Tag Archives: CB(1) and CB(2) receptors

Cannabis Finds Its Way into Treatment of Crohn’s Disease.

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“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.

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“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.”

http://www.ncbi.nlm.nih.gov/pubmed/24323810

Direct modulation of the outer mitochondrial membrane channel, voltage-dependent anion channel 1 (VDAC1) by cannabidiol: a novel mechanism for cannabinoid-induced cell death.

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“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.”

http://www.ncbi.nlm.nih.gov/pubmed/24309936

The endocannabinoid system mediates aerobic exercise-induced antinociception in rats.

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“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.”

http://www.ncbi.nlm.nih.gov/pubmed/24148812

Endocannabinoid system and pain: an introduction.

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“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.”

http://www.ncbi.nlm.nih.gov/pubmed/24148358

The endocannabinoid system and multiple sclerosis.

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“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.”

http://www.ncbi.nlm.nih.gov/pubmed/18781983

Control of Spasticity in a Multiple Sclerosis Model is mediated by CB1, not CB2, Cannabinoid Receptors

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Figure 1

“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.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2189718/

Therapeutic Potential of a Novel Cannabinoid Agent CB52 in the Mouse Model ofExperimental Autoimmune Encephalomyelitis.

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“The endocannabinoid system has recently emerged as a promising therapeutic target for MS. The protective mechanisms of cannabinoids are thought to be mediated by activation of cannabinoid receptor 1 (CB1) and 2 (CB2)…

activation of CB1 receptors contributes significantly to the anti-inflammatory and neuroprotective effects of cannabinoids on MS.”

http://www.ncbi.nlm.nih.gov/pubmed/24036373

Treatment of spasticity in multiple sclerosis: new perspectives regarding the use of cannabinoids.

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“Spasticity remains a prevalent symptom in multiple sclerosis, with a significant associated disability and quality of life impairment… Cannabinoids provide a new way for therapy.

A delta-9-tetrahydrocannabinol plus cannabidiol (1:1) association, administered through an oromucosal route, has been approved in several countries including Spain; it causes a specific effect on CB(1) and CB(2) receptors, with traditional psychotropic cannabis actions being minimized.

Randomized, placebo-controlled trials, as well as longer-term open-label extensions, have shown a clear-cut efficacy to reduce spasticity and their associated symptoms in those patients refractory to other therapies, with a good tolerability/safety profile.

No tolerance, abuse or addictive issues have been found…”

http://www.ncbi.nlm.nih.gov/pubmed/23011861

Cannabinoid receptors expression in bone marrow trephine biopsy of chronic lymphocytic leukaemia patients treated with purine analogues.

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“Cannabinoid receptors CB1 and CB2 are part the endocannabinoid system that plays an important role in the process of proliferation and apoptosis of different neoplastic cells. B-cell chronic lymphocytic leukaemia is one of the diseases in which these processes are altered… The aim of our study was the assessment of cannabinoid receptor expression on the B-lymphocytes in bone marrow trephine biopsy from leukaemic patients at diagnosis and after purine analogue treatment….

CONCLUSION:

The study provides original evidence for the existence of cannabinoid receptors on B-lymphocytes in chronic lymphocytic leukaemia patients. The receptors are thought to be a new structure that can modify the course of the disease and may be considered as a new target in leukaemia treatment.”

http://www.ncbi.nlm.nih.gov/pubmed/18004250