“The endocannabinoid (eCB) system consists of several endogenous lipids, their target CB1 and CB2 receptors and enzymes responsible for their synthesis and degradation. The most abundant eCB in the central nervous system (CNS), 2-arachidonoyl glycerol (2-AG), triggers a broad range of signalling events by acting on CB1, the most abundant G protein-coupled receptor in the CNS. The eCB system regulates many physiological processes including neurogenesis, axon guidance and synaptic plasticity. Recent studies have highlighted an additional important role for eCB signalling in neuronal migration, which is crucial to achieve the complex architecture and efficient wiring of the CNS. Indeed, eCB signalling controls migration both pre- and post-natally, regulating interneuron positioning in the developing cortex and hippocampus and the polarized motility of stem cell-derived neuroblasts. While these effects may contribute to cognitive deficits associated with cannabis consumption, they also provide potential opportunities for endogenous stem cell-based neuroregenerative strategies.”
Tag Archives: CB(1) and CB(2) receptors
Cannabinoid Receptors as Target for Treatment of Osteoporosis: A Tale of Two Therapies
“This review summarises in vitro and in vivo findings relating to the influence of cannabinoid ligands on bone metabolism and argues in favour of the exploitation of cannabinoid receptors as targets for both anabolic and anti-resorptive therapy for treatment of complex multifaceted bone diseases such as osteoporosis.”
The promise and dilemma of cannabinoid therapy: lessons from animal studies of bone disease.
“The endocannabinoid system plays an important role in numerous physiological processes and represents a potential drug target for diseases ranging from brain disorders to cancer…
In the aging skeleton, CB1 deficiency causes accelerated osteoporosis characterized mainly by a significant reduction in bone formation coupled to enhanced adipocyte accumulation in the bone marrow.
A similar acceleration of bone loss was also reported in aging CB2-deficient mice but found to be associated with enhanced bone turnover.
This perspective describes the role of cannabinoid ligands and their receptors in bone metabolism and highlights the promise and dilemma of therapeutic exploitation of the endocannabinoid system for treatment of bone disorders.”
Cannabis Finds Its Way into Treatment of Crohn’s Disease.
“In ancient medicine, cannabis has been widely used to cure disturbances and inflammation of the bowel. A recent clinical study now shows that the medicinal plant Cannabis sativa has lived up to expectations and proved to be highly efficient in cases of inflammatory bowel diseases.
In a prospective placebo-controlled study, it has been shown what has been largely anticipated from anecdotal reports, i.e. that cannabis produces significant clinical benefits in patients with Crohn’s disease. The mechanisms involved are not yet clear but most likely include peripheral actions on cannabinoid receptors 1 and 2, and may also include central actions.”
http://www.ncbi.nlm.nih.gov/pubmed/24356243
“In their prospective study, Naftali et al. used THC-free Cannabis as placebo with no other cannabinoids present. However, we should consider that also other ingredients of Cannabis, such as cannabidiol, cannabigerol, and tetrahydrocannabivarine (THCV), all of them non-psychotropic components of Cannabis, have proven antiinflammatory effects in experimental intestinal inflammation. Their actions partly involve non-CB receptor mechanisms via, for instance, peroxisome proliferator-activated receptors (PPAR) and transient receptor potential cation channels subfamily V receptors (TRPV) and should be regarded as additive beneficial effects of Cannabis in the improvement of colitis in addition to THC-mediated effects.
…an 8-week treatment with THC-rich Cannabis caused a decrease of the Crohn’s disease activity index (CDAI) in 90% of patients without producing significant side effects…
In summary, in agreement with the ancient use of Cannabis in intestinal disturbances and one decade of animal research, Cannabis was shown in a clinical trial to reduce symptoms in patients with CD. This elegant translation should be followed by larger trials confirming these results and by trials establishing the involved mechanisms to open a promising direction for future treatment of IBD.”
Full-text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4076530/
Unique effects of compounds active at both cannabinoid and serotonin receptors during stroke.
“We reported previously that both a cannabinoid receptor 2 (CB2R) agonist and a cannabinoid receptor 1 (CB1R) antagonist were protective in the treatment of transient middle cerebral artery occlusion/reperfusion injury (MCAO/R) and that they acted in a synergistic manner when administered in combination. The goal of the current study was to determine which of the potential cannabinoid receptors participate in the protective effects of this drug combination in a mouse model of MCAO/R.
The effects of administration of the CB2R agonist/CB1R antagonist combination on infarct size and cerebral blood flow during a 1-h occlusion were tested…
In conclusion, administration of the CB2R agonist/CB1R antagonist combination causes a significant reduction in infarct size in the MCAO/R model. The protective effect involves both the CB2R and the 5-HT1A receptor. Neither the CB1R nor the TRPV1 receptors appear to participate in this response.”
Direct modulation of the outer mitochondrial membrane channel, voltage-dependent anion channel 1 (VDAC1) by cannabidiol: a novel mechanism for cannabinoid-induced cell death.
“Cannabidiol (CBD) is a non-psychoactive plant cannabinoid that inhibits cell proliferation and induces cell death of cancer cells and activated immune cells. It is not an agonist of the classical CB1/CB2 cannabinoid receptors and the mechanism by which it functions is unknown.
…using microscale thermophoresis, we showed a direct interaction between purified fluorescently labeled VDAC1 and CBD.
Thus, VDAC1 seems to serve as a novel mitochondrial target for CBD.
The inhibition of VDAC1 by CBD may be responsible for the immunosuppressive and anticancer effects of CBD.”
The endocannabinoid system mediates aerobic exercise-induced antinociception in rats.
“These results indicate that exercise could activate the endocannabinoid system, producing antinociception.
Supporting this hypothesis, liquid-chromatography/mass-spectrometry measurements demonstrated that plasma levels of endocannabinoids (anandamide and 2-arachidonoylglycerol) and of anandamide-related mediators (palmitoylethanolamide and oleoylethanolamide) were increased after AE.
Therefore, these results suggest that the endocannabinoid system mediates aerobic exercise-induced antinociception at peripheral and central levels.”
Endocannabinoid system and pain: an introduction.
“The endocannabinoid (EC) system consists of two main receptors: cannabinoid type 1 receptor cannabinoid receptors are found in both the central nervous system (CNS) and periphery, whereas the cannabinoid type 2 receptor cannabinoid receptor is found principally in the immune system and to a lesser extent in the CNS.
The EC family consists of two classes of well characterised ligands; the N-acyl ethanolamines, such as N-arachidonoyl ethanolamide or anandamide (AEA), and the monoacylglycerols, such as 2-arachidonoyl glycerol. The various synthetic and catabolic pathways for these enzymes have been (with the exception of AEA synthesis) elucidated.
To date, much work has examined the role of EC in nociceptive processing and the potential of targeting the EC system to produce analgesia.
Cannabinoid receptors and ligands are found at almost every level of the pain pathway from peripheral sites, such as peripheral nerves and immune cells, to central integration sites such as the spinal cord, and higher brain regions such as the periaqueductal grey and the rostral ventrolateral medulla associated with descending control of pain. EC have been shown to induce analgesia in preclinical models of acute nociception and chronic pain states.
The purpose of this review is to critically evaluate the evidence for the role of EC in the pain pathway and the therapeutic potential of EC to produce analgesia. We also review the present clinical work conducted with EC, and examine whether targeting the EC system might offer a novel target for analgesics, and also potentially disease-modifying interventions for pathophysiological pain states.”
The endocannabinoid system and multiple sclerosis.
“Multiple sclerosis (MS) is a neurodegenerative disease that is characterised by repeated inflammatory/demyelinating events within the central nervous system (CNS). In addition to relapsing-remitting neurological insults, leading to loss of function, patients are often left with residual, troublesome symptoms such as spasticity and pain. These greatly diminish “quality of life” and have prompted some patients to self-medicate with and perceive benefit from cannabis.
Recent advances in cannabinoid biology are beginning to support these anecdotal observations, notably the demonstration that spasticity is tonically regulated by the endogenous cannabinoid system.
Recent clinical trials may indeed suggest that cannabis has some potential to relieve, pain, spasms and spasticity in MS. However, because the CB(1) cannabinoid receptor mediates both the positive and adverse effects of cannabis, therapy will invariably be associated with some unwanted, psychoactive effects.
In an experimental model of MS, and in MS tissue, there are local perturbations of the endocannabinoid system in lesional areas. Stimulation of endocannabinoid activity in these areas either through increase of synthesis or inhibition of endocannabinoid degradation offers the positive therapeutic potential of the cannabinoid system whilst limiting adverse events by locally targeting the lesion.
In addition, CB(1) and CB(2) cannabinoid receptor stimulation may also have anti-inflammatory and neuroprotective potential as the endocannabinoid system controls the level of neurodegeneration that occurs as a result of the inflammatory insults.
Therefore cannabinoids may not only offer symptom control but may also slow the neurodegenerative disease progression that ultimately leads to the accumulation of disability.”
Control of Spasticity in a Multiple Sclerosis Model is mediated by CB1, not CB2, Cannabinoid Receptors
“There is increasing evidence to suggest that cannabis can ameliorate muscle-spasticity in multiple sclerosis, as was objectively shown in experimental autoimmune encephalomyelitis models. The purpose of this study was to investigate further the involvement of CB1 and CB2 cannabinoid receptors in the control of experimental spasticity…
Conclusions and Implications:
The CB1 receptor controls spasticity and cross-reactivity to this receptor appears to account for the therapeutic action of some CB2 agonists.
As cannabinoid-induced psychoactivity is also mediated by the CB1 receptor, it will be difficult to truly dissociate the therapeutic effects from the well-known, adverse effects of cannabinoids when using cannabis as a medicine.
The lack of knowledge on the true diversity of the cannabinoid system coupled with the lack of total specificity of current cannabinoid reagents makes interpretation of in vivo results difficult, if using a purely pharmacological approach.
Gene knockout technology provides an important tool in target validation and indicates that the CB1 receptor is the main cannabinoid target for an anti-spastic effect.”