Category Archives: Endocannabinoid System

Cannabinoid receptor antagonists: pharmacological opportunities, clinical experience, and translational prognosis.

Posted on by

Abstract

“The endogenous cannabinoid (CB) (endocannabinoid) signaling system is involved in a variety of (patho)physiological processes, primarily by virtue of natural, arachidonic acid-derived lipids (endocannabinoids) that activate G protein-coupled CB1 and CB2 receptors. A hyperactive endocannabinoid system appears to contribute to the etiology of several disease states that constitute significant global threats to human health. Consequently, mounting interest surrounds the design and profiling of receptor-targeted CB antagonists as pharmacotherapeutics that attenuate endocannabinoid transmission for salutary gain. Experimental and clinical evidence supports the therapeutic potential of CB1 receptor antagonists to treat overweight/obesity, obesity-related cardiometabolic disorders, and substance abuse. Laboratory data suggest that CB2 receptor antagonists might be effective immunomodulatory and, perhaps, anti-inflammatory drugs. One CB1 receptor antagonist/inverse agonist, rimonabant, has emerged as the first-in-class drug approved outside the United States for weight control. Select follow-on agents (taranabant, otenabant, surinabant, rosonabant, SLV-319, AVE1625, V24343) have also been studied in the clinic. However, rimonabant’s market withdrawal in the European Union and suspension of rimonabant’s, taranabant’s, and otenabant’s ongoing development programs have highlighted some adverse clinical side effects (especially nausea and psychiatric disturbances) of CB1 receptor antagonists/inverse agonists. Novel CB1 receptor ligands that are peripherally directed and/or exhibit neutral antagonism (the latter not affecting constitutive CB1 receptor signaling) may optimize the benefits of CB1 receptor antagonists while minimizing any risk. Indeed, CB1 receptor-neutral antagonists appear from preclinical data to offer efficacy comparable to or better than that of prototype CB1 receptor antagonists/inverse agonists, with less propensity to induce nausea. Continued pharmacological profiling, as the prelude to first-in-man testing of CB1 receptor antagonists with unique modes of targeting/pharmacological action, represents an exciting translational frontier in the critical path to CB receptor blockers as medicines.”

http://www.ncbi.nlm.nih.gov/pubmed/19249987

Inverse agonism and neutral antagonism at cannabinoid CB1 receptors.

Posted on by

Abstract

“There are at least two types of cannabinoid receptor, CB1 and CB2, both G protein coupled. CB1 receptors are expressed predominantly at nerve terminals and mediate inhibition of transmitter release whereas CB2 receptors are found mainly on immune cells, one of their roles being to modulate cytokine release. Endogenous cannabinoid receptor agonists also exist and these “endocannabinoids” together with their receptors constitute the “endocannabinoid system”. These discoveries were followed by the development of a number of CB1- and CB2-selective antagonists that in some CB1 or CB2 receptor-containing systems also produce “inverse cannabimimetic effects”, effects opposite in direction from those produced by cannabinoid receptor agonists. This review focuses on the CB1-selective antagonists, SR141716A, AM251, AM281 and LY320135, and discusses possible mechanisms by which these ligands produce their inverse effects: (1) competitive surmountable antagonism at CB1 receptors of endogenously released endocannabinoids, (2) inverse agonism resulting from negative, possibly allosteric, modulation of the constitutive activity of CB1 receptors in which CB1 receptors are shifted from a constitutively active “on” state to one or more constitutively inactive “off” states and (3) CB1 receptor-independent mechanisms, for example antagonism of endogenously released adenosine at A1 receptors. Recently developed neutral competitive CB1 receptor antagonists, which are expected to produce inverse effects through antagonism of endogenously released endocannabinoids but not by modulating CB1 receptor constitutive activity, are also discussed. So too are possible clinical consequences of the production of inverse cannabimimetic effects, there being convincing evidence that released endocannabinoids can have “autoprotective” roles.”

http://www.ncbi.nlm.nih.gov/pubmed/15670612

‘Cannabis’ receptor discovery may help understanding of obesity and pain

Posted on by

“Aberdeen scientists believe that the findings—published in the —might help our understanding of these conditions and also be a step towards the development of personalised therapies to help treat them.

The team from the University’s Kosterlitz Centre for Therapeutics studied around the gene CNR1. This gene produces what are known as cannabinoid receptors, which are found in the brain, and which activate parts of the brain involved in memory, mood, appetite and pain.

activate these areas of the brain when they are triggered by chemicals produced naturally in our bodies called .

Chemicals found in the drug cannabis mimic the action of these endocannabinoids and there is growing evidence that cannabis has pain relieving and anti-inflammatory properties which can help treat diseases such as and arthritis. 

In order to understand more about these side effects and the which determine how people respond, the scientists studied genetic differences around the CNR1 gene.

Dr Alasdair MacKenzie, who helped lead the team, said: “We chose to look at one specific genetic difference in CNR1 because we know it is linked to and addiction. What we found was a mutation that caused a change in the genetic switch for the gene itself—a switch that is very ancient and has remained relatively unchanged in overthree hundred million years of evolution, since before the time of the dinosaurs.”

http://phys.org/news/2012-08-cannabis-receptor-discovery-obesity-pain.html

Marijuana May Deflect Obesity

Posted on by
   

“Cannabis seems to have many different allures. It can produce a “high.” It can give the feeling of munchies. Now, it can possibly help combat obesity. Scientists recently revealed that they found two compounds from cannabis leaves that could up the total energy that the body burns.

Previous studies of two specific compounds demonstrated that they could be used to treat type-two diabetes. The compounds were also discovered to have the ability to reduce cholesterol levels in the blood stream and decrease fat in important organs such as the liver. With the aim of treating patients who have “metabolic syndrome,” the researchers are currently conducting clinical trials in 200 patients with the drug. With “metabolic syndrome,” diabetes, high blood pressure, and obesity combine to heighten the risk of heart disease and stroke in patients.

“We are conducting four Phase 2a clinical trials and we expect some results later this year,” commented Dr. Steph Wright, director of research and development at GW Pharmaceuticals, in a Telegraph article. “The results in animal models have been very encouraging. We are interested in how these drugs effect the fat distribution and utilization in the body as a treatment for metabolic diseases… Humans have been using these plants for thousands of years so we have quite a lot of experience of the chemicals in the plants.”

GW Pharmaceuticals was given a license to grow cannabis in greenhouses that were specially constructed for project. The company produces cannabis plants that have a number of cannabinoids, which are varied compounds of cannabis. They are already working on creating drugs that can assist in treating epilepsy and multiple sclerosis. Interesting enough, when the scientists studied two specific compounds, THCV and cannabioidol, they found that they had the ability to suppress appetite but the effect lasted for a short amount of time. Upon further examination, the investigators discovered that the compounds could influence the fat level in the body as well as its effects to the hormone insulin.

Likewise, the studies of the compounds in mice showed that they increased the metabolism of the animals, causing decreased levels of fat in livers and minimized levels of cholesterol in the blood stream. In particular, THCV showed the ability of boosting the animals’ sensitivity to insulin but also shielding the insulin-producing cells. With these actions, the cells were able to work at a longer and more durable pace.

The researchers hope that the findings will help in the development of treatments for obesity-related illnesses and type-two diabetes.”

http://www.redorbit.com/news/health/1112653330/research-finds-marijuana-may-deflect-obesity/
redOrbit (http://s.tt/1hqLQ)

Pot Smokers May Have Lower Risk of Obesity

Posted on by

“Despite the tendency of marijuana users to experience the “munchies,” pot smokers may have a lower risk of obesity that those who don’t use the drug, a new study finds.

The results show the prevalence of obesity is lower among people who frequently smoke pot compared with those who have never inhaled.

The researchers said they were surprised by their initial results, because they expected to find the opposite. So they examined a second sample of people, and found exactly the same result. Together, the two samples studied more than 50,000 people.

The reason behind the link is not clear. It could be that people who use cannabis also engage in other behaviors that lower their obesity risk. Or it may be that pot smokers exercise more or have a specific diet that keeps them thin, said study researcher Yann Le Strat, a psychiatrist at Louis Mourier Hospital in France.”

http://www.myhealthnewsdaily.com/1651-cannabis-obesity-risk.html

Fight obesity… with marijuana?

Posted on by

“What did the study find?
Dr. Yann Le Strat, a psychiatrist at France’s Louis-Mourier Hospital, looked at data from two studies of U.S. adults from the early 2000s and noted the weight differences between those who used cannabis and those who didn’t. In both studies, cannabis users had relatively low rates of obesity: 14.3 and 17.2 percent. American adults who didn’t use cannabis had obesity rates of 22 and 25.3 percent.

Is this what researchers expected?
Nope. “Cannabis is supposed to increase appetite,” says Le Strat. “So we hypothesized that cannabis users would be more likely to have higher weight than non-users and be more likely to be obese.” Marijuana activist Michelle Aldrich isn’t all that surprised. “It’s true,” she says. “I don’t know too many fat marijuana smokers.”

What’s causing this phenomenon?
“There could be many other reasons why pot smokers have less obesity,” says dietitian Andrea Giancoli. “Maybe they’re inclined to exercise more, be outdoors more, eat more fruits and vegetables.” Aldrich thinks it could be related to the body’s endocannabinoid system — a group of receptors, primarily in the brain, that respond to compounds in marijuana. But the bottom line is that the exact mechanism responsible for this correlation remains a mystery — for now.”

http://news.yahoo.com/fight-obesity-marijuana-114000508.html

The endocannabinoid system and the treatment of obesity.

Posted on by

Abstract

“The endocannabinoids are endogenous lipids capable of binding to both cannabinoid receptors (CB) CB1 and CB2. These receptors belong to the G protein-coupled family receptors and they were discovered while investigating the mode of action of ?(9)-tetrahydrocannabinol, a component of Cannabis sativa, to which they bind with high affinity. Among many other brain sites, CB1 is present in the hypothalamic nuclei involved in the control of energy balance and body weight, as well as in neurons of the mesolimbic system which is believed to mediate the incentive value of food. At central nervous system level, CB1 activation is necessary to induce food intake after a short period of food deprivation, and when CB1 is activated by endocannabinoids produced in situ, a stimulation of the ingestion of palatable food has been described. CB1 stimulation leads to modulation of the release of some hypothalamic anorexigenic and orexigenic mediators, as well as of dopamine in the nucleus accumbens shell. Recent evidence has proved that CB1 is also present in the peripheral organs, such as the adipose tissue and gastrointestinal system, key organs in the regulation of energy metabolism. Animal models have provided solid evidence that genetically induced obesity leads to long-lasting overstimulation of endocannabinoid system synthesis resulting in permanent overactivation of CB1, which may then contribute to the maintenance of this disease. Importantly, at peripheral level, CB1 activation has been shown to stimulate lipogenesis in adipocytes. CB1 blockers increase adiponectin production in adipocytes, which leads to increased fatty acid oxidation and free fatty acid clearance. Moreover, CB1 has been shown to be up-regulated in adipocytes derived from obese rodents. These results support the role of endocannabinoids in the development and maintenance of obesity, paving the way for the development of a new class of drugs such as the CB1 blockers as a therapy for tackling obesity and the associated major cardiovascular risk factors.”

http://www.ncbi.nlm.nih.gov/pubmed/16019725

The endocannabinoid system: a new target for the regulation of energy balance and metabolism.

Posted on by

Abstract

“Recent studies have provided evidence that the endocannabinoid (EC) system has very significant effects on energy balance and metabolism through the central control of appetite and by affecting peripheral metabolism. Endocannabinoids are endogenous phospholipid derivatives which bind and activate cannabinoid receptors type 1 and type 2 (CB1 and CB2 receptors). The CB1 receptor, a G-protein coupled receptor, is believed to be responsible for the majority of the central effects of endocannaboids on appetite. Chronic positive energy balance and obesity have been associated with an overactivation of the endocannaboid system which has been suggested to contribute to the development of abdominal obesity and to associated metabolic abnormalities which increase the risk of cardiovascular disease and type 2 diabetes. Animal studies had shown that stimulation of the cannabinoid CB1 receptor with endocannaboids such as anandamide could induce first an increase in food intake leading to body weight gain. Furthermore, an exciting development in this field has been the discovery of CB1 receptors in many peripheral tissues, including key organs involved in carbohydrate and lipid metabolism such as the adipose tissue and liver. Thus, blocking CB1 receptors located in the liver and adipose tissue could have an additional impact on the metabolic risk profile beyond what could be explained by the reduction in food intake and the related body weight loss. Preclinical studies have shown that rimonabant, the first CB1-receptor blocker to be available in clinical practice, could not only induce a reduction in food intake, but could also produce body weight loss beyond what could be explained by its effect on food intake. Thus, the evidence from preclinical studies have suggested that CB1 blockade could represent a relevant approach to reduce food intake, to induce body weight loss, and, most importantly, to “fix” the dysmetabolic state of viscerally obese patients at increased cardiometabolic risk.”

http://www.ncbi.nlm.nih.gov/pubmed/17667864

The role of the endocannabinoid system in skeletal muscle and metabolic adaptations to exercise: potential implications for the treatment of obesity.

Posted on by

Abstract

“The results of recent studies add the endocannabinoid system, and more specifically CB1 receptor signalling, to the complex mechanisms that negatively modulate insulin sensitivity and substrate oxidation in skeletal muscle. CB1 receptors might become overactive in the skeletal muscle during obesity due to increased levels of endocannabinoids. However, quite surprisingly, one of the most studied endocannabinoids, anandamide, when administered in a sufficient dose, was shown to improve muscle glucose uptake and activate some key molecules of insulin signalling and mitochondrial biogenesis. This is probably because anandamide is only a partial agonist at CB1 receptors and interacts with other receptors (PPARγ, TRPV1), which may trigger positive metabolic effects. This putative beneficial role of anandamide is worth considering because increased plasma anandamide levels were recently reported after intense exercise. Whether the endocannabinoid system is involved in the positive exercise effects on mitochondrial biogenesis and glucose fatty acid oxidation remains to be confirmed. Noteworthy, when exercise becomes chronic, a decrease in CB1 receptor expression in obese metabolically deregulated tissues occurs. It is then tempting to hypothesize that physical activity would represent a complementary alternative approach for the clinical management of endocannabinoid system deregulation in obesity, without the side effects occurring with CB1 receptor antagonists.”

http://www.ncbi.nlm.nih.gov/pubmed/22943701

Investigations of the endocannabinoid system in adipose tissue: effects of obesity/ weight loss and treatment options.

Posted on by

Abstract

“Obesity is a world wide epidemic; it is becoming more usual to be overweight or obese than to be normal weight. Obesity increases the risk of an extensive range of diseases such as cardiovascular disease, diabetes mellitus type 2, hypertension, depression and some types of cancer. Adipose tissue is more than a storage organ for surplus energy – it is also a setting for complex metabolic processes and adipose tissue releases substances that interact with other parts of the body to influence several systems including food intake and energy metabolism. The endocannabinoid system (ECS) is one of the signalling systems that control feeding behaviour. The ECS is implicated in many functions, such as pain, memory, addiction, inflammation, and feeding, and could be considered a stress recovery system. It also seems to integrate nutrient intake, metabolism and storage maintaining homeostatic balance. The ECS is a recently discovered system, and research indicates hyperactivity in obesity. The aim of this thesis is to elaborate on the relationships of this widespread system and its elements in adipose tissue in obesity. Study I is a 4 weeks rat intervention study to investigate whether weight independent effect of Rimonabant treatment exists. We found that food intake-tolerance development could be circumvented by cyclic administration of Rimonabant and implications of weight independent effects of treatment. Study II is a cross-sectional study to establish the expression of cannabinoid receptor 1 from various adipose tissue depots of lean and obese persons. In this study we conclude, that the subcutaneous adipose tissue express more CBR1 than the visceral depot in lean, but comparable levels in obese. Study III is a 10 weeks human intervention study to asses the effects on the ECS of 10% weight loss. We found reduction in the ECS in obesity that normalised with weight loss. Our results clearly show the presence of all the components of the ECS in human adipose tissue, and suggest that the ECS is reduced in adipose tissue in obesity. Our results do not support the hypothesis of hyperactivity of the ECS in human obesity. Possible future treatment of obesity with CBR1 antagonist could involve cyclic treatment of specific peripheral compounds.”

http://www.ncbi.nlm.nih.gov/pubmed/21466769