The recent discovery of cannabinoid receptors and their natural ligands, the endocannabinoids, has provoked an accelerated program of research to uncover the physiological roles of these systems.

Sanofi, a leader in research into the Endocannobid System, has provided this backgrounder.

The Endocannabinoid System (EC System) is a physiological system of cannabinoid receptors and corresponding chemical messengers that is believed to play an important role in regulating body weight and glucose and lipid metabolism. The EC System also plays a role in tobacco dependence. 3

The chemical messengers of the EC System are endocannabinoids (ECBs) which bind to and activate the cannabinoid (CB 1) receptors. CB 1 receptors are found in the brain as well as in some peripheral tissues of the body such as adipocytes (or “fat cells”) which are associated with lipid and glucose metabolism. 3

Fig 1. CB1 receptor on a cell membrane being activated by an ECB

Through both this central and peripheral activity, the EC System helps to regulate food intake and energy expenditure. It is also involved in the body’s response to tobacco use. 3

Physiologically, the EC System is activated in response to stressful stimuli to help re-establish the normal steady state of the affected cells or tissues. Therefore, the effects of EC System activation are short-lasting, confined to those cells or tissues that have been subjected to stress or damage, and normally end once the organism has recovered from a transient “unbalanced” condition. 3

Central Activity

In the central nervous system, CB 1-receptors are necessary to kick-start food intake after a short period of food deprivation and, when activated, they also preferentially stimulate the ingestion of palatable food. Studies using a variety of behavioural paradigms indicate that ECBs may play a very specific role in appetite control. This is achieved by modulating the expression and release of appetite suppressing and appetite stimulating chemical messengers in the hypothalamus region of the brain. 3

CB 1 receptor activation is also apparent in an area of the brain called the nucleus accumbens shell, a small subcortical area which is believed to be important in motivational processes that mediate the incentive value of food, and which is also important in the process by which tobacco dependence is acquired and maintained. 3

Peripheral Activity

The EC System functions in many levels of the energy balance system including the gastro intestinal tract and adipocyte. At the peripheral level the activation of the CB 1 receptor has been shown to stimulate lipogenesis in adipocytes which results in fat accumulation and modulation of the expression of adiponectin 3, a hormone that regulates the metabolism of lipids and glucose. Through its effects on the multiple components of the energy balance system, the EC System helps regulate the physiological need to eat and the energy storage state.

Fig 2. The EC System [Source: Uberto Pagotto’s poster: The Endocannabinoid System: A New Player in Reinforcement and Energy Control Functions ]

Over-activation of the EC System in obesity and metabolic disorders

Obesity has reached global epidemic proportions with more than 1 billion adults overweight and at least 300 million of them recognised as clinically obese (BMI >30 kg/m2). 4 Current prevalence data from individual national studies suggests that the range of obesity prevalence in European countries is from 10 to 20 percent for men and 10 to 25 percent for women. 5 Obesity is usually defined by an indirect measure of body fat, the body mass index (BMI) (weight/ (kg)/height (m 2). 1 The World Health Organization (WHO) defines overweight as a BMI of 25.0-29.9 and obesity as a BMI >30. 4 Obesity is widely recognised as a major contributor to the global burden of chronic disease and disability and appears on the WHO list of Top 10 global health risks. 6

Food storage and adjustment to environmental changes are critical to all living organisms. There is interplay between multiple mechanisms in our body and brain that signal hunger and satiety in an extremely precise fashion. Signals from stored and available fuel are integrated and help determine food intake and energy expenditure. The EC System plays a major role within this complex interplay of mechanisms, helping to maintain energy balance by regulating what and how much we eat and how much fat we store or use. This energy balance system can be disturbed externally by environmental factors or internally by genetic factors. 2

An emerging scientific point-of-view on the explosive world-wide growth of obesity is the theory that our nutritional environment has altered since our ancestors evolved even though physiological mechanisms have not. The “hunter-gatherer”, “feast or famine” existence of our ancestors has vanished and has been replaced with a constant abundance of food and a more sedentary lifestyle. Furthermore, less calorie-dense foods of archaic times have been replaced with the modern high-fat, high-carbohydrate menu. This combination of a sedentary lifestyle and a calorie-dense diet can disrupt the energy balance system, leading to obesity and chronic over-stimulation of the EC System.

Some chronic pathologic states such as obesity lead to long-lasting over-stimulation of ECB synthesis (or under-stimulation of their breakdown), resulting in permanent over-activation of CB 1 receptors, which may then contribute to the symptoms of these disorders. 3

In the obesity setting, the EC System is operating out of its normal range and receives aberrant signals from the malfunctioning weight control system. Its activity is up-regulated and it is converted from a system that is intermittently transiently activated, to one that is chronically overactivated. This overactivity not only promotes fat storage in the adipocytes, but can also be associated with insulin resistance, glucose intolerance, elevated triglycerides and low HDL cholesterol levels, all of which are risk factors for cardiovascular disease. Therefore, regulating the EC System is important in the control of food/energy storage and release in the body.

CB 1 receptor blockade modulates overactivity of the EC System resulting in the restoration of balance. Blocking the CB 1 receptor eliminates the part of obesity that is controlled by the EC System such as increased appetite, excessive hunger and food intake. 7 It also increases adiponectin levels, which is thught to result in increased fat metabolism and an improvement in glucose metabolism. This may result in reducing cardiovascular risk factors through weight loss and an improvement in metabolic risk factor profile.

Over-activation of the EC System in nicotine dependence

Today almost one billion men and 250 million women in the world smoke tobacco. 8 Tobacco use, particularly smoking, remains the leading preventable cause of death in the world. An estimated 4.9 million premature deaths from smoking occurred in the year 2000, approximately evenly divided between the industrialised and developing world. 8

Nicotine is the chemical within tobacco smoke that causes addiction. It is difficult to explain why some people become dependent on nicotine, while others develop a pattern of occasional use or abstain from it completely. In the US, it has been estimated that 70 percent of smokers want to quit, but only 2.5 percent per year succeed in quitting smoking permanently. 9

It has been demonstrated that chronic nicotine consumption results in persistent over-stimulation of the EC System in animals. Dopamine release into the nucleus accumbens is one of the neurochemical substrates underlying the motivation to consume nicotine. The chronic consumption of nicotine permanently over-stimulates the EC System in the nucleus accumbens shell, with subsequent reinforcement of dopamine release and nicotine abuse. 7

Blockade of CB 1, possibly by impairing the release of dopamine in the nucleus accumbens shell, reduces motivation to self-administer nicotine. 7

Targeting the EC System

The EC System exerts significant influence on a number of risk factors for cardiovascular disease. Overeating and increased fat storage due to dysregulation of endocannabinoid signalling can contribute to obesity and other hallmarks of the metabolic syndrome, such as dyslipidemia and type 2 diabetes. In addition, dysregulated endocannabinoid signalling can reinforce tobacco dependence. Thus, using a selective CB 1 blocker to regulate endocannabinoid signalling represents a potential t herapeutic strategy in managing cardiovascular risk factors.

In 1994, sanofi-aventis discovered rimonabant, the first selective CB 1 blocker. This discovery has helped characterise and increase understanding of the many facets of the EC System and opened the door for the development of novel pharmacotherapies.

The cloning and characterisation of the human cannabinoid receptors triggered the search for corresponding ligands (agonists and antagonists). Researchers focused on the discovery of molecules with potential inhibitory activity against this receptor and then screened the most effective one for pharmacological activity. Rimonabant emerged from this screening process as a potent and selective CB 1 blocker. Today, rimonabant shows promise as a new approach to address cardiovascular risk factor management, specifically in the areas of obesity, metabolic disorders, and tobacco dependence. By selectively blocking the CB 1 receptor, rimonabant modulates over-activity of the EC System, which is thought to result in weight loss and improvement of metabolic risk factors (i.e. HDL, triglycerides and insulin resistance) in obesity. In chronic tobacco use, rimonabant similarly balances the activity of the EC System, which is thought to result in reduced dependence on tobacco, which in turn helps achieve smoking cessation without associated post-cessation weight gain.

Several major studies are currently underway to investigate the safety of efficacy of rimonabant in weight loss and smoking cessation. First year data from the Rimonabant In Obesity - Europe (RIO-Europe) trial released in August 2004, indicated that patients treated for one year with rimonabant 20mg/day lost an average of 8.6kg (about 19 lbs) (p<0.001 vs placebo) compared to 4.8kg (about 11 lbs) for patients on rimonabant 5mg/day (p=0.038 vs placebo) and 3.6kg (about 8 lbs) for those on placebo. Moreover, 39 percent (p<0.001 vs placebo) of patients on rimonabant 20mg/day lost more than 10 percent of their initial body weight compared 12.4 percent of those on placebo. 10 People taking rimonabant 20mg also had a significant reduction in waist circumference and improvements in lipid and glycemic profiles. 10

Early results of the STudies with Rimonabant And Tobacco USe-US (STRATUS-US) trial indicated that, at ten weeks of follow-up, treatment with rimonabant 20mg/day doubled the odds of quitting smoking versus placebo and significantly reduced post-cessation weight gain. 11

Both the RIO-Europe and STRATUS-US studies also indicated a favourable safety profile of rimonabant. In the RIO-Europe study side effects were mainly mild and transient and most frequently involved nausea (4.3 percent, 5.1 percent and 12.9 percent for placebo, rimonabant 5mg and rimonabant 20 mg respectively), diarrhoea (3.0 percent, 6.0 percent and 7.2 percent for placebo, rimonabant 5mg and rimonabant 20 mg respectively) and dizziness (4.9 percent, 7.0 percent and 8.7 percent for placebo, rimonabant 5mg and rimonabant 20 mg respectively). Only in a very small number of cases did these side effects lead to discontinuation of drug use. Similar safety and tolerability was seen in the STRATUS-US study.

References

2. Kirkham TC. Endogenous cannabinoids: a new target for the treatment of obesity. Am J Regul Integr Comp Physiol. 2003, 284: R343-R344

3. Pagotto U. The Endocannabinoid System: A New Player in Reinforcement and Energy Control Functions. Poster presented at the Metabolic Syndrome, Type 2 Diabetes and Atherosclerosis Conference, Marrakech, 19 – 23 May 2004

4. Obesity and Overweight. World Health Organization. - last accessed 24 October 2004.

5. IOTF Website – incidence, prevalence and co-morbidity of obesity. - last accessed 24 October 2004.

6. Neglected Global Epidemics: three growing threats. World Health Organization. - last accessed 24 October 2004

7. Sanofi-Synthelabo data on file. Pagotto U et al The Endocannabinoid System (EC System): Key Modulator of Energy Balance at both Central and Peripheral Levels

8. Tobacco Control Country Profiles 2003. American Cancer Society, World Health Organization, and the International Union Against Cancer. -l ast accessed 24 October 2004

9. The Surgeon General’s Report on Reducing Tobacco Use. Management of Nicotine Addiction Fact Sheet. - last accessed 24 October 2004

10. Van Gaal L. The RIO-Europe Study: Use of a Selective CB1 Receptor Blocker (Rimonabant) in the Management of Obesity and Related Metabolic Risk Factors. ESC Abstract, August 2004.

11. Dale, L. Anthenelli R. Rimonabant as an Aid to Smoking Cessation in Smokers Motivated to Quit. ACC Abstract, March 2004.

Source: Sanofi-Aventis