“Marijuana has been used to relieve pain for centuries.
The analgesic mechanism of its constituents, the cannabinoids, was only revealed after the discovery of cannabinoid receptors (CB1 and CB2) two decades ago.”
Tag Archives: CB(1) and CB(2) receptors
Overactivity of the intestinal endocannabinoid system in celiac disease and in methotrexate-treated rats.
“The endocannabinoid system is upregulated in both human inflammatory bowel diseases and experimental models of colitis. In this study, we investigated whether this upregulation is a marker also of celiac disease-induced atrophy. The levels of the cannabinoid CB(1) receptor, of the endocannabinoids, anandamide, and 2-arachidonoyl-glycerol (2-AG), and of the anti-inflammatory mediator palmitoylethanolamide (PEA) were analyzed in bioptic samples from the duodenal mucosa of celiac patients at first diagnosis assessed by the determination of antiendomysial antibodies and histological examination. Samples were analyzed during the active phase of atrophy and after remission and compared to control samples from non-celiac patients. The levels of anandamide and PEA were significantly elevated (approx. 2- and 1.8-fold, respectively) in active celiac patients and so were those of CB(1) receptors. Anandamide levels returned to normal after remission with a gluten-free diet. We also analyzed endocannabinoid and PEA levels in the jejunum of rats 2, 3, and 7 days after treatment with methotrexate, which causes inflammatory features (assessed by histopathological analyses and myeloperoxidase activity) similar to those of celiac patients. In both muscle/serosa and mucosa layers, the levels of anandamide, 2-AG, and PEA peaked 3 days after treatment and returned to basal levels at remission, 7 days after treatment. Thus, intestinal endocannabinoid levels peak with atrophy and regress with remission in both celiac patients and methotrexate-treated rats. The latter might be used as a model to study the role of the endocannabinoid system in celiac disease.”
Altered Expression of Type-1 and Type-2 Cannabinoid Receptors in Celiac Disease
“Anandamide (AEA) is the prominent member of the endocannabinoid family and its biological action is mediated through the binding to both type-1 (CB1) and type-2 (CB2) cannabinoid receptors (CBR). The presence of AEA and CBR in the gastrointestinal tract highlighted their pathophysiological role in several gut diseases, including celiac disease. Here, we aimed to investigate the expression of CBR at transcriptional and translational levels in the duodenal mucosa of untreated celiac patients, celiac patients on a gluten-free diet for at least 12 months and control subjects. Also biopsies from treated celiac patients cultured ex vivo with peptic-tryptic digest of gliadin were investigated. Our data show higher levels of both CB1 and CB2 receptors during active disease and normal CBR levels in treated celiac patients. In conclusion, we demonstrate an up-regulation of CB1 and CB2 mRNA and protein expression, that points to the therapeutic potential of targeting CBR in patients with celiac disease.
In conclusion, our findings together with those published in a previous study, suggest that an abnormal modulation of the endocannabinoid system, both at CBR and AEA levels, may be implicated in the pathogenesis of celiac disease. Further studies are needed to ascertain whether targeting these changes might have a therapeutic role, at least in those patients who are no longer responsive to gluten-free diet.”
Does modulation of the endocannabinoid system have potential therapeutic utility in cerebellar ataxia?
“Cerebellar ataxias represent a spectrum of disorders which are, however, linked by common symptoms of motor incoordination and are typically associated with deficient in Purkinje cell firing activity and, often, degeneration. Cerebellar ataxias currently lack a curative agent.
The endocannabinoid (eCB) system includes eCB compounds and their associated metabolic enzymes, together with cannabinoid receptors, predominantly the cannabinoid CB1 receptor (CB1 R) in the cerebellum; activation of this system in the cerebellar cortex is associated with deficits in motor coordination characteristic of ataxia, effects which can be prevented by CB1 R antagonists.
Of further interest are various findings that CB1 R deficits may also induce a progressive ataxic phenotype.
Together these studies suggest that motor coordination is reliant on maintaining the correct balance in eCB system signalling.
Recent work also demonstrates deficient cannabinoid signalling in the mouse ‘ducky2J ‘ model of ataxia.
In light of these points, the potential mechanisms whereby cannabinoids may modulate the eCB system to ameliorate dysfunction associated with cerebellar ataxias are considered.”
Endocannabinoids and Endocannabinoid-Related Mediators: Targets, Metabolism and Role In Neurological Disorders.
“The endocannabinoid system (ECS) is composed of two G protein-coupled receptors (GPCRs), the cannabinoid CB1 and CB2 receptors, and the two main endogenous lipid ligands of such receptors (also known as the “endocannabinoids”), anandamide and 2-arachidonoyl-glycerol. The ECS is a pleiotropic signalling systems involved in all aspects of mammalian physiology and pathology, and for this reason it represents a potential target for the design and development of new therapeutic drugs. However, the endocannabinoids as well as some of their congeners also interact with a much wider range of receptors, including members of the Transient Receptor Potential (TRP) channels, Peroxisome Proliferator-Activated Receptors (PPARs), and other GPCRs. Indeed, following the discovery of the endocannabinoids, endocannabinoid-related lipid mediators, which often share the same metabolic pathways of the endocannabinoids, have also been identified or rediscovered. In this review article, we discuss the role of endocannabinoids and related lipids during physiological functions, as well as their involvement is some of the most common neurological disorders.”
Cannabinoid receptors are involved in the protective effect of a novel curcumin derivative C66 against CCl4-induced liver fibrosis.
“Liver fibrosis is one of the major causes of morbidity and mortality worldwide and lacks efficient therapy. Recent studies suggest the curcumin protects liver from fibrosis. However, curcumin itself is in low bioavailable concentration when administered orally, and the protective mechanism remains poorly understood. The current study aimed to investigate whether a more stable derivative of curcumin, C66, protects against CCl4-inudced liver fibrosis and examine the underlying mechanism involving cannabinoid receptor (CB receptor). At a dose lower than curcumin itself, C66 displayed a superior anti-fibrotic effect. C66 significantly reduced collagen deposition, pro-inflammatory cytokine expression, and liver enzyme activities. Mechanistic study revealed that C66 treatment decreased CCl4-induced cannabinoid receptor 1 (CB1 receptor) expression and increased cannabinoidreceptor 2 (CB2 receptor) expression, along with an inhibition of JNK/NF-κB-mediated inflammatory signaling. In conclusion, this curcumin derivative attenuates liver fibrosis likely involving a CB/JNK/NF-κB-mediated pathway.”
Plant-derived, synthetic and endogenous cannabinoids as neuroprotective agents. Non-psychoactive cannabinoids, ‘entourage’ compounds and inhibitors of N-acyl ethanolamine breakdown as therapeutic strategies to avoid pyschotropic effects.
“There is good evidence that plant-derived and synthetic cannabinoids possess neuroprotective properties.
These compounds, as a result of effects upon CB(1) cannabinoid receptors, reduce the release of glutamate, and in addition reduce the influx of calcium following NMDA receptor activation.
The major obstacle to the therapeutic utilization of such compounds are their psychotropic effects, which are also brought about by actions on CB(1) receptors. However, synthesis of the endogenous cannabinoids anandamide and 2-arachidonoylglycerol, which also have neuroprotective properties, are increased under conditions of severe inflammation and ischemia, raising the possibility that compounds that prevent their metabolism may be of therapeutic utility without having the drawback of producing psychotropic effects.
In this review, the evidence indicating neuroprotective actions of plant-derived, synthetic and endogenous cannabinoids is presented. In addition, the pharmacological properties of endogenous anandamide-related compounds that are not active upon cannabinoid receptors, but which are also produced during conditions of severe inflammation and ischemia and may contribute to a neuroprotective action are reviewed.”
Endocannabinoid system in the brain…and elsewhere.
“The endocannabinoid system is a complex system with endogenous ligands, synthesis and transport processes, specific receptors (CB1 and CB2) and intracellular degrading enzymes.
It is widely distributed in the central nervous system, but also in peripheral organs.
In the brain, endocannabinoids and CB1 receptors are almost ubiquitous and play a role in synaptic plasticity: they modulate, through an inhibitory retrograde action, the release of classical neurotransmitters such as amines, acetylcholine or amino acids.
They may exert a neuroprotective effect, but are also involved in appetite and alcohol/drug dependence.
At the periphery, they are present (and overexpressed in case of abdominal obesity) in various organs involved in energy control and metabolic regulation.
Furthermore, CB2 receptors are also present in the brain, although less numerous than CB1 receptors.
They could attenuate pain and also be neuroprotective.
Selective agonists, antagonists and inverse agonists of CB1 and CB2 receptors are currently developed and open new interesting therapeutic perspectives.”
The endocannabinoid system: a new approach to control cardiovascular disease.
“The endocannabinoid (EC) system consists of 2 types of G-protein-coupled cannabinoid receptors–cannabinoid type 1 (CB1) and cannabinoid type 2 (CB2)–and their natural ligands.
The EC system plays a key role in the regulation of food intake and fat accumulation, as well as glucose and lipid metabolism.
When overactivated, the EC system triggers dyslipidemia, thrombotic and inflammatory states, and insulin resistance.
Blocking CB1 receptors centrally and peripherally in adipose tissue can help normalize an overactivated EC system. CB1 blockade helps regulate food intake and adipose tissue metabolism, contributing to improved insulin sensitivity and other features of the metabolic syndrome.
Visceral adipose tissue is most closely associated with the metabolic syndrome, which is a constellation of conditions that place people at high risk for coronary artery disease.
Targeting the EC system represents a new approach to treating visceral obesity and reducing cardiovascular risk factors.”
Development and Pharmacological Characterization of Selective Blockers of 2-Arachidonoyl Glycerol Degradation with Efficacy in Rodent Models of Multiple Sclerosis and Pain.
“We report the discovery of compound 4a, a potent β-lactam-based monoacylglycerol lipase (MGL) inhibitor characterized by an irreversible and stereoselective mechanism of action, high membrane permeability, high brain penetration evaluated using a human in vitro blood brain barrier model, high selectivity in binding and affinity-based proteomic profiling assays, and low in vitro toxicity.
Mode-of-action studies demonstrate that 4a, by blocking MGL, increases 2-arachidonoylglycerol, and behaves as cannabinoid (CB1/CB2) receptor indirect agonist.
Administration of 4a in mice suffering from experimental autoimmune encephalitis ameliorates the severity of the clinical symptoms in a CB1/CB2-dependent manner. Moreover, 4a produced analgesic effects in a rodent model of acute inflammatory pain, which was antagonized by CB1 and CB2 receptor antagonists/inverse agonists. 4a also relieves the neuropathic hypersensitivity induced by oxaliplatin.
Given these evidences, 4a, as MGL selective inhibitor, could represent a valuable lead for the future development of therapeutic options for multiple sclerosis and chronic pain.”