Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Endocannabinoids”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 343 records · Page 19Linked to original sources
PubMedDate not supplied

[The endocannabinoid system and food intake control].

Acylethanolamides are endogenous compounds with lipid structure including anandamide (AEA), palmitoilethanolamide, oleylamide and oleylethanolamide (OEA). AEA binds to the cannabinoid receptor CB1, located at the central nervous system, while OEA is an endogenous ligand for the alpha subtype of peroxisome-proliferator activating receptor (PPARalpha). Since AEA acts on the same receptor which binds marihuana active derivatives, this group of compounds were called endocannabinoids. Besides typical central effects of cannabinoids, CB1 receptor activation leads to hyperphagia, whereas its pharmacological blockade is followed by changes in energy metabolism favouring substrate oxidation. OEA has inhibitory effects on food intake by acting on PPARalpha receptors which modulate the autonomous nervous system. Both acylethanolamides, AEA and OEA, have opposite effects suggesting that they form part of a satiety sensor system. Whereas fasting triggers AEA release and inhibits OEA synthesis, eating has the reverse effect. Additionally OEA is also produced by adipocytes ad has some effects on lipid metabolism. All these data suggest a role for acylethanolamides and the endocannabinoid system in the pathophysiology of obesity, diabetes and atherosclerosis.

Adipocytes↗
PubMed2005

[Endocannabinoids--the new option in the treatment of metabolic syndrome and in smoking cessation].

Development of the metabolic syndrome results from the interaction of genetic and environmental factors. Metabolic syndrome together with smoking represents risk factors for the development of cardiovascular complications. They may result from the hyperstimulation of the endocannabinoid system. The CB1 receptor has been assumed to play an important role in the endocannabionoid system. It is abundantly expressed in the brain, and in other parts of human body such as in the fat tissue. Rimonabant is a selective blocker of cannabinoid-1 (CB1) receptors and participates in the regulation of impaired endocannabinoid system. In the overweight humans, it stimulates sustained reduction of the body weight, girth size and it improves lipid and glucose metabolism. Rimonabant also reduces nicotine self-administration and may be effective not only as an aid for smoking cessation but also in the prevention of body weight increase related to the smoking cessation as it was documented in Rio-Lipids and Stratus-us studies.

Arachidonic Acids↗
PubMed2005

The endocannabinoid system: a drug discovery perspective.

The endocannabinoids are lipid messengers that engage the same cell surface receptors targeted by delta9-tetrahydrocannabinol, the active component of marijuana. They are produced by cells in the brain and other tissues and combine with two subtypes of G protein-coupled cannabinoid receptors, CB1 and CB2. Their ability to modulate a variety of pathophysiological processes, including appetite, pain and mood, provides unique opportunities for drug discovery. Three such opportunities are discussed here: reduction of body weight through blockade of CB1 receptors, alleviation of pain through activation of extracerebral cannabinoid receptors, and modulation of pain and anxiety through inhibition of endocannabinoid degradation.

Animals↗
PubMed2006

Endocannabinoids and the gastrointestinal tract.

In the past centuries, different preparations of marijuana have been used for the treatment of gastrointestinal (GI) disorders, such as GI pain, gastroenteritis and diarrhea. Delta9-tetrahydrocannabinol (THC; the active component of marijuana), as well as endogenous and synthetic cannabinoids, exert their biological functions on the gastrointestinal tract by activating two types of cannabinoid receptors, cannabinoid type 1 receptor (CB1 receptor) and cannabinoid type 2 receptor (CB2 receptor). While CB1 receptors are located in the enteric nervous system and in sensory terminals of vagal and spinal neurons and regulate neurotransmitter release, CB2 receptors are mostly distributed in the immune system, with a role presently still difficult to establish. Under pathophysiological conditions, the endocannabinoid system conveys protection to the GI tract, eg from inflammation and abnormally high gastric and enteric secretion. For such protective activities, the endocannabinoid system may represent a new promising therapeutic target against different GI disorders, including frankly inflammatory bowel diseases (eg, Crohn's disease), functional bowel diseases (eg, irritable bowel syndrome), and secretion- and motility-related disorders.

Animals↗
PubMed2006

Endocannabinoids and energy metabolism.

Although adjustments to nutritional lifestyle and increased physical activity remain the milestones of weight loss therapy, it is evident from the exponential increase of the number of obese subjects in Western countries that these two approaches alone are no longer able to limit this progression. This alarming phenomenon occurs in spite of a great effort exerted in the last 10 yr to shed light on the pathogenetic mechanisms inducing obesity, although many inconclusive hopes have been generated in the field of pharmacotherapeutics to tackle obesity. Among the several targets exploited in recent years, the endocannabinoid system nowadays constitutes the most promising and the most intriguing proposed so far. On one hand, our aim is to provide an overview on the role of the endocannabinoid system in the physiology of energy metabolism, on the other hand a further aim is to summarize how the system also controls food intake and energy balance by acting at both cerebral and peripheral level.

Animals↗
PubMed2003

An optimized approach to study endocannabinoid signaling: evidence against constitutive activity of rat brain adenosine A1 and cannabinoid CB1 receptors.

At nanomolar concentrations, SR141716 and AM251 act as specific and selective antagonists of the cannabinoid CB1 receptor. In the micromolar range, these compounds were shown to inhibit basal G-protein activity, and this is often interpreted to implicate constitutive activity of the CB1 receptors in native tissue. We show here, using [35S]GTPgammaS binding techniques, that micromolar concentrations of SR141716 and AM251 inhibit basal G-protein activity in rat cerebellar membranes, but only in conditions where tonic adenosine A1 receptor signaling is not eliminated. Unlike lipophilic A1 receptor antagonists (potency order DPCPX>>N-0840 approximately cirsimarin>caffeine), adenosine deaminase (ADA) was not fully capable in eliminating basal A1 receptor-dependent G-protein activity. Importantly, all antagonists reduced basal signal to the same extent (20%), and the response evoked by the inverse agonist DPCPX was not reversed by the neutral antagonist N-0840. These data indicate that rat brain A1 receptors are not constitutively active, but that an ADA-resistant adenosine pool is responsible for tonic A1 receptor activity in brain membranes. SR141716 and AM251, at concentrations fully effective in reversing CB1-mediated responses (10-6 m), did not reduce basal G-protein activity, indicating that CB1 receptors are not constitutively active in these preparations.4 At higher concentrations (1-2.5 x 10-5 m), both antagonists reduced basal G-protein activity in control and ADA-treated membranes, but had no effect when A1 receptor signaling was blocked with DPCPX. Moreover, the CB1 antagonists right-shifted A1 agonist dose-response curves without affecting maximal responses, suggesting competitive mode of antagonist action. The CB1 antagonists did not affect muscarinic acetylcholine or GABAB receptor signaling. When further optimizing G-protein activation assay for the labile endocannabinoid 2-arachidonoylglycerol (2-AG), we show, by using HPLC, that pretreatment of cerebellar membranes with methyl arachidonoyl fluorophosphonate (MAFP) fully prevented enzymatic degradation of 2-AG and concomitantly enhanced the potency of 2-AG. In contrast to previous claims, MAFP exhibited no antagonist activity at the CB1 receptor.6 The findings establish an optimized method with improved signal-to-noise ratio to assess endocannabinoid-dependent G-protein activity in brain membranes, under assay conditions where basal adenosinergic tone and enzymatic degradation of 2-AG are fully eliminated.

Adenosine A1 Receptor Antagonists↗
PubMed2005

Identification of a high-affinity binding site involved in the transport of endocannabinoids.

Phytocannabinoids, such as the principal bioactive component of marijuana, delta9-tetrahydrocannabinol, have been used for thousands of years for medical and recreational purposes. delta9-Tetrahydrocannabinol and endogenous cannabinoids (e.g., anandamide) initiate their agonist properties by stimulating the cannabinoid family of G protein-coupled receptors (CB1 and CB2). The biosynthesis and physiology of anandamide is well understood, but its mechanism of uptake (resulting in signal termination by fatty acid amide hydrolase) has been elusive. Mounting evidence points to the existence of a specific anandamide transport protein; however, no direct evidence for this protein has been provided. Here, we use a potent, competitive small molecule inhibitor of anandamide uptake (LY2318912, IC50 7.27 +/- 0.510 nM) to identify a high-affinity, saturable anandamide transporter binding site (LY2318912; K(d) = 7.62 +/- 1.18 nM, B(max) = 31.6 +/- 1.80 fmol/mg protein) that is distinct from fatty acid amide hydrolase. Systemic administration of the inhibitor into rodents elevates anandamide levels 5-fold in the brain and demonstrates efficacy in the formalin paw-licking model of persistent pain with no obvious adverse effects on motor function. Identification of the anandamide transporter binding site resolves a missing mechanistic link in endocannabinoid signaling, and in vivo results suggest that endocannabinoid transporter antagonists may provide a strategy for positive modulation of cannabinoid receptors.

Animals↗
PubMedDate not supplied

Endocannabinoids and their implications for epilepsy.

This review covers the main features of a newly discovered intercellular signaling system in which endogenous ligands of the brain's cannabinoid receptors, or endocannabinoids, serve as retrograde messengers that enable a cell to control the strength of its own synaptic inputs. Endocannabinoids are released by bursts of action potentials, including events resembling interictal spikes, and probably by seizures as well. Activation of cannabinoid receptors has been implicated in neuroprotection against excitotoxicity and can help explain the anticonvulsant properties of cannabinoids that have been known since antiquity.

Journal Article↗
PubMed2003

Endocannabinoid signalling in the blood of patients with schizophrenia.

AIM: To test the hypothesis that schizophrenia might be associated with alterations of the endogenous cannabinoid system in human blood. RESULTS: Blood from 20 healthy volunteers and 12 patients with schizophrenia, 5 of which both before and after a successful antipsychotic treatment, was analysed for: 1) the amounts of the endocannabinoid anandamide; 2) the levels of cannabinoid CB1 and CB2 receptor mRNAs, and 3) the levels of the mRNA encoding the enzyme fatty acid amide hydrolase (FAAH), responsible for anandamide degradation. The amounts of anandamide were significantly higher in the blood of patients with acute schizophrenia than in healthy volunteers (7.79 +/- 0.50 vs. 2.58 +/- 0.28 pmol/ml). Clinical remission was accompanied by a significant decrease of the levels of anandamide (3.88 +/- 0.72 pmol/ml) and of the mRNA transcripts for CB2 receptors and FAAH. CONCLUSION: These findings indicate that endocannabinoid signalling might be altered during the acute phase of schizophrenia not only in the central nervous system but also in the blood. These changes might be related to the several immunological alterations described in schizophrenia.

Journal Article↗
PubMed2005

Endocannabinoid signaling in rat somatosensory cortex: laminar differences and involvement of specific interneuron types.

Endocannabinoid-mediated retrograde signaling exerts powerful control over synaptic transmission in many brain areas. However, in the neocortex, the precise laminar, cellular, and subcellular localization of the type 1 cannabinoid receptor (CB1) as well as its function has been elusive. Here we combined multiple immunolabeling with whole-cell recordings to investigate the morpho-functional characteristics of cannabinoid signaling in rat somatosensory cortex. Immunostaining for CB1 revealed axonal and somatic labeling with striking layer specificity: a high density of CB1-positive fibers was seen in layers II-III, in layer VI, and in upper layer V, whereas other layers had sparse (layer IV) or hardly any (layer I) staining. Membrane staining for CB1 was only found in axon terminals, all of which contained GABA and formed symmetric synapses. Double immunostaining also revealed that CB1-positive cells formed two neurochemically distinct subpopulations: two-thirds were cholecystokinin positive and one-third expressed calbindin, each subserving specific inhibitory functions in cortical networks. In addition, cannabinoid sensitivity of GABAergic input showed striking layer specificity, as revealed by both electrophysiological and anatomical experiments. We found a unique population of large pyramidal neurons in layer VB that received much less perisomatic innervation from CB1-expressing GABAergic axon terminals and, accordingly, showed no depolarization-induced suppression of inhibition, unlike pyramidal cells in layer II, and a population of small pyramidal cells in layer V. This suggests that inhibitory control of pyramidal cells involved in intracortical or corticostriatal processing is fine-tuned by activity-dependent endocannabinoid signaling, whereas inhibition of pyramidal cells relaying cortical information to lower subcortical effector centers often lacks this plasticity.

Animals↗
PubMed2004

Endocannabinoid-independent retrograde signaling at inhibitory synapses in layer 2/3 of neocortex: involvement of vesicular glutamate transporter 3.

Recent studies implicate dendritic endocannabinoid release from subsynaptic dendrites and subsequent inhibition of neurotransmitter release from nerve terminals as a means of retrograde signaling in multiple brain regions. Here we show that type 1 cannabinoid receptor-mediated endocannabinoid signaling is not involved in the retrograde control of synaptic efficacy at inhibitory synapses between fast-spiking interneurons and pyramidal cells in layer 2/3 of the neocortex. Vesicular neurotransmitter transporters, such as vesicular glutamate transporters (VGLUTs) 1 and 2, are localized to presynaptic terminals and accumulate neurotransmitters into synaptic vesicles. A third subtype of VGLUTs (VGLUT3) was recently identified and found localized to dendrites of various cell types. We demonstrate, using multiple immunofluorescence labeling and confocal laser-scanning microscopy, that VGLUT3-like immunoreactivity is present in dendrites of layer 2/3 pyramidal neurons in the rat neocortex. Electron microscopy analysis confirmed that VGLUT3-like labeling is localized to vesicular structures, which show a tendency to accumulate in close proximity to postsynaptic specializations in dendritic shafts of pyramidal cells. Dual whole-cell recordings revealed that retrograde signaling between fast-spiking interneurons and pyramidal cells was enhanced under conditions of maximal efficacy of VGLUT3-mediated glutamate uptake, whereas it was reduced when glutamate uptake was inhibited by incrementing concentrations of the nonselective VGLUT inhibitor Evans blue (0.5-5.0 microm) or intracellular Cl- concentrations (4-145 mm). Our results present further evidence that dendritic vesicular glutamate release, controlled by novel VGLUT isoforms, provides fast negative feedback at inhibitory neocortical synapses, and demonstrate that glutamate can act as a retrograde messenger in the CNS.

Amino Acid Transport Systems, Acidic↗
PubMed2026

Effects of an internet-based combined exercise and cognitive-behavioral therapy intervention on endocannabinoid system biomarkers and physical fitness in adults with mild-to-moderate depression: a SONRIE randomized controlled trial.

BACKGROUND: This SONRIE randomized controlled trial (NCT05849792) examined the effects of a 12-week combined physical exercise and internet-based cognitive-behavioral therapy (iCBT) intervention on endocannabinoid system (ES) biomarkers and physical fitness in adults with mild-to-moderate depression. METHODS: Eighty adults were randomly assigned 1:1 to an intervention (IG) or control (CG) group. Outcomes included nine ES biomarkers (2-arachidonoylglycerol, 2-AG; anandamide, AEA; seven analogues) and physical fitness, including cardiorespiratory fitness (CRF; 6-minute walking test) and muscular strength. Measurements were taken at baseline, post-intervention and 8-week follow-up. Primary analysis performed 2 × 3 repeated-measures ANOVA on completers; mixed-effects intention-to-treat model as sensitivity analysis. RESULTS: No significant time × group interaction was detected for any ES biomarker, including 2-AG (F(2,88) = 0.17, p = 0.844) and AEA (F(2,88) = 1.20, p = 0.306); both groups showed comparable within-group decreases in 2-AG, 2-LG and 2-OG. The intervention significantly improved CRF [between-group difference + 81.6 m at 12 weeks (F(2,78) = 7.88, p = 0.001)], exceeding the established minimal clinically important difference. None of the exploratory muscular fitness outcomes reached statistical significance; the arm curl test showed a borderline non-significant interaction (F(2,78) = 2.83, p = 0.065). CONCLUSION: A 12-week internet-based combined exercise and iCBT intervention significantly improved CRF in adults with mild-to-moderate depression. We did not find evidence of an intervention-specific effect on plasma ES biomarkers. These findings support the inclusion of internet-delivered exercise and psychological interventions in comprehensive treatment strategies for depression. TRIAL REGISTRATION: ClinicalTrials.gov NCT05849792 (registered 6 May 2023).

Humans↗
PubMed2026

Exploring sex differences in endocannabinoid system biomarkers and their relationship with antidepressant treatment outcomes in major depressive disorder: a CAN-BIND 1 secondary analysis.

BACKGROUND: Sex differences in major depressive disorder (MDD) are well documented, but it remains unclear whether sex-related variation in peripheral endocannabinoid system (ECS)-related biomarkers is detectable in MDD. OBJECTIVES: To examine baseline sex differences in ECS-related mRNA expression, DNA methylation, and single nucleotide polymorphisms (SNPs) in MDD, and associations between baseline ECS markers and antidepressant outcomes in sex-stratified analyses. METHODS: Among 178 participants with MDD from CAN-BIND-1, all received escitalopram for 8 weeks; non-responders then received adjunctive aripiprazole from Weeks 8-16.Response was defined as ≥ 50% reduction in MADRS score, and remission as MADRS ≤ 10. ANCOVAs examined baseline sex differences and sex-stratified biomarker associations with percent MADRS reduction at Weeks 8 and 16, as well as categorical response and remission outcomes. Covariates included site, baseline MADRS, age, and ethnicity. False discovery rate correction was applied. RESULTS: Baseline sex differences in methylation were observed for CACNA1H, GABRB2, MAGL, and GABRR2, though none survived correction. No baseline sex differences in mRNA expression or SNPs were detected after correction. Lower baseline DAGLA mRNA in males was associated with greater Week 8 symptom improvement (FDR corrected). This association was not observed in females. No associations with response or remission at Weeks 8 or 16 survived correction. IMPLICATIONS: Baseline sex differences in peripheral ECS-related markers were not detected in this sample. Larger studies are needed to verify whether ECS-related biomarkers, particularly DAGLA, contribute to antidepressant outcomes in a sex-specific manner.

Humans↗
PubMed2007

Antiangiogenic activity of the endocannabinoid anandamide: correlation to its tumor-suppressor efficacy.

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 induced apoptosis, both effects reliant on cannabinoid CB1 receptor stimulation. Analyzing the signaling pathways implicated in angiogenesis, we observed that the bFGF-induced ERK phosphorylation was antagonized by Met-F-AEA, and we found that p38 MAPK was involved in Met-F-AEA-induced apoptosis. Moreover, Met-F-AEA was able to inhibit bi-dimensional capillary-like tube formation and activity of matrix metalloprotease MMP-2, a major matrix degrading enzyme. Importantly, we demonstrated that Met-F-AEA is also functional in vivo since it inhibited angiogenesis in the chick chorioallantoic neovascularization model. Finally, Met-F-AEA inhibited tumor-induced angiogenesis in a three-dimensional model of endothelial and thyroid tumor cell (KiMol) spheroids co-cultures in different 3-D polymeric matrices that resemble tumor microenvironment and architecture. Thus, our results suggest that anandamide could be involved in the control of cancer growth targeting both tumor cell proliferation and the angiogenic stimulation of the vasculature.

Angiogenesis Inhibitors↗
PubMed2005

Modulators of endocannabinoid enzymic hydrolysis and membrane transport.

Tissue concentrations of the endocannabinoids N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) are regulated by both synthesis and inactivation. The purpose of this review is to compile available data regarding three inactivation processes: fatty acid amide hydrolase, monoacylglycerol lipase, and cellular membrane transport. In particular, we have focused on mechanisms by which these processes are modulated. We describe the in vitro and in vivo effects of inhibitors of these processes as well as available evidence regarding their modulation by other factors.

Amidohydrolases↗
PubMed2003

Antioxidant properties of the vasoactive endocannabinoid, 2-arachidonoyl glycerol (2-AG).

Reactive oxygen species (ROS) were shown to play a role in altering blood-brain barrier (BBB) permeability and formation of brain edema induced by trauma and/or ischemia. 2-arachidonoyl glycerol (2-AG), a novel, potent vasodilatory and cytoprotective endocannabinoid has been implicated to act as an antioxidative agent. This study examines: 1) the possible 2-AG modulation of BBB injury and edema formation induced by closed head injury (CHI); and 2) comparable effects between 2-AG and 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (TPL), a known antioxidant nitroxide on endothelial Ca2+ and cytoskeletal responses to H2O2 (ROS). 2-AG treatment reduced the CHI-induced increase in BBB permeability and brain edema. The endothelial H2O2-stimulated Ca2+ mobilization and cytoskeleton (vimentin) rearrangement was modified by either 2-AG or TPL. These findings provide evidence of 2-AG antioxidant activity and are consistent with the involvement of ROS in the pathomechanism of CHI-induced BBB injury and brain edema.

Animals↗
PubMed2004

Role of endocannabinoid system in mental diseases.

In the last decade, a large number of studies using Delta9-tetrahydrocannabinol (THC), the main active principle derivative of the marijuana plant, or cannabinoid synthetic derivatives have substantially contributed to advance the understanding of the pharmacology and neurobiological mechanisms produced by cannabinoid receptor activation. Cannabis has been historically used to relieve some of the symptoms associated with central nervous system disorders. Nowadays, there are anecdotal evidences for the use of cannabis in many patients suffering from multiple sclerosis or chronic pain. Following the historical reports of the use of cannabis for medicinal purposes, recent research has highlighted the potential of cannabinoids to treat a wide variety of clinical disorders. Some of these disorders that are being investigated are pain, motor dysfunctions or psychiatric illness. On the other hand, cannabis abuse has been related to several psychiatric disorders such as dependence, anxiety, depression, cognitive impairment, and psychosis. Considering that cannabis or cannabinoid pharmaceutical preparations may no longer be exclusively recreational drugs but may also present potential therapeutic uses, it has become of great interest to analyze the neurobiological and behavioral consequences of their administration. This review attempts to link current understanding of the basic neurobiology of the endocannabinoid system to novel opportunities for therapeutic intervention and its effects on the central nervous system.

Analgesia↗
PubMed2007

Endocannabinoids in adipocytes during differentiation and their role in glucose uptake.

The molecular basis for the control of energy balance by the endocannabinoid anandamide (AEA) is still unclear. Here, we show that murine 3T3-L1 fibroblasts have the machinery to bind, synthesize and degrade AEA, and that their differentiation into adipocytes increases by approximately twofold the binding efficiency of cannabinoid receptors (CBR), and by approximately twofold and approximately threefold, respectively, the catalytic efficiency of the AEA transporter and AEA hydrolase. In contrast, the activity of the AEA synthetase and the binding efficiency of vanilloid receptor were not affected by the differentiation process. In addition, we demonstrate that AEA increases by approximately twofold insulin-stimulated glucose uptake in differentiated adipocytes, according to a CB1R-dependent mechanism that involves nitric oxide synthase, but not lipoxygenase or cyclooxygenase. We also show that AEA binding to peroxisome proliferator-activated receptor-gamma, known to induce differentiation of 3T3-L1 fibroblasts into adipocytes, is not involved in the stimulation of glucose uptake.

3T3 Cells↗