Tag Archives: cannabinoid receptors

5-lipoxygenase mediates docosahexaenoyl ethanolamide and N-arachidonoyl-L-alanine-induced reactive oxygen species production and inhibition of proliferation of head and neck squamous cell carcinoma cells.

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“Endocannabinoids have recently drawn attention as promising anti-cancer agents. We previously observed that anandamide (AEA), one of the representative endocannabinoids, effectively inhibited the proliferation of head and neck squamous cell carcinoma (HNSCC) cell lines in a receptor-independent manner. In this study, using HNSCC cell lines, we examined the anti-cancer effects and the mechanisms of action of docosahexaenoyl ethanolamide (DHEA) and N-arachidonoyl-L-alanine (NALA), which are polyunsaturated fatty acid (PUFA)-based ethanolamides like AEA. From these findings, we suggest that ROS production induced by the 5-LO pathway mediates the anti-cancer effects of DHEA and NALA on HNSCC cells. Finally, our findings suggest the possibility of a new cancer-specific therapeutic strategy, which utilizes 5-LO activity rather than inhibiting it.”  http://www.ncbi.nlm.nih.gov/pubmed/27411387

https://bmccancer.biomedcentral.com/articles/10.1186/s12885-016-2499-3

Expression and function of cannabinoid receptors CB1 and CB2 and their cognate cannabinoid ligands in murine embryonic stem cells.

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“Characterization of intrinsic and extrinsic factors regulating the self-renewal/division and differentiation of stem cells is crucial in determining embryonic stem (ES) cell fate.

ES cells differentiate into multiple hematopoietic lineages during embryoid body (EB) formation in vitro, which provides an experimental platform to define the molecular mechanisms controlling germ layer fate determination and tissue formation.

This work has not been addressed previously and yields new information on the function of cannabinoid receptors, CB1 and CB2, as components of a novel pathway regulating murine ES cell differentiation.

This study provides insights into cannabinoid system involvement in ES cell survival and hematopoietic differentiation.

Thus, these observations together with our results strongly suggest that both CB1 and CB2 activation are involved in the maintenance of mES cells and that the endocannabinoid system is essential in stem cell survival and stem cell hematopoietic differentiation.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1919431/

 

Regulation of hematopoietic stem cell trafficking and mobilization by the endocannabinoid system.

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“The cannabinoid receptors CB(1) and CB(2) are seven-transmembrane Gαi protein-coupled receptors and are expressed in certain mature hematopoietic cells.

We recently showed that these receptors are expressed in murine and human hematopoietic stem cells (HSCs) and that CB(2) agonists induced chemotaxis, enhanced colony formation of marrow cells, as well as caused in vivo mobilization of murine HSCs with short- and long-term repopulating abilities. Based on these observations, we have further explored the role of CB(2) and its agonist AM1241 on hematopoietic recovery following sublethal irradiation in mice.

Cannabinoid receptor 2 knockout mice (Cnr2(-/-) deficient mice) exhibited impaired recovery following sublethal irradiation as compared with irradiated wild-type (WT) mice, as determined by low colony-forming units and low peripheral blood counts. WT mice treated with CB(2) agonist AM1241 following sublethal irradiation demonstrated accelerated marrow recovery and increased total marrow cells (approximately twofold) and total lineage- c-kit(+) cells (approximately sevenfold) as well as enhanced HSC survival as compared with vehicle control-treated mice.

When the CB(2) agonist AM1241 was administered to WT mice 12 days before their sublethal irradiation, analysis of hematopoiesis in these mice showed decreased apoptosis of HSCs, enhanced survival of HSCs, as well as increase in total marrow cells and c-kit+ cells in the marrow.

Thus, CB(2) agonist AM1241 promoted recovery after sublethal irradiation by inhibiting apoptosis of HSCs and promoting survival, as well as enhancing the number of HSCs entering the cell cycle.”

http://www.ncbi.nlm.nih.gov/pubmed/22074629

Cannabinoid Receptor-2 Regulates Embryonic Hematopoietic Stem Cell Development via Prostaglandin E2 and P-Selectin Activity

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Cannabinoids (CB) modulate adult hematopoietic stem and progenitor cell (HSPCs) function, however, impact on the production, expansion, or migration of embryonic HSCs is currently uncharacterized.

Here, using chemical and genetic approaches targeting CB-signaling in zebrafish, we show that CB receptor (CNR) 2, but not CNR1, regulates embryonic HSC development.

Together, these data suggest CNR2-signaling optimizes the production, expansion, and migration of embryonic HSCs by modulating multiple downstream signaling pathways.

Our work indicates that CB/CNR2 activity acts as a modifier of embryonic HSC formation by fine-tuning signaling pathways essential for HSC emergence and colonization of secondary niches.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4781665/

Cannabinoids for Symptom Management and Cancer Therapy: The Evidence.

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“Cannabinoids bind not only to classical receptors (CB1 and CB2) but also to certain orphan receptors (GPR55 and GPR119), ion channels (transient receptor potential vanilloid), and peroxisome proliferator-activated receptors. Cannabinoids are known to modulate a multitude of monoamine receptors. Structurally, there are 3 groups of cannabinoids.

Multiple studies, most of which are of moderate to low quality, demonstrate that tetrahydrocannabinol (THC) and oromucosal cannabinoid combinations of THC and cannabidiol (CBD) modestly reduce cancer pain.

Dronabinol and nabilone are better antiemetics for chemotherapy-induced nausea and vomiting (CINV) than certain neuroleptics, but are not better than serotonin receptor antagonists in reducing delayed emesis, and cannabinoids have largely been superseded by neurokinin-1 receptor antagonists and olanzapine; both cannabinoids have been recommended for breakthrough nausea and vomiting among other antiemetics. Dronabinol is ineffective in ameliorating cancer anorexia but does improve associated cancer-related dysgeusia.

Multiple cancers express cannabinoid receptors directly related to the degree of anaplasia and grade of tumor.

Preclinical in vitro and in vivo studies suggest that cannabinoids may have anticancer activity.

Paradoxically, cannabinoid receptor antagonists also have antitumor activity.

There are few randomized smoked or vaporized cannabis trials in cancer on which to judge the benefits of these forms of cannabinoids on symptoms and the clinical course of cancer. Smoked cannabis has been found to contain Aspergillosis. Immunosuppressed patients should be advised of the risks of using “medical marijuana” in this regard.”

http://www.ncbi.nlm.nih.gov/pubmed/27407130

Association between cerebral cannabinoid 1 receptor availability and body mass index in patients with food intake disorders and healthy subjects: a [18F]MK-9470 PET study.

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“Although of great public health relevance, the mechanisms underlying disordered eating behavior and body weight regulation remain insufficiently understood.

Compelling preclinical evidence corroborates a critical role of the endocannabinoid system (ECS) in the central regulation of appetite and food intake.  However, in vivo human evidence on ECS functioning in brain circuits involved in food intake regulation as well as its relationship with body weight is lacking, both in health and disease.

Here, we measured cannabinoid 1 receptor (CB1R) availability using positron emission tomography (PET) with [18F]MK-9470 in 54 patients with food intake disorders (FID) covering a wide body mass index (BMI) range (anorexia nervosa, bulimia nervosa, functional dyspepsia with weight loss and obesity; BMI range=12.5-40.6 kg/m2) and 26 age-, gender- and average BMI-matched healthy subjects (BMI range=18.5-26.6 kg/m2).

The association between regional CB1R availability and BMI was assessed within predefined homeostatic and reward-related regions of interest using voxel-based linear regression analyses. CB1R availability was inversely associated with BMI in homeostatic brain regions such as the hypothalamus and brainstem areas in both patients with FID and healthy subjects. However, in FID patients, CB1R availability was also negatively correlated with BMI throughout the mesolimbic reward system (midbrain, striatum, insula, amygdala and orbitofrontal cortex), which constitutes the key circuit implicated in processing appetitive motivation and hedonic value of perceived food rewards.

Our results indicate that the cerebral homeostatic CB1R system is inextricably linked to BMI, with additional involvement of reward areas under conditions of disordered body weight.”

http://www.ncbi.nlm.nih.gov/pubmed/27404285

Mechanical and material properties of cortical and trabecular bone from cannabinoid receptor-1-null (Cnr1-/-) mice.

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“The endocannabinoid system is known for its regulatory effects on bone metabolism through the cannabinoid receptors, Cnr1 and Cnr2. In this study we analysed the mechanical and material properties of long bones from Cnr1-/- mice on a C57BL/6 background. Tibiae and femora from 5- and 12-week-old mice were subjected to three-point bending to measure bending stiffness and yield strength. Elastic modulus, density and mineral content were measured in the diaphysis. Second moment of area (MOA2), inner and outer perimeters of the cortical shaft and trabecular fractional bone volume (BV/TV) were measured using micro-CT. In Cnr1-/- males and females at both ages the bending stiffness was reduced due to a smaller MOA2. Bone from Cnr1-/- females had a greater modulus than wild-type controls, although no differences were observed in males. BV/TV of 12-week-old Cnr1-/- females was greater than controls, although no difference was seen at 5-weeks. On the contrary, Cnr1-/- males had the same BV/TV as controls at 12-weeks while they had significantly lower values at 5-weeks. This study shows that deleting Cnr1 decreases the amount of cortical bone in both males and females at 12-weeks, but increases the amount of trabecular bone only in females.”

http://www.ncbi.nlm.nih.gov/pubmed/27401043

The CB2 receptor and its role as a regulator of inflammation.

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“The CB2 receptor is the peripheral receptor for cannabinoids.

It is mainly expressed in immune tissues, highlighting the possibility that the endocannabinoid system has an immunomodulatory role.

In this respect, the CB2 receptor was shown to modulate immune cell functions, both in cellulo and in animal models of inflammatory diseases.

In this regard, numerous studies have reported that mice lacking the CB2 receptor have an exacerbated inflammatory phenotype.

This suggests that therapeutic strategies aiming at modulating CB2 signaling could be promising for the treatment of various inflammatory conditions.

Herein, we review the pharmacology of the CB2 receptor, its expression pattern, and the signaling pathways induced by its activation. We next examine the regulation of immune cell functions by the CB2 receptor and the evidence obtained from primary human cells, immortalized cell lines, and animal models of inflammation.

Finally, we discuss the possible therapies targeting the CB2receptor and the questions that remain to be addressed to determine whether this receptor could be a potential target to treat inflammatory disease.”

http://www.ncbi.nlm.nih.gov/pubmed/27402121

Cannabinoid receptor 1 binding activity and quantitative analysis of Cannabis sativa L. smoke and vapor.

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“Cannabis sativa L. (cannabis) extracts, vapor produced by the Volcano vaporizer and smoke made from burning cannabis joints were analyzed by GC-flame ionization detecter (FID), GC-MS and HPLC. Three different medicinal cannabis varieties were investigated Bedrocan, Bedrobinol and Bediol.

Cannabinoids plus other components such as terpenoids and pyrolytic by-products were identified and quantified in all samples. Cannabis vapor and smoke was tested for cannabinoid receptor 1 (CB1) binding activity and compared to pure Delta(9)-tetrahydrocannabinol (Delta(9)-THC).

The top five major compounds in Bedrocan extracts were Delta(9)-THC, cannabigerol (CBG), terpinolene, myrcene, and cis-ocimene in Bedrobinol Delta(9)-THC, myrcene, CBG, cannabichromene (CBC), and camphene in Bediol cannabidiol (CBD), Delta(9)-THC, myrcene, CBC, and CBG.

The major components in Bedrocan vapor (>1.0 mg/g) were Delta(9)-THC, terpinolene, myrcene, CBG, cis-ocimene and CBD in Bedrobinol Delta(9)-THC, myrcene and CBD in Bediol CBD, Delta(9)-THC, myrcene, CBC and terpinolene.

The major components in Bedrocan smoke (>1.0 mg/g) were Delta(9)-THC, cannabinol (CBN), terpinolene, CBG, myrcene and cis-ocimene in Bedrobinol Delta(9)-THC, CBN and myrcene in Bediol CBD, Delta(9)-THC, CBN, myrcene, CBC and terpinolene.

There was no statistically significant difference between CB1 binding of pure Delta(9)-THC compared to cannabis smoke and vapor at an equivalent concentration of Delta(9)-THC.”

http://www.ncbi.nlm.nih.gov/pubmed/20118579

Fibromyalgia Research Might Benefit from Finding Cannabinoid Receptors in Muscles

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Fibromyalgia News Today

“Receptors for the body’s own cannabinoid substances are present in muscle fascia — soft connective tissue surrounding all muscles and involved in several pain states, according to recent research from the University of Padua in Italy.

In addition to casting light on disease processes in fibromyalgia, the findings might lead to better approaches for managing pain and inflammation in the disease, for which current treatments often fail to adequately treat symptoms.

Endocannabinoids are bodily substances chemically resembling the cannabinoid molecules in cannabis. The factors send signals through two receptors that scientists have primarily explored in the brain and in immune cells, and studies show that stimulating the receptors can relieve pain and suppress inflammation.

 Patients with pain conditions such as fibromyalgia often turn to cannabis when prescription drugs are not enough to manage their symptoms. A 2005 study from the United Kingdom listed fibromyalgia among those conditions where patients frequently turn to marijuana for symptom relief, and a 2014 study of 217 U.S. patients showed that pain was the most commonly reported ailment in patients who use medical cannabis.

Research has also demonstrated that patients with fibromyalgia report that marijuana use lowers pain and improves health-related quality of life, making researchers suspect that endocannabinoid receptors, which also mediate the effects of marijuana, might exist in tissues other than the brain and immune cells.

To explore this, the study, “Expression of the endocannabinoid receptors in human fascial tissue,“ published in the European Journal of Histochemistry, turned to muscle fascia, a tissue that has also been linked to other muscle pain conditions.

Extracting the tissue from thigh muscles of 11 volunteers who had orthopedic surgery, researchers isolated the main cell type of the fascia, called fibroblasts. They found both types of receptors, called CB1 and CB2, in the cells. Examining whole tissue levels of the two receptors, researchers noted somewhat higher levels, indicating that the receptors may also be present in other cell types.

A better understanding of how endocannabinoid receptors are involved in fibromyalgia might lead to treatments specifically targeting the receptors in the muscles, avoiding the effects of manipulating cannabinoid receptors in the brain which mediate the psychotropic actions of cannabis.”

https://fibromyalgianewstoday.com/2016/07/08/fibromyalgia-drug-research-might-benefit-from-finding-cannabinoid-receptors-in-muscles/