Tag Archives: endocannabinoid system

Targeting CB2 receptors and the endocannabinoid system for the treatment of pain.

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Abstract

“The endocannabinoid system consists of the cannabinoid (CB) receptors, CB(1) and CB(2), the endogenous ligands anandamide (AEA, arachidonoylethanolamide) and 2-arachidonoylglycerol (2-AG), and their synthetic and metabolic machinery. The use of cannabis has been described in classical and recent literature for the treatment of pain, but the potential for psychotropic effects as a result of the activation of central CB(1) receptors places a limitation upon its use. There are, however, a number of modern approaches being undertaken to circumvent this problem, and this review represents a concise summary of these approaches, with a particular emphasis upon CB(2) receptor agonists. Selective CB(2) agonists and peripherally restricted CB(1) or CB(1)/CB(2) dual agonists are being developed for the treatment of inflammatory and neuropathic pain, as they demonstrate efficacy in a range of pain models. CB(2) receptors were originally described as being restricted to cells of immune origin, but there is evidence for their expression in human primary sensory neurons, and increased levels of CB(2) receptors reported in human peripheral nerves have been seen after injury, particularly in painful neuromas. CB(2) receptor agonists produce antinociceptive effects in models of inflammatory and nociceptive pain, and in some cases these effects involve activation of the opioid system. In addition, CB receptor agonists enhance the effect of mu-opioid receptor agonists in a variety of models of analgesia, and combinations of cannabinoids and opioids may produce synergistic effects. Antinociceptive effects of compounds blocking the metabolism of anandamide have been reported, particularly in models of inflammatory pain. There is also evidence that such compounds increase the analgesic effect of non-steroidal anti-inflammatory drugs (NSAIDs), raising the possibility that a combination of suitable agents could, by reducing the NSAID dose needed, provide an efficacious treatment strategy, while minimizing the potential for NSAID-induced gastrointestinal and cardiovascular disturbances. Other potential “partners” for endocannabinoid modulatory agents include alpha(2)-adrenoceptor modulators, peroxisome proliferator-activated receptor alpha agonists and TRPV1 antagonists. An extension of the polypharmacological approach is to combine the desired pharmacological properties of the treatment within a single molecule. Hopefully, these approaches will yield novel analgesics that do not produce the psychotropic effects that limit the medicinal use of cannabis.”

http://www.ncbi.nlm.nih.gov/pubmed/19150370

Involvement of peripheral cannabinoid and opioid receptors in β-caryophyllene-induced antinociception.

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“BACKGROUND:

  β-caryophyllene (BCP) is a common constitute of the essential oils of numerous spice, food plants and major component in Cannabis. The present study investigated the contribution of peripheral cannabinoid (CB) and opioid systems in the antinociception produced by intraplantar (i.pl.) injection of BCP. The interaction between peripheral BCP and morphine was also examined.”

“CONCLUSIONS:

The present results demonstrate that antinociception produced by i.pl. BCP is mediated by activation of CB(2) receptors, which stimulates the local release from keratinocytes of the endogenous opioid β-endorphin. The combined injection of morphine and BCP may be an alternative in treating chemogenic pain.”

http://www.ncbi.nlm.nih.gov/pubmed/23138934

Therapeutic potential of the endocannabinoid system in the brain.

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Abstract

“Cannabinoids have been predominantly considered as the substances responsible of the psychoactive properties of marijuana and other derivatives of Cannabis sativa. However, these compounds are now being also considered for their therapeutic potential, since the term “cannabinoid” includes much more compounds than those present in Cannabis sativa derivatives. Among them, there are numerous synthetic cannabinoids obtained by modifications from plant-derived cannabinoids, but also from the compounds that behave as endogenous ligands for the different cannabinoid receptor subtypes. Within the family of “cannabinoid-related compounds”, one should also include some prototypes of selective antagonists for these receptors, and also the recently developed inhibitors of the mechanism of finalization of the biological action of endocannabinoids (transporter + FAAH). All this boom of the cannabinoid pharmacology has, therefore, an explanation in the recent discovery and characterization of the endocannabinoid signaling system, which plays a modulatory role mainly in the brain but also in the periphery. The objective of the present article will be to review, from pharmacological and biochemical points of view, the more recent advances in the study of the endocannabinoid system and their functions in the brain, as well as their alterations in a variety of pathologies and the proposed therapeutic benefits of novel cannabinoid-related compounds that improve the pharmacokinetic and pharmacodynamic properties of classic cannabinoids.”

http://www.ncbi.nlm.nih.gov/pubmed/16026307

From cannabis to the endocannabinoid system: refocussing attention on potential clinical benefits.

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“Cannabis sativa is one of the oldest herbal remedies known to man. Over the past four thousand years, it has been used for the treatment of numerous diseases but due to its psychoactive properties, its current medicinal usage is highly restricted. In this review, we seek to highlight advances made over the last forty years in the understanding of the mechanisms responsible for the effects of cannabis on the human body and how these can potentially be utilized in clinical practice. During this time, the primary active ingredients in cannabis have been isolated, specific cannabinoid receptors have been discovered and at least five endogenous cannabinoid neurotransmitters (endocannabinoids) have been identified. Together, these form the framework of a complex endocannabinoid signalling system that has widespread distribution in the body and plays a role in regulating numerous physiological processes within the body. Cannabinoid ligands are therefore thought to display considerable therapeutic potential and the drive to develop compounds that can be targeted to specific neuronal systems at low enough doses so as to eliminate cognitive side effects remains the ‘holy grail’ of endocannabinoid research.”

http://www.ncbi.nlm.nih.gov/pubmed/23155985

Reversal of liver fibrosis by the antagonism of endocannabinoid CB1 receptor in a rat model of CCl(4)-induced advanced cirrhosis.

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Abstract

“The endocannabinoid system is involved in the pathogenesis of liver fibrosis. Although many substances have been proved to reduce fibrosis in experimental models of chronic liver injury, most of them appear to be effective only if given as a prophylactic or early treatment. This study aimed to explore the effect of pharmacological antagonism of the endocannabinoid cannabinoid type 1 (CB1) receptor started after the stage of full-blown cirrhosis had been reached. Wistar-Han rats with carbon tetrachloride (CCl(4))-induced cirrhosis were randomized to receive the CB1 receptor antagonist Rimonabant (10 mg/kg/day) or the vehicle for 2 weeks. Age-matched healthy rats served as controls. Liver fibrosis was assessed using Sirius red staining, hydroxyproline concentration and α-smooth muscle actin expression. Hepatic gene expression of mediators of fibrogenesis and inflammation were evaluated by real-time PCR. We also assessed the hepatic expression of CB1 and CB2 receptors and that of the enzymes implicated in the endocannabinoid metabolism. Fibrosis was significantly reduced in rats treated with Rimonabant compared with rats receiving the vehicle. CB1 receptor antagonism limited the gene upregulation of fibrogenic and inflammatory mediators occurring in untreated cirrhotic rats. CB1 and CB2 receptor expression was increased in cirrhotic animals. Interestingly, pharmacological CB1 receptor antagonism was associated with a further induction of the CB2 receptor expression. Regression of fibrosis can be achieved by pharmacological blockade of the CB1 receptor even when started in an advanced stage of the disease. This effect is associated with the suppression of pro-fibrogenic and inflammatory mediators and may have been indirectly favoured by the induction of CB2 receptor expression.”

http://www.ncbi.nlm.nih.gov/pubmed/22184091

The endocannabinoid system as a key mediator during liver diseases: new insights and therapeutic openings

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  “Alcohol abuse, viral hepatitis and non-alcoholic fatty liver disease (NAFLD) represent the major causes of chronic liver injury, resulting in progressive accumulation of fibrosis within the liver parenchyma. Progression to cirrhosis exposes patients to life-threatening complications of portal hypertension liver failure and hepatic encephalopathy, and to a high risk of developing hepatocellular carcinoma. Overall, chronic liver diseases represent a major health problem with an estimated rate of death in the range of 1 400 000 per year worldwide. Recent findings have revealed a role of endocannabinoids and their receptors in the pathogenesis of several key steps of acute and chronic liver injury, therefore identifying pharmacological modulation of cannabinoid receptors as an attractive strategy for the management of morbidity related to liver injury .”

 

“Chronic liver diseases represent a major health problem due to cirrhosis and its complications. During the last decade, endocannabinoids and their receptors have emerged as major regulators of several pathophysiological aspects associated with chronic liver disease progression. Hence, hepatic cannabinoid receptor 2 (CB2) receptors display beneficial effects on alcoholic fatty liver, hepatic inflammation, liver injury, regeneration and fibrosis. Cannabinoid receptor 1 (CB1) receptors have been implicated in the pathogenesis of several lesions such as alcoholic and metabolic steatosis, liver fibrogenesis, or circulatory failure associated with cirrhosis. Although the development of CB1 antagonists has recently been suspended due to the high incidence of central side effects, preliminary preclinical data obtained with peripherally restricted CB1 antagonists give real hopes in the development of active CB1 molecules devoid of central adverse effects. CB2-selective molecules may also offer novel perspectives for the treatment of liver diseases, and their clinical development is clearly awaited. Whether combined treatment with a peripherally restricted CB1 antagonist and a CB2 agonist might result in an increased therapeutic potential will warrant further investigation.”

 

“Cannabis Sativa has a long-standing history of recreational and therapeutic use, starting over 200 years ago. Understanding of pathways involved in the pharmacological properties of cannabinoids has only emerged with the identification of an endocannabinoid system that comprises at least two specific G-protein coupled receptors [cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2)], their endogenous lipidic ligands (endocannabinoids), and enzymes involved in endocannabinoid synthesis and degradation.”

“Over the past 10 years, the endocannabinoid system has emerged as a major player in the pathogenesis of liver diseases. CB1 receptors have been implicated in the pathogenesis of several lesions such as liver fibrogenesis, alcoholic and metabolic steatosis, or circulatory failure associated with cirrhosis. In contrast, stimulation of hepatic CB2 receptors is emerging as an overall protective pathway with antifibrogenic properties and beneficial effects on liver inflammation, alcoholic fatty liver and hepatocyte survival and regeneration. Exciting therapeutic developments expected with the availability of CB1 receptor antagonists have been put to a hold, due to the high incidence of central side effects of first generation compounds. Fortunately, CB1 antagonists devoid of brain penetrance are increasingly being synthetized and initial results suggest that they exhibit beneficial effects expected from previous studies. The clinical development of CB2-selective agonists is also eagerly awaited.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3165953/

Endocannabinoids in Liver Disease.

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“Marijuana has been used for its psychoactive and medicinal properties for millennia. As other plant-derived substances, marijuana has been slow to yield its secrets, with insights into its mechanism of action beginning to emerge only during the last decades. The existence of specific CB receptors in mammalian tissues was first revealed by radioligand binding, followed by the molecular cloning of two G protein-coupled cannabinoid receptors (1). CB1 receptors are the most abundant receptors in the mammalian brain, but are also expressed in peripheral tissues, including various cell types of the liver, at much lower yet functionally relevant concentrations. CB2 receptors are expressed primarily in immune and hematopoietic cells, and have also been detected in the liver in certain pathological states. Additional CB receptors may exist…”

“Endocannabinoids are lipid mediators of the same cannabinoid (CB) receptors that mediate the effects of marijuana. The endocannabinoid system (ECS) consists of CB receptors, endocannabinoids, and the enzymes involved in their biosynthesis and degradation, and is present both in brain and peripheral tissues, including the liver. The hepatic ECS is activated in various liver diseases, which contributes to the underlying pathologies. In cirrhosis of various etiologies, activation of vascular and cardiac CB1 receptors by macrophage- and platelet-derived endocannabinoids contribute to the vasodilated state and cardiomyopathy, which can be reversed by CB1 blockade. In mouse models of liver fibrosis, activation of CB1 receptors on hepatic stellate cells is fibrogenic, and CB1 blockade slows the progression of fibrosis. Fatty liver induced by high-fat diets or chronic alcohol feeding depend on activation of peripheral, including hepatic CB1 receptors, which also contribute to insulin resistance and dyslipidemias. Although the documented therapeutic potential of CB1 blockade is limited by neuropsychiatric side effects, these may be mitigated by using novel, peripherally restricted CB1 antagonists.”

“Concluding Remarks

The ECS is present in the liver and is involved in the control of various hepatic functions with important therapeutic implications. Increased CB1 activity contributes to the hemodynamic abnormalities and promotes fibrosis in liver cirrhosis, whereas CB1 blockade attenuates and delays these changes. Endocannabinoids acting via hepatic CB1 receptors have emerged as mediators of both diet-induced and alcoholic fatty liver which, together, account for the majority of cirrhosis in Western societies. Additionally, hepatic CB1 activation contributes to obesity-related insulin- and leptin-resistance and dyslipidemias. This provides strong rationale for the therapeutic use of CB1 antagonists in these conditions. Although neuropsychiatric side effects limit the therapeutic potential of brain-penetrant CB1 antagonists, the recent emergence of second generation, peripherally-restricted CB1 antagonists may mitigate this problem. Additionally, non-psychoactive CB2 agonists may offer therapeutic benefit in attenuating liver injury and promoting tissue repair in the fibrotic liver.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3073545/

Endocannabinoids and Liver Disease. III. Endocannabinoid effects on immune cells: implications for inflammatory liver diseases

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  “Recent studies have implicated dysregulation of the endocannabinoid system in various liver diseases and their complications (e.g., hepatitis, fibrosis, cirrhosis, cirrhotic cardiomyopathy, and ischemia-reper-fusion), and demonstrated that its modulation by either cannabinoid 2 (CB2) receptor agonists or CB1 antagonists may be of significant therapeutic benefits. This review is aimed to focus on the triggers and sources of endocannabinoids during liver inflammation and on the novel role of CB2 receptors in the interplay between the activated endothelium and various inflammatory cells (leukocytes, lymphocytes, etc.), which play pivotal role in the early development and progression of inflammatory and other liver diseases.”

“Dysregulation of the endocannabinoid system (ECS) has been implicated in virtually all diseases affecting humans, and its pharmacological modulation holds tremendous promise in the treatment of pain, cancer, and metabolic, cardiovascular, and various inflammatory disorders. Numerous recent studies have linked dysregulation of the ECS to a number of liver diseases including hepatitis, nonalcoholic fatty liver disease, hepatic ischemia-reperfusion (I/R) injury, and liver fibrosis and cirrhosis and its hemo-dynamic consequences. In aggregate these studies have suggested that modulation of the ECS by either CB1 antagonists or CB2 receptor agonists may be of significant therapeutic benefit. This synopsis will focus on sources and triggers of endocannabinoids during liver inflammatory disorders (in both leukocytes and parenchymal cells) and on the novel role of CB2 receptors in the interplay between inflammatory cells and the activated endothelium, which plays a crucial role in the early development and progression of inflammatory liver diseases”.

“Collectively, the studies discussed above emphasize the potential immunoregulatory role of the endocannabinoid system in a variety of inflammatory liver disorders, opening new avenues for their pharmacotherapy. There is considerable interest in the development of selective CB2 receptor agonists, which are devoid of psychoactive properties of CB1 agonists, for various inflammatory disorders. Selective CB2 cannabinoid agonists may protect against hepatic inflammatory disorders by attenuating the endothelial cell activation/inflammatory response (e.g., the expression of adhesion molecules, release of chemotactic factors, inflammatory mediators, etc.) and by decreasing the migration and the adhesion of inflammatory cells to the endothelium, transendothelial migration, adhesion to parenchymal cells and activation, and interrelated oxidativenitrosative stress-inflammatory response. It appears that CB1 antagonists might be beneficial in slowing the progression of liver fibrosis and the neurological decline associated with hepatic encephalopathy, in addition to the attenuation of the adverse hemodynamic consequences of cirrhosis, thus extending life until a suitable liver becomes available for transplantation. CB1 antagonists may also be useful in the treatment of obesity-associated liver diseases and related features of metabolic syndrome by improving dyslipidemia and attenuating systemic and liver inflammation.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2376822/

Endocannabinoids and Liver Disease. II. Endocannabinoids in the pathogenesis and treatment of liver fibrosis

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“Plant-derived cannabinoids such as delta-9-tetrahydrocannabinol (THC) have been used for medicinal purposes for thousands of years. Two G protein-coupled receptors termed CB1 and CB2 were identified in the early 1990s as receptors for cannabinoids…”

“Hepatic fibrosis is the response of the liver to chronic injury and is associated with portal hypertension, progression to hepatic cirrhosis, liver failure, and high incidence of hepatocellular carcinoma. On a molecular level, a large number of signaling pathways have been shown to contribute to the activation of fibrogenic cell types and the subsequent accumulation of extracellular matrix in the liver. Recent evidence suggests that the endocannabinoid system is an important part of this complex signaling network. In the injured liver, the endocannabinoid system is upregulated both at the level of endocannabinoids and at the endocannabinoid receptors CB1 and CB2. The hepatic endocannabinoid system mediates both pro- and antifibrogenic effects by activating distinct signaling pathways that differentially affect proliferation and death of fibrogenic cell types. Here we will summarize current findings on the role of the hepatic endocannabinoid system in liver fibrosis and discuss emerging options for its therapeutic exploitation.”

“There is overwhelming evidence that the endocannabinoid system plays a major role in the pathophysiology of chronic liver injury and wound healing responses and that modulation of the endocannabinoid system may be exploited for the treatment of liver fibrosis. Among all candidates, CB1 represents the most promising target for antifibrotic therapies. In addition to the antifibrogenic effects of CB1 blockade, one can expect positive effects on other complications such as portal hypertension, ascites formation, hepatic encephalopathy, and cardiomyopathy. Moreover, CB1 antagonism appears to have beneficial effects on hepatic steatosis…”

http://ajpgi.physiology.org/content/294/2/G357.long

Endocannabinoids and Liver Disease. I. Endocannabinoids and their receptors in the liver

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  “The medicinal properties of cannabis (Cannabis sativa, marijuana) have been known for millennia, as shown by reports from China and India underscoring its analgesic, antiemetic, and appetite-stimulating properties. During the 19th century, the prescription of cannabis gained popularity for a variety of conditions ranging from epilepsy to rheumatism and abdominal symptoms. Concerns about abuse led to discontinuation of therapeutic use in the 1940s. The characterization of marijuana-derived bioactive molecules began during the early 20th century with the identification of several hydrophobic compounds and culminated in 1964 with the isolation of Δ9-tetrahydrocannabinol (THC), the main psychoactive constituent of the plant. Subsequent studies identified over 60 other phytocannabinoids and allowed the synthesis of active analogs with varying potencies. This step was critical in the identification of the endocannabinoid system, comprising specific cannabinoid binding sites (CB1 and CB2), their endogenous ligands (endocannabinoids), and synthetic and degradative pathways.”

“Cannabinoid receptors (CB1 and CB2) and their endogenous ligands (endocannabinoids) have recently emerged as novel mediators of liver diseases. Endogenous activation of CB1 receptors promotes nonalcoholic fatty liver disease (NAFLD) and progression of liver fibrosis associated with chronic liver injury; in addition, CB1 receptors contribute to the pathogenesis of portal hypertension and cirrhotic cardiomyopathy. CB2 receptor-dependent effects are also increasingly characterized, including antifibrogenic effects and regulation of liver inflammation during ischemia-reperfusion and NAFLD. It is likely that the next few years will allow us to delineate whether molecules targeting CB1 and CB2 receptors are useful therapeutic agents for the treatment of chronic liver diseases.”

http://ajpgi.physiology.org/content/294/1/G9.long