Tag Archives: endocannabinoid system

Second Cannabinoid Receptor Has the Yin to the First Receptor’s Yang

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“Understanding the diverse effects that cannabis has on the human body is imperative if we hope to take advantage of its medicinal properties to treat various disorders. As such, elucidating the molecular structure of the receptors that bind endocannabinoids is a critical step toward developing selective drugs that can differentiate between the two known receptors—CB1 and CB2—for these molecules. Since the structure of the CB1 receptor was resolved a few years ago, an international team of researchers led by scientists at the iHuman Institute within ShanghaiTech University has just published the crystal structure of the human type 2 cannabinoid receptor, CB2.

Findings from the new study—published recently in Cell through an article titled “Crystal Structure of the Human Cannabinoid Receptor CB2”—should be helpful in the development of drugs against inflammatory, neurodegenerative, and other diseases. The study authors compared the newly discovered structure to that of the CB1 receptor, deeming the two receptors to be the “yin and yang” of the human endocannabinoid system.”

“Crystal Structure of the Human Cannabinoid Receptor CB1” https://www.cell.com/fulltext/S0092-8674(16)31385-X
“Crystal Structure of the Human Cannabinoid Receptor CB2” https://www.cell.com/cell/pdf/S0092-8674(18)31625-8.pdf
“This study compares newly discovered structures to those of the CB1 receptor, and deems the two receptors to be the Yin and Yang of the human endocannabinoid system, which is a signalling system that regulates biological processes such as pain, immune function, metabolism, and neuronal activities among others.” https://www.worldhealth.net/news/ying-yang-second-cannabinoid-receptor/

Role of endocannabinoid system in dopamine signalling within the reward circuits affected by chronic pain.

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Pharmacological Research

“The association between chronic pain, depression and anxiety has gained particular attention due to high rates of comorbidity. Recent data demonstrated that the mesolimbic reward circuitry is involved in the pathology of chronic pain. Interestingly, the mesolimbic reward circuit participates both in pain perception and in pain relief.

The endocannabinoid system (ECS) has emerged as a highly relevant player involved in both pain perception and reward processing. Targeting ECS could become a novel treatment strategy for chronic pain patients.

However, little is known about the underlying mechanisms of action of cannabinoids at the intersection of neurochemical changes in reward circuits and chronic pain. Because understanding the benefits and risks of cannabinoids is paramount, the aim of this review is to evaluate the state-of-art knowledge about the involvement of the ECS in dopamine signalling within the reward circuits affected by chronic pain.”

https://www.ncbi.nlm.nih.gov/pubmed/30831242

https://www.sciencedirect.com/science/article/abs/pii/S1043661819300088?via%3Dihub

Association Between Cannabis Use and Complications Related to Crohn’s Disease: A Retrospective Cohort Study.

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“Crohn’s disease is an idiopathic inflammatory process that is occasionally associated with complications, which cause significant morbidity and mortality. The anti-inflammatory effect of cannabis in intestinal inflammation has been shown in several experimental models; it is unknown whether this correlates with fewer complications in Crohn’s disease patients.

AIMS:

To compare the prevalence of Crohn’s disease-related complications among cannabis users and non-users in patients admitted with a primary diagnosis of Crohn’s disease or a primary diagnosis of Crohn’s related complication and a secondary diagnosis of Crohn’s disease between 2012 and 2014.

METHODS:

We used data from the Healthcare Cost and Utilization Project-National Inpatient Sample. Cannabis users (615) were compared directly after propensity score match to non-users, in aspects of various complications and clinical end-points.

RESULTS:

Among matched cohorts, Cannabis users were less likely to have the following: active fistulizing disease and intra-abdominal abscess (11.5% vs. 15.9%; aOR 0.68 [0.49 to 0.94], p = 0.025), blood product transfusion (5.0% vs. 8.0%; aOR 0.48 [0.30 to 0.79], p = 0.037), colectomy (3.7% vs. 7.5%; aOR 0.48 [0.29-0.80], p = 0.004), and parenteral nutrition requirement (3.4% vs. 6.7%, aOR 0.39 [0.23 to 0.68], p = 0.009).

CONCLUSION:

Cannabis use may mitigate several of the well-described complications of Crohn’s disease among hospital inpatients. These effects could possibly be through the effect of cannabis in the endocannabinoid system.”

https://www.ncbi.nlm.nih.gov/pubmed/30825109

https://link.springer.com/article/10.1007%2Fs10620-019-05556-z

Cannabinoid derivatives acting as dual PPARγ/CB2 agonists as therapeutic agents for Systemic Sclerosis.

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Biochemical Pharmacology

“The endocannabinoid system(ECS) may play a role in the pathophysiology of systemic sclerosis (SSc). Cannabinoids actingas dual PPARγ/CB2agonists, such as VCE-004.8 and Ajulemic acid (AjA), havebeen shown to alleviate skin fibrosis and inflammation in SSc models. Since bothcompounds are being tested in humans, we compared their activities in the bleomycin(BLM) SSc model.Specifically, the pharmacotranscriptomicsignature of the compounds was determined by RNA-Seq changes in the skin of BLM mice treated orallywith AjA or EHP-101, a lipidicformulation of VCE-004.8. While both compounds down-regulatedthe expression of genes involved in the inflammatoryand fibrotic components of the disease and the pharmacotranscriptomicsignatures were similar for both compounds in some pathways, we found keydifferences between the compounds in vasculogenesis. Additionally, we found 28 specific genes withtranslation potential by comparing with a list of humanscleroderma genes. Immunohistochemical analysis revealed that both compounds prevented fibrosis, collagen accumulation andTenascin C (TNC) expression. Theendothelial CD31+/CD34+ cells and telocyteswere reduced in BLM mice and restored only byEHP-101 treatment. Finally, differences were found inplasmatic biomarker analysis; EHP-101, but not AjA, enhanced the expressionof some factors related to angiogenesisand vasculogenesis. Altogether the results indicate that dual PPARγ/CB2agonists qualify as a novel therapeutic approach for the treatment of SSc and other fibrotic diseases. EHP-101 demonstratedunique mechanisms of action related to the pathophysiology of SSc that could be beneficial in the treatment of this complex disease without current therapeutic options.”

https://www.ncbi.nlm.nih.gov/pubmed/30825431

https://www.sciencedirect.com/science/article/abs/pii/S0006295219300772?via%3Dihub

Plant-Based Modulators of Endocannabinoid Signaling.

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Journal of Natural Products

“Extracts from Cannabis species have aided the discovery of the endocannabinoid signaling system (ECSS) and phytocannabinoids that possess broad therapeutic potential. Whereas the reinforcing effects of C. sativa are largely attributed to CB1 receptor agonism by Δ9-tetrahydrocannabinol (Δ9-THC), the observed medicinal effects of Cannabis arise from the combined actions of various compounds. In addition to compounds bearing a classical cannabinoid structure, naturally occurring fatty acid amides and esters resembling anandamide and 2-arachidonoyl glycerol isolated from non- Cannabis species are also valuable tools for studying ECSS function. This review highlights the potential of plant-based secondary metabolites from Cannabis and unrelated species as ECSS modulators.”

https://www.ncbi.nlm.nih.gov/pubmed/30816712

https://pubs.acs.org/doi/10.1021/acs.jnatprod.8b00874

Crystal Structure of the Human Cannabinoid Receptor CB2

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“The cannabinoid receptor CB2 is predominately expressed in the immune system, and selective modulation of CB2 without the psychoactivity of CB1 has therapeutic potential in inflammatory, fibrotic, and neurodegenerative diseases. Here, we report the crystal structure of human CB2 in complex with a rationally designed antagonist, AM10257, at 2.8 Å resolution. The CB2-AM10257 structure reveals a distinctly different binding pose compared with CB1. However, the extracellular portion of the antagonist-bound CB2 shares a high degree of conformational similarity with the agonist-bound CB1, which led to the discovery of AM10257’s unexpected opposing functional profile of CB2 antagonism versus CB1 agonism. Further structural analysis using mutagenesis studies and molecular docking revealed the molecular basis of their function and selectivity for CB2 and CB1. Additional analyses of our designed antagonist and agonist pairs provide important insight into the activation mechanism of CB2. The present findings should facilitate rational drug design toward precise modulation of the endocannabinoid system.”
https://www.cell.com/cell/pdf/S0092-8674(18)31625-8.pdf

“Structure of human type 2 cannabinoid receptor revealed” https://www.news-medical.net/news/20190228/Structure-of-human-type-2-cannabinoid-receptor-revealed.aspx

“Study reveals the structure of the 2nd human cannabinoid receptor”   HTTPS://MIPT.RU/ENGLISH/NEWS/STUDY_REVEALS_THE_STRUCTURE_OF_THE_2ND_HUMAN_CANNABINOID_RECEPTOR

“Structure of the Human Cannabinoid Receptor CB2 Solved”  https://www.technologynetworks.com/drug-discovery/news/structure-of-the-human-cannabinoid-receptor-cb2-solved-316091

Decreased Expression of Cannabinoid Receptors in the Eutopic and Ectopic Endometrium of Patients with Adenomyosis.

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“Adenomyosis is a common gynecologic benign disease that may have a life-long negative impact on women.

Previous studies have indicated that the endocannabinoid system may participate in the progress of endometriosis.

Our research aims to analyze the expression patterns of the typical cannabinoid receptors (CB1 and CB2), the main constituents of the endocannabinoid system, in endometrial samples derived from patients diagnosed as adenomyosis or not.

RESULTS:

In either the proliferative or the secretory phase, CB1 and CB2 protein and mRNA levels were both significantly lower in the eutopic and ectopic endometrium of adenomyosis when compared with normal endometrium. For women with adenomyosis, CB1 and CB2 protein and mRNA levels were much lower in the ectopic endometrium than the eutopic in both phases of the cycle. Both CB1 and CB2 protein and mRNA levels were increased during the secretory phase in normal endometrium, while CB1 lost its cyclic variation in the eutopic and ectopic endometrium from patients diagnosed as adenomyosis.

CONCLUSION:

The decreased expression of CB1 and CB2 in the eutopic and ectopic endometrium from patients diagnosed as adenomyosis suggests that cannabinoid receptors may participate in the pathogenesis of adenomyosis.”

https://www.ncbi.nlm.nih.gov/pubmed/30800671

“In conclusion, we found a significant decrease in the cannabinoid receptors CB1 and CB2 in the eutopic and ectopic endometrium of patients with adenomyosis, regardless of the menstrual phase, suggesting that CB1 and CB2 participate in the pathogenesis of this condition.”

https://www.hindawi.com/journals/bmri/2019/5468954/

Activation of cannabinoid 2 receptor relieves colonic hypermotility in a rat model of irritable bowel syndrome.

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“Irritable bowel syndrome (IBS) is a common disease with intestinal dysmotility, whose mechanism remains elusive.

The endocannabinoid system is emerging as an important modulator of gastrointestinal (GI) motility in multiple diseases, but its involvement in IBS is unknown.

We aimed to determine whether cannabinoid 2 (CB2) receptor modulates intestinal motility associated with stress-induced IBS.

CONCLUSION:

CB2 receptor may exert an important inhibitory effect in stress-induced colonic hypermotility by modulating NO synthesis through p38 mitogen-activated protein kinase signaling. AM1241 could be used as a potential drug to treat disorders with colonic hypermotility.”

https://www.ncbi.nlm.nih.gov/pubmed/30793435

https://onlinelibrary.wiley.com/doi/abs/10.1111/nmo.13555

The Endocannabinoid System, Our Universal Regulator

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“The endocannabinoid system (ECS) plays a very important role in the human body for our survival. This is due to its ability to play a critical role in maintaining the homeostasis of the human body, which encompasses the brain, endocrine, and immune system, to name a few. ECS is a unique system in multiple dimensions.

To begin with, it is a retrograde system functioning post- to pre-synapse, allowing it to be a “master regulator” in the body. Secondly, it has a very wide scope of influence due to an abundance of cannabinoid receptors located anywhere from immune cells to neurons. Finally, cannabinoids are rapidly synthesized and degraded, so they do not stay in the body for very long in high amounts, possibly enabling cannabinoid therapy to be a safer alternative to opioids or benzodiazepines. This paper will discuss how ECS functions through the regulation of neurotransmitter function, apoptosis, mitochondrial function, and ion-gated channels. The practical applications of the ECS, as well as the avenues for diseases such as epilepsy, cancer, amyotrophic lateral sclerosis (ALS), and autism, which have no known cure as of now, will be explored.

The ECS is one of the, if not the most, important systems in our body. Its role in the homeostatic function of our body is undeniable, and its sphere of influence is incredible. Additionally, it also plays a major role in apoptotic diseases, mitochondrial function, and brain function.

Its contribution is more than maintaining homeostasis; it also has a profound ability in regulation. Working in a retrograde fashion and with a generally inhibitory nature, ECS can act as a “kill switch.” However, it has been shown to play an inhibitory or stimulatory role based on the size of the influx of cannabinoids, resulting in a bimodal regulation. Furthermore, due to the nature of the rate of degradation of cannabinoids, it does not have as many long-term side effects as most of the current drugs on the market.

The ECS may not only provide answers for diseases with no known cures, but it could change the way we approach medicine. This system would allow us to change our focus from invasive pharmacological interventions (i.e. SSRIs for depression, benzodiazepines for anxiety, chemotherapies for cancer) to uncovering the mystery of why the body is failing to maintain homeostasis. Understanding the roles of ECS in these diseases confers a new direction for medicine which may eradicate the use of some of the less tolerable therapeutics.”

https://www.jyi.org/2018-june/2018/6/1/the-endocannabinoid-system-our-universal-regulator

Cannabinoids: a new approach for pain control?

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“To analyze available data related to the use of cannabinoids in medicine, with a special focus on pain management in cancer. The use of cannabis for medical purposes is growing but there are still numerous questions to be solved: effectiveness, safety, and specific indications.

RECENT FINDINGS:

There is considerable variation between countries in the approaches taken, reflecting a variety of historical and cultural factors and despite few randomized controlled studies using natural cannabinoids, there is a trend to state that the use of cannabis should be taken seriously as a potential treatment of cancer-related pain. Cannabidiol, a nontoxic phytocannabinoid with few side-effects is promising in various indications in medicine.

SUMMARY:

The endocannabinoid system is a potential therapeutic target. Cannabinoids may be considered as potential adjuvant in cancer-related pain management. Cannabidiol appears to be the drug of choice. Analgesic trial designs should evolve to get closer to real-life practice and to avoid biases.”

https://www.ncbi.nlm.nih.gov/pubmed/30789867

https://insights.ovid.com/crossref?an=00001622-900000000-00002