Tag Archives: cannabinoid receptors

The Endocannabinoid Signaling System in the CNS: A Primer.

Posted on by

“The purpose of this chapter is to provide an introduction to the mechanisms for the regulation of endocannabinoid signaling through CB1 cannabinoid receptors in the central nervous system.

The processes involved in the synthesis and degradation of the two most well-studied endocannabinoids, 2-arachidonoylglycerol and N-arachidonylethanolamine are outlined along with information regarding the regulation of the proteins involved.

Signaling mechanisms and pharmacology of the CB1 cannabinoid receptor are outlined, as is the paradigm of endocannabinoid/CB1 receptor regulation of neurotransmitter release.

The reader is encouraged to appreciate the importance of the endocannabinoid/CB1 receptor signaling system in the regulation of synaptic activity in the brain.”

Inhibitors of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase: New Targets for Future Antidepressants.

Posted on by

“Cannabis and analogs of Δ9-tetrahydrocannabinol have been used for therapeutic purposes…

Endogenous cannabinoids have been discovered, and dysregulation of endocannabinoid signaling is implicated in the pathophysiology of major depressive disorder (MDD).

Recently, endocannabinoid hydrolytic enzymes such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) have become new therapeutic targets in the treatment of MDD.

Several FAAH or MAGL inhibitors are reported to have no cannabimimetic side effects and, therefore, are new potential therapeutic options for patients with MDD who are resistant to first-line antidepressants (selective serotonin and serotonin-norepinephrine reuptake inhibitors).

In this review, we focus on the possible relationships between MDD and the endocannabinoid system as well as the inhibitors’ therapeutic potential.

MAGL inhibitors may reduce inflammatory responses through activation of cannabinoid receptor type 2.

In the hypothalamic-pituitary-adrenal axis, repeated FAAH inhibitor administration may be beneficial for reducing circulating glucocorticoid levels. Both FAAH and MAGL inhibitors may contribute to dopaminergic system regulation. Recently, several new inhibitors have been developed with strong potency and selectivity. FAAH inhibitor, MAGL inhibitor, or dual blocker use would be promising new treatments for MDD. Further pre-clinical studies and clinical trials using these inhibitors are warranted.”

http://www.ncbi.nlm.nih.gov/pubmed/26630956

CB1 cannabinoid receptor enrichment in the ependymal region of the adult human spinal cord

Posted on by

Figure 1

“Cannabinoids are involved in the regulation of neural stem cell biology and their receptors are expressed in the neurogenic niches of adult rodents.

In the spinal cord of rats and mice, neural stem cells can be found in the ependymal region, surrounding the central canal, but there is evidence that this region is largely different in adult humans: lacks a patent canal and presents perivascular pseudorosettes, typically found in low grade ependymomas.

Using Laser Capture Microdissection, Taqman gene expression assays and immunohistochemistry, we have studied the expression of endocannabinoid system components (receptors and enzymes) at the human spinal cord ependymal region.

We observe that ependymal region is enriched in CB1 cannabinoid receptor, due to high CB1 expression in GFAP+ astrocytic domains. However, in human spinal cord levels that retain central canal patency we found ependymal cells with high CB1 expression, equivalent to the CB1HIGH cell subpopulation described in rodents.

Our results support the existence of ependymal CB1HIGH cells across species, and may encourage further studies on this subpopulation, although only in cases when central canal is patent. In the adult human ependyma, which usually shows central canal absence, CB1 may play a different role by modulating astrocyte functions.”

http://www.nature.com/articles/srep17745

Computational Prediction and Biochemical Analyses of New Inverse Agonists for the CB1 Receptor.

Posted on by

“Human cannabinoid type 1 (CB1) G-protein coupled receptor is a potential therapeutic target for obesity.

The previously predicted and experimentally validated ensemble of ligand-free conformations of CB1 are used here to predict the binding sites for known CB1-selective inverse agonists including rimonabant and its seven known derivatives.

This binding pocket, which differs significantly from previously published models, is used to identify 16 novel compounds expected to be CB1 inverse agonists by exploiting potential new interactions.

We show experimentally that two of these compounds exhibit inverse agonist properties including inhibition of basal and agonist-induced G-protein coupling activity, as well as an enhanced level of CB1 cell surface localization.

This demonstrates the utility of using the predicted binding sites for an ensemble of CB1 receptor structures for designing new CB1 inverse agonists.”

Prevention of Diet-Induced Obesity Effects on Body Weight and Gut Microbiota in Mice Treated Chronically with Δ9-Tetrahydrocannabinol.

Posted on by

“Acute administration of cannabinoid CB1 receptor agonists, or the ingestion of cannabis, induces short-term hyperphagia. However, the incidence of obesity is lower in frequent cannabis users compared to non-users.

Gut microbiota affects host metabolism and altered microbial profiles are observed in obese states. Gut microbiota modifies adipogenesis through actions on the endocannabinoid system. This study investigated the effect of chronic THC administration on body weight and gut microbiota in diet-induced obese (DIO) and lean mice.

THC reduced weight gain, fat mass gain and energy intake in DIO but not lean mice. DIO-induced changes in select gut microbiota were prevented in mice chronically administered THC.

Chronic THC treatment reduced energy intake and prevented high fat diet-induced increases in body weight and adiposity; effects that were unlikely to be a result of sedation or altered gastrointestinal transit. Changes in gut microbiota potentially contribute to chronic THC-induced actions on body weight in obesity.”

http://www.ncbi.nlm.nih.gov/pubmed/26633823

“Prevention of Diet-Induced Obesity Effects on Body Weight and Gut Microbiota in Mice Treated Chronically with Δ9-Tetrahydrocannabinol… To follow up on our hypothesis that exposure to THC may produce weight loss, in the current study we investigated whether chronic THC inhibits weight gain in lean and diet-induced obese (DIO) mice… We present data showing that chronic administration of the CB1/CB2 receptor partial agonist, THC, prevents weight gain in DIO mice. Furthermore, we show evidence that DIO-mediated modifications in gut microbiota are prevented in chronically THC treated mice… In conclusion, we present data showing the CB1/CB2 receptor partial agonist THC, induces hypophagia and prevents weight gain in obesity and suggest these actions may be mediated in part by modifications of the gut microbiota.”  http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0144270

Involvement of PAR-4 in cannabinoid-dependent sensitization of osteosarcoma cells to TRAIL-induced apoptosis.

Posted on by

Logo of ijbiosci

“Osteosarcoma is the most common malignant bone tumor in childhood and adolescence.

Cannabinoids (CBs), the active constituents of Cannabis sativa, are known to exert a wide range of central and peripheral effects.

Recently, numerous studies evidenced the role of cannabinoids in the regulation of cell death and survival, focusing the anti-proliferative effects of these compounds in various tumours… cannabinoids can also activate autophagic process…

The aim of the present study was to investigate the effects induced by cannabinoids in osteosarcoma cells and the molecular pathway…

The synthetic cannabinoid WIN 55,212-2 is a potent cannabinoid receptor agonist with anticancer potential.

Moreover, we indicate that a key role in WIN action is played by the tumor suppressor protein PAR-4.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4007360/

 

Liver’s cannabinoid receptors could be targeted to combat liver cancer in some patients

Posted on by

News Medical - Life Sciences & Medicine

“A new study reveals that the liver’s cannabinoid receptors could be targeted to fight liver cancer in some patients; and it offers a way to predict what treatments have the best chance of working.

The body’s own marijuana-like substances, — called endocannabinoids — are known to increase the biosynthesis of fatty acids in the liver by activating cannabinoid type 1 receptors (CB1). CB1 receptors can be found in the brain, lungs, liver and kidney, and they are involved in a number of physiological processes, including mood, appetite, pain sensation and memory.

The study found that the expression of these receptors increased in cancerous liver samples, when compared with cancer-free samples. This suggests that drugs that block CB1 receptors may be effective against HCC.

“Although such drugs were found to cause unwanted psychiatric side effects, non brain-penetrant CB1 receptor antagonists devoid of such side effects — but retaining therapeutic efficacy via peripheral CB1 receptors — are currently being developed,” says study co-author George Kunos, scientific director at the U.S. National Institute on Alcohol Abuse and Alcoholism (NIAAA).”

http://www.news-medical.net/news/20151123/Livers-cannabinoid-receptors-could-be-targeted-to-combat-liver-cancer-in-some-patients.aspx

Cannabinoid receptors and their role in neuroprotection.

Posted on by

“Evidence has accumulated over the last few years suggesting that endocannabinoid-based drugs may potentially be useful to reduce the effects of neurodegeneration. In fact, exogenous and endogenous cannabinoids were shown to exert neuroprotection in a variety of in vitro and in vivo models of neuronal injury via different mechanisms,”

http://www.ncbi.nlm.nih.gov/pubmed/16052037

Involvement of opioid system in antidepressant-like effect of the cannabinoid CB1 receptor inverse agonist AM-251 after physical stress in mice.

Posted on by

“Cannabinoid inverse agonists possess antidepressant-like properties…

Numerous studies reported the interaction between opioid and cannabinoid pathways.

In this study, we used acute foot-shock stress in mice to investigate the involvement of opioid pathway in the antidepressant-like effect of the cannabinoid CB1 receptor inverse agonist AM-251.

In conclusion, the present study for the first time revealed the possible role of opioid signaling in the antidepressant-like properties of AM-251 in foot-shock stress model. “

http://www.ncbi.nlm.nih.gov/pubmed/26609670

The disease-modifying effects of a Sativex-like combination of phytocannabinoids in mice with experimental autoimmune encephalomyelitis are preferentially due to Δ9-tetrahydrocannabinol acting through CB1 receptors.

Posted on by

“Sativex®, an equimolecular combination of Δ9-tetrahydrocannabinol-botanical drug substance (Δ9-THC-BDS) and cannabidiol-botanical drug substance (CBD-BDS), is a licensed medicine that may be prescribed for alleviating specific symptoms of multiple sclerosis (MS) such as spasticity and pain.

However, further evidence suggest that it could be also active as disease-modifying therapy given the immunomodulatory, anti-inflammatory and cytoprotective properties of their two major components.

In this study, we investigated this potential in the experimental autoimmune encephalitis (EAE) model of MS in mice.

We compared the effect of a Sativex-like combination of Δ9-THC-BDS (10mg/kg) and CBD-BDS (10mg/kg) with Δ9-THC-BDS (20mg/kg) or CBD-BDS (20mg/kg) administered separately by intraperitoneal administration to EAE mice.

Treatments were initiated at the time that symptoms appear and continued up to the first relapse of the disease.

The results show that the treatment with a Sativex-like combination significantly improved the neurological deficits typical of EAE mice, in parallel with a reduction in the number and extent of cell aggregates present in the spinal cord which derived from cell infiltration to the CNS.

These effects were completely reproduced by the treatment with Δ9-THC-BDS alone, but not by CBD-BDS alone which only delayed the onset of the disease without improving disease progression and reducing the cell infiltrates in the spinal cord.

Next, we investigated the potential targets involved in the effects of Δ9-THC-BDS by selectively blocking CB1 or PPAR-γ receptors, and we found a complete reversion of neurological benefits and the reduction in cell aggregates only with rimonabant, a selective CB1 receptor antagonist.

Collectively, our data support the therapeutic potential of Sativex as a phytocannabinoid formulation capable of attenuating EAE progression, and that the active compound was Δ9-THC-BDS acting through CB1 receptors.”