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: The ‘‘classic’’ endocannabinoid (eCB) system includes the cannabinoid receptors CB1 and CB2, the eCB ligands anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and their metabolic enzymes. An emerging literature documents the ‘‘eCB deficiency syndrome’’ as an etiology in migraine, fibromyalgia, irritable bowel syndrome, psychological disorders, and other conditions. We performed a systematic review of clinical interventions that enhance the eCB system—ways to upregulate cannabinoid receptors, increase ligand synthesis, or inhibit ligand degradation. Methodology/Principal Findings: We searched PubMed for clinical trials, observational studies, and preclinical research. Data synthesis was qualitative. Exclusion criteria limited the results to 184 in vitro studies, 102 in vivo animal studies, and...

Background and purpose: Cannabis is the source of at least seventy phytocannabinoids. The pharmacology of most of these has been little investigated, three notable exceptions being D9 -tetrahydrocannabinol, cannabidiol and D9 -tetrahydrocannabivarin. This investigation addressed the question of whether the little-studied phytocannabinoid, cannabigerol, can activate or block any G protein-coupled receptor. Experimental approach: The [35S]GTPgS binding assay, performed with mouse brain membranes, was used to test the ability of cannabigerol to produce G protein-coupled receptor activation or blockade. Its ability to displace [3 H]CP55940 from mouse CB1 and human CB2 cannabinoid receptors and to inhibit electrically evoked contractions of the mouse isolated vas deferens...

We have recently reported that in bone the cannabinoid CB1 receptor is present in sympathetic terminals. Here we show that traumatic brain injury (TBI), which in humans enhances peripheral osteogenesis and fracture healing, acutely stimulates bone formation in a distant skeletal site. At this site we demonstrate i) a high level of the main endocannabinoid, 2-arachidonoylglycerol (2-AG), and expression of diacylglycerol lipases, enzymes essential for 2-AG synthesis; ii) that the TBIinduced increase in bone formation is preceded by elevation of the 2-AG and a decrease in norepinephrine (NE) levels. The TBI stimulation of bone formation was absent in CB1-null mice. In wild-type animals it...

Endocannabinoids are now emerging as suppressors of key cell-signaling pathways involved in cancer cell growth, invasion, and metastasis. We have previously observed that the metabolically stable anandamide analog, 2-methyl-2'-F-anandamide (Met-F-AEA) can inhibit the growth of thyroid cancer in vivo. Our hypothesis was that the anti-tumor effect observed could be at least in part ascribed to inhibition of neo-angiogenesis. Therefore, the aim of this study was to assess the anti-angiogenic activity of Met-F-AEA, to investigate the molecular mechanisms underlying this effect and whether Met-F-AEA could antagonize tumor-induced endothelial cell sprouting. We show that Met-F-AEA inhibited bFGF-stimulated endothelial cell proliferation, in a dose-dependent manner, and also...

Abstract Objectives: This study examines the concept of clinical endocannabinoid deficiency (CECD), and the prospect that it could underlie the pathophysiology of migraine, fibromyalgia, irritable bowel syndrome, and other functional conditions alleviated by clinical cannabis. Methods: Available literature was reviewed, and literature searches pursued via the National Library of Medicine database and other resources. Results: Migraine has numerous relationships to endocannabinoid function. Anandamide (AEA) potentiates 5-HT1A and inhibits 5-HT2A receptors supporting therapeutic efficacy in acute and preventive migraine treatment. Cannabinoids also demonstrate dopamine-blocking and anti-inflammatory effects. AEA is tonically active in the periaqueductal gray matter, a migraine generator. THC modulates glutamatergic neurotransmission via NMDA receptors. Fibromyalgia is...

Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) occur naturally in marijuana (Cannabis) and may be formulated, individually or in combination in pharmaceuticals such as Marinol or Sativex. While it is known that these hydrophobic compounds can be transported in blood by albumin or lipoproteins, intracellular carrier have not been identified. Recent reports suggest that CBD and THC elevates the levels of the endocannabinoid anandamide (AEA) when administered to humans, suggesting that phytocannabinoids target cellular proteins involved in endocannabinoid clearance. Fatty acid binding proteins (FABPs) are intracellular proteins that mediate AEA transport to its catabolic enzyme fatty acid amide hydrolase (FAAH). By computational analysis and ligand displacement...

Abstract Background and purpose: The endocannabinoid system has been involved in the modulation of neural stem cells proliferation, survival and differentiation as well as in the generation of new oligodendrocyte progenitors in the postnatal brain. The present work aims to test the effect of the synthetic Type 1 and Type 2 cannabinoid receptor agonist WIN55212-2 on these processes in the context of neonatal rat brain hypoxia-ischemia (HI). Methods: P7 Wistar rats were subjected to HI and treated either with WIN55212-2 (1 mg/kg) or vehicle twice daily for 7 days after HI and euthanized at 1, 2, 7, 14, or 28 days to explore white matter injury...

Cannabinoids have been shown to critically modulate cholinergic neurotransmission in the hippocampus, yet opposing effects of cannabinoid receptor 1 (CB1R) agonists on hippocampal synaptic acetylcholine (ACh) efflux have been reported. This study shows that administration of a synthetic CB1R agonist results in a biphasic, dose-dependent, effect on hippocampal ACh: a low (0.5 mg/kg, i.p.) and a high (5 mg/kg, i.p) dose of WIN55,212-2 induces a transient stimulation and a prolonged inhibition of hippocampal ACh efflux, respectively. Both effects of WIN55,212-2 are mediated through CB1 receptors coupled to Gi but involve different neuroanatomical sites. Thus, intrahippocampal infusion of the CB1R antagonist SR141716A or pertussis toxin...

Medicine continues to struggle in its approaches to numerous common subjective pain syndromes that lack objective signs and remain treatment resistant. Foremost among these are migraine, fibromyalgia, and irritable bowel syndrome, disorders that may overlap in their affected populations and whose sufferers have all endured the stigma of a psychosomatic label, as well as the failure of endless pharmacotherapeutic interventions with substandard benefit. The commonality in symptomatology in these conditions displaying hyperalgesia and central sensitization with possible common underlying pathophysiology suggests that a clinical endocannabinoid deficiency might characterize their origin. Its base hypothesis is that all humans have an underlying endocannabinoid tone that is...