Category Archives: Endocannabinoid System

Cannabinoid 2 Receptor Agonist Improves Systemic Sensitivity to Insulin in High-Fat Diet/Streptozotocin-Induced Diabetic Mice.

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“The endocannabinoid signalling (ECS) system has been known to regulate glucose homeostasis.

Previous studies have suggested that the cannabinoid 2 (CB2) receptor may play a regulatory role on insulin secretion, immune modulation and insulin resistance.

Given that diabetes and insulin resistance are attributable to elevated inflammatory tone, we investigated the role of CB2 receptor on glucose tolerance and insulin sensitivity in high-fat diet (HFD)/streptozotocin (STZ)-induced mice.

Our data suggest a lipolytic role of SER601 in HFD/STZ-induced diabetic mice, which results in significant improvement of systemic insulin sensitivity.

Thus, the CB2 receptor may be considered a promising target for therapeutic development against insulin resistance and obesity-related diabetes.”

https://www.ncbi.nlm.nih.gov/pubmed/27960161

Fetal Syndrome of Endocannabinoid Deficiency (FSECD) In Maternal Obesity.

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“The theory of a fetal origin of adult diseases links many pathological conditions to very early life events and is known as a “developmental programming” phenomenon. The mechanisms of this phenomenon are not quite understood and have been explained by inflammation, stress, etc. In particular the epidemic of obesity, with more than 64% of women being overweight or obese, has been associated with conditions in later life such as mental disorders, diabetes, asthma, and irritable bowel syndrome.

Interestingly, these diseases were classified a decade ago as Clinical Syndrome of Endocannabinoid Deficiency (CECD), which was first described by Russo in 2004.

Cannabinoids have been used for the treatment of chronic pain for millenniums and act through the mechanism of “kick-starting” the components of the endogenous cannabinoid system (ECS).

ECS is a pharmacological target for the treatment of obesity, inflammation, cardiovascular and neuronal damage, and pain.

We hypothesize that the deteriorating effect of maternal obesity on offspring health is explained by the mechanism of Fetal Syndrome of Endocannabinoid Deficiency (FSECD), which accompanies maternal obesity. Here we provide support for this hypothesis.”

https://www.ncbi.nlm.nih.gov/pubmed/27959272

Tolerability of dronabinol alone, ondansetron alone and the combination of dronabinol plus ondansetron in delayed chemotherapy-induced nausea and vomiting.

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“Dronabinol (Marinol), the synthetic version of tetrahydrocannabinol, is used to treat nausea and vomiting following cancer chemotherapy (CINV).

It has a unique mechanism of action (cannabinoid receptor binding) compared to the more frequently used serotonin receptor antagonists. Tolerability of dronabinol versus ondansetron and the combination of dronabinol plus ondansetron was explored in subjects with delayed CINV.

Dronabinol was well tolerated and resulted in few terminations due to adverse events. The low rate of CNS-related adverse events following D treatment may make it a suitable alternative to serotonin antagonist therapy for delayed CINV.”

https://www.ncbi.nlm.nih.gov/pubmed/27946950

Compensatory activation of cannabinoid CB2 receptor inhibition of GABA release in the rostral ventromedial medulla (RVM) in inflammatory pain.

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“The rostral ventromedial medulla (RVM) is a relay in the descending pain modulatory system and an important site of endocannabinoid modulation of pain.

These studies demonstrate that endocannabinoid signaling to CB1- and CB2-receptors in adult RVM is altered in persistent inflammation.

The emergence of CB2 receptor function in the RVM provides additional rationale for the development of CB2 receptor-selective agonists as useful therapeutics for chronic inflammatory pain.”

https://www.ncbi.nlm.nih.gov/pubmed/27940994

Tamoxifen Isomers and Metabolites Exhibit Distinct Affinity and Activity at Cannabinoid Receptors: Potential Scaffold for Drug Development.

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“Tamoxifen (Tam) is a selective estrogen receptor (ER) modulator (SERM) that is an essential drug to treat ER-positive breast cancer. Aside from known actions at ERs, recent studies have suggested that some SERMs like Tam also exhibit novel activity at cannabinoidsubtype 1 and 2 receptors (CB1R and CB2Rs).

Collectively, these results suggest that the SERMs Tam, 4OHT and End elicit ER-independent actions via CBRs in an isomer-specific manner.

As such, this novel structural scaffold might be used to develop therapeutically useful drugs for treatment of a variety of diseases mediated via CBRs.”

 https://www.ncbi.nlm.nih.gov/pubmed/27936172

From adolescent to elder rats: Motivation for palatable food and cannabinoids receptors.

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“To analyze motivation, food self-administration and decision-making was evaluated in adolescent, adult and aged rats.

Adolescent rats exhibited low expression of CB1R in the NAcc and low expression of both CB1R and CB2R in the PFC compared to adult and aged rats.

Adolescent rats display higher motivation for palatable food and an indiscriminate seeking behavior suggesting involvement of both homeostatic and hedonic systems in their decision-making processes.”

https://www.ncbi.nlm.nih.gov/pubmed/27935269

Two Janus cannabinoids that are both CB2 agonists and CB1 antagonists.

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“The cannabinoid signaling system includes two G protein coupled receptors, CB1 and CB2. These receptors are widely distributed throughout the body and have each been implicated in many physiologically important processes.

Though the cannabinoid signaling system has therapeutic potential, a persistent hurdle has remained the development of receptor-selective ligands. Because CB1 and CB2 are involved in diverse processes, it would be advantageous develop ligands that differentially engaging CB1 and CB2.

In summary we have determined that GW405833 and AM1710 are not only CB2 agonists but also CB1 antagonists, with distinctive and complex signaling properties. Thus experiments using these compounds must take into account their potential activity at CB1 receptors.”

https://www.ncbi.nlm.nih.gov/pubmed/27927913

Anti-inflammatory effect of cannabinoid agonist WIN55, 212 on mouse experimental colitis is related to inhibition of p38MAPK.

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“To investigate the anti-inflammatory effect and the possible mechanisms of an agonist of cannabinoid (CB) receptors, WIN55-212-2 (WIN55), in mice with experimental colitis, so as to supply experimental evidence for its clinical use in future.

These results confirmed the anti-inflammatory effect and protective role of WIN55 on the mice with experimental colitis, and revealed that this agent exercises its action at least partially by inhibiting p38MAPK.

Furthermore, the results showed that SB203580, affected the expression of CB1 and CB2 receptors in the mouse colon, suggesting a close linkage and cross-talk between the p38MAPK signaling pathway and the endogenous CB system.”

https://www.ncbi.nlm.nih.gov/pubmed/27920472

Plant cannabinoids: a neglected pharmacological treasure trove.

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“Most of the cannabinoids in Cannabis sativa L. have not been fully evaluated for their pharmacological activity.

A publication in this issue presents evidence that a plant cannabinoid, Δ9-tetrahydrocannabivarin is a potent antagonist of anandamide, a major endogenous cannabinoid.

It seems possible that many of the non-psychoactive constituents of this plant will be of biological interest.

I sincerely believe that the plant cannabinoids are a neglected pharmacological treasure trove.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1751232/

Targeted proteomics of cannabinoid receptor CB1 and the CB1b isoform.

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“Cannabinoid receptors (CBR), including CB1 and CB2 have been therapeutic targets for a number of conditions.

Recently, splice variants of the CB1R have been identified in humans.

The isoforms differ in their N-terminus sequence and pharmacological activity relative to the CB1R, as a result, the differentiation between the CB1 receptor and its isoform is required.

As a result, a selected reaction monitoring mass spectrometry (SRM-MS) method was developed for the quantitation of CB1 and the CB1b isoform in CHO cells transduced with CB1 and CB1b.

The SRM-MS protocol was assessed with isotopically labeled peptide standards and had high reproducibility of intra-day assay (CVs from 1.9 to 4.3% for CB1 and 0.5 to 5.9% for CB1b) and inter-day assay (CVs from 1.2 to 5.2% for CB1 and 1.2 to 6.1% for CB1b).”

https://www.ncbi.nlm.nih.gov/pubmed/27914737