGL is responsible for approx. 85% of 2-AG hydrolysis and colocalizes with CB1R in axon terminals. It is therefore...

The cannabinoid CB1 and CB2 receptors are Class A G protein-coupled receptors (GPCRs). While many Class A GPCRs have endogenous ligands that are hydrophilic cations (e.g., the serotonin and dopamine receptors), the cannabinoid receptors have neutral, highly lipophilic ligands derived from the fatty acid, arachidonic acid. The most well-studied of these are Narachidonoylethanolamine (anandamide, AEA) and sn-2-arachidonoylglycerol (2-AG). This review focuses on the experimental and computational studies that have been used to probe the nature of endocannabinoid interaction with the cannabinoid receptors. These studies include mutation, SAR and NMR studies, as well as, QSAR, docking and molecular dynamics simulations. Gaps in our knowledge are...

2-Arachidonoyl-glycerol 2-Ara-Gl has been isolated from various tissues and identified as an endogenous ligand for both cannabinoid receptors, CB and CB . Here we report that in spleen, as in brain and gut, 2-Ara-Gl is accompanied by several 1 2 2-acyl-glycerol esters, two major ones being 2-linoleoyl-glycerol 2-Lino-Gl and 2-palmitoyl-glycerol 2-Palm-Gl . These two esters do not bind to the cannabinoid receptors, nor do they inhibit adenylyl cyclase via either CB or CB ; however, they significantly potentiate 1 2 the apparent binding of 2-Ara-Gl and its apparent capacity to inhibit adenylyl cyclase. Together these esters also significantly potentiate 2-Ara-Gl inhibition of motor behavior,...

Since the discovery of endocannabinoids and their receptors, two major members of the endocannabinoid family, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), have been regarded almost as twin brothers. Pharmacological properties were initially considered to be similar, as these molecules were believed mutually exchangeable and almost indistinguishable in the regulation of synaptic functions, such as long- and short-term synaptic plasticity, and in behavioral aspects, such as learning and memory, reward and addiction, antinociception, and anxiety. In recent years, however, endocannabinoid signaling specificity began to emerge, in particular, due to the production of genetically engineered mice lacking key enzymes in endocannabinoid synthesis or degradation, together with the...

Background and purpose: Cannabidiol has been reported to act as an antagonist of cannabinoid agonists at type 1 cannabinoid receptors (CB1). We hypothesized that cannabidiol can inhibit cannabinoid agonist activity through negative allosteric modulation of CB1. Experimental approach: CB1 internalization, arrestin2 recruitment, and PLCβ3 and ERK1/2 phosphorylation, were quantified in HEK 293A cells heterologously expressing CB1 and in the STHdhQ7/Q7 cell model of striatal neurons endogenously expressing CB1. Cells were treated with 2- arachidonylglycerol or Δ9 -tetrahydrocannabinol alone and in combination with different concentrations of cannabidiol. Key results: Cannabidiol reduced the efficacy and potency of 2-arachidonylglycerol and Δ9 - tetrahydrocannabinol on PLCβ3- and ERK1/2-dependent...

Research into the pharmacology of individual cannabinoids that began in the 1940s, several decades after the presence of a cannabinoid was first detected in cannabis, is concisely reviewed. Also described is how this pharmacological research led to the discovery of cannabinoid CB1 and CB2 receptors and of endogenous ligands for these receptors, to the development of CB1- and CB2-selective agonists and antagonists and to the realization that the endogenous cannabinoid system has significant roles in both health and disease, and that drugs which mimic, augment or block the actions of endogenously released cannabinoids must have important therapeutic applications. Some goals for future research are...

Abstract Chemotherapy-induced nausea is one of the most distressing symptoms reported by patients undergoing treatment, and even with the introduction of newer antiemetics such as ondansetron and aprepitant, nausea remains problematic in the clinic. Indeed, when acute nausea is not properly managed, the cues of the clinic can become associated with this distressing symptom resulting in anticipatory nausea for which no effective treatments are available. Clinical trials exploring the potential of exogenous or endogenous cannabinoids to reduce chemotherapy-induced nausea are sparse; therefore, we must rely on the data from pre-clinical rat models of nausea. In this review, we explore the human and pre-clinical animal...

BACKGROUND AND PURPOSE Both CB1 and CB2 cannabinoid receptors have been shown to play a role in bone metabolism. Crucially, previous studies have focussed on the effects of cannabinoid ligands in murine bone cells. This study aimed to investigate the effects of cannabinoids on human bone cells in vitro. EXPERIMENTAL APPROACH Quantitative RT-PCR was used to determine expression of cannabinoid receptors and liquid chromatography-electrospray ionization tandem mass spectrometry was used to determine the presence of endocannabinoids in human bone cells. The effect of cannabinoids on human osteoclast formation, polarization and resorption was determined by assessing the number of cells expressing avb3 or with F-actin...

It has been hypothesized that tinnitus is a form of sensory epilepsy, arising partly from neuronal hyperactivity in auditory regions of the brain such as the cochlear nucleus and inferior colliculus. Although there is currently no effective drug treatment for tinnitus, anti-epileptic drugs are used in some cases as a potential treatment option. There is increasing evidence to suggest that cannabinoid drugs, i.e. cannabinoid receptor agonists, can also have anti-epileptic effects, at least in some cases and in some parts of the brain. It has been reported that cannabinoid CB1 receptors and the endogenous cannabinoid, 2-arachidonylglycerol (2-AG), are expressed in the cochlear nucleus and...

Abstract Background Levels of cannabinoid 1 receptor (CB1R) mRNA and protein, which are expressed most heavily in the cholecystokinin class of GABA neurons, are lower in the dorsolateral prefrontal cortex (DLPFC) in schizophrenia, and the magnitude of these differences is strongly correlated with that for glutamic acid decarboxylase (GAD67) mRNA, a synthesizing enzyme for GABA. However, whether this correlation reflects a cause-effect relationship is unknown. Methods Using quantitative in situ hybridization, we measured CB1R, GAD67, and diacylglycerol lipase alpha (DAGLα; the synthesizing enzyme for the endocannabinoid 2-arachidonoylglycerol) mRNA levels in the medial prefrontal cortex of genetically-engineered GAD67 heterozygous (GAD67+/−), CB1R heterozygous (CB1R+/−), CB1R knockout (CB1R−/−), and matched...