Tag Archives: CB(1) and CB(2) receptors

Targeting cannabinoid agonists for inflammatory and neuropathic pain.

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Abstract

“The cannabinoid receptors CB(1) and CB(2) are class A G-protein-coupled receptors. It is well known that cannabinoid receptor agonists produce relief of pain in a variety of animal models by interacting with cannabinoid receptors. CB(1) receptors are located centrally and peripherally, whereas CB(2) receptors are expressed primarily on immune cells and tissues. A large body of preclinical data supports the hypothesis that either CB(2)-selective agonists or CB(1) agonists acting at peripheral sites, or with limited CNS exposure, will inhibit pain and neuroinflammation without side effects within the CNS. There has been a growing interest in developing cannabinoid agonists. Many new cannabinoid ligands have been synthesized and studied covering a wide variety of novel structural scaffolds. This review focuses on the present development of cannabinoid agonists with an emphasis on selective CB(2) agonists and peripherally restricted CB(1) or CB(1)/CB(2) dual agonists for treatment of inflammatory and neuropathic pain.”

http://www.ncbi.nlm.nih.gov/pubmed/17594182

Cannabinoid receptors and pain.

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Abstract

“Mammalian tissues contain at least two types of cannabinoid receptor, CB(1) and CB(2), both coupled to G proteins. CB(1) receptors are expressed mainly by neurones of the central and peripheral nervous system whereas CB(2) receptors occur centrally and peripherally in certain non-neuronal tissues, particularly in immune cells. The existence of endogenous ligands for cannabinoid receptors has also been demonstrated. The discovery of this ‘endocannabinoid system’ has prompted the development of a range of novel cannabinoid receptor agonists and antagonists, including several that show marked selectivity for CB(1) or CB(2) receptors. It has also been paralleled by a renewed interest in cannabinoid-induced antinociception. This review summarizes current knowledge about the ability of cannabinoids to produce antinociception in animal models of acute pain as well as about the ability of these drugs to suppress signs of tonic pain induced in animals by nerve damage or by the injection of an inflammatory agent. Particular attention is paid to the types of pain against which cannabinoids may be effective, the distribution pattern of cannabinoid receptors in central and peripheral pain pathways and the part that these receptors play in cannabinoid-induced antinociception. The possibility that antinociception can be mediated by cannabinoid receptors other than CB(1) and CB(2) receptors, for example CB(2)-like receptors, is also discussed as is the evidence firstly that one endogenous cannabinoid, anandamide, produces antinociception through mechanisms that differ from those of other types of cannabinoid, for example by acting on vanilloid receptors, and secondly that the endocannabinoid system has physiological and/or pathophysiological roles in the modulation of pain.”

http://www.ncbi.nlm.nih.gov/pubmed/11164622

Cannabinoid CB2 receptor-mediated anti-nociception in models of acute and chronic pain.

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Abstract

“The endocannabinoid system consists of cannabinoid CB(1) and CB(2) receptors, endogenous ligands and their synthesising/metabolising enzymes. Cannabinoid receptors are present at key sites involved in the relay and modulation of nociceptive information. The analgesic effects of cannabinoids have been well documented. The usefulness of nonselective cannabinoid agonists can, however, be limited by psychoactive side effects associated with activation of CB(1) receptors. Following the recent evidence for CB(2) receptors existing in the nervous system and reports of their up-regulation in chronic pain states and neurodegenerative diseases, much research is now aimed at shedding light on the role of the CB(2) receptor in human disease. Recent studies have demonstrated anti-nociceptive effects of selective CB(2) receptor agonists in animal models of pain in the absence of CNS side effects. This review focuses on the analgesic potential of CB(2) receptor agonists for inflammatory, post-operative and neuropathic pain states and discusses their possible sites and mechanisms of action”

http://www.ncbi.nlm.nih.gov/pubmed/17952647

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

Inhibition of pain responses by activation of CB(2) cannabinoid receptors.

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Abstract

“Cannabinoid receptor agonists diminish responses to painful stimuli. Extensive evidence demonstrates that CB(1) cannabinoid receptor activation inhibits pain responses. Recently, the synthesis of CB(2) cannabinoid receptor-selective agonists has allowed testing whether CB(2) receptor activation inhibits pain. CB(2) receptor activation is sufficient to inhibit acute nociception, inflammatory hyperalgesia, and the allodynia and hyperalgesia produced in a neuropathic pain model. Studies using site-specific administration of agonist and antagonist have suggested that CB(2) receptor agonists inhibit pain responses by acting at peripheral sites. CB(2) receptor activation also inhibits edema and plasma extravasation produced by inflammation. CB(2) receptor-selective agonists do not produce central nervous system (CNS) effects typical of cannabinoids retaining agonist activity at the CB(1) receptor. Peripheral antinociception without CNS effects is consistent with the peripheral distribution of CB(2) receptors. CB(2) receptor agonists may have promise for the treatment of pain and inflammation without CNS side effects.”

http://www.ncbi.nlm.nih.gov/pubmed/12505700

CB1 cannabinoid receptor antagonism: a new strategy for the treatment of liver fibrosis.

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“Hepatic fibrosis, the common response associated with chronic liver diseases, ultimately leads to cirrhosis, a major public health problem worldwide. We recently showed that activation of hepatic cannabinoid CB2 receptors limits progression of experimental liver fibrosis… In conclusion, our study shows that CB1 receptor antagonists hold promise for the treatment of liver fibrosis.”

http://www.ncbi.nlm.nih.gov/pubmed/16715087

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 as novel mediators of liver diseases.

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Abstract

“In the past two decades, cannabinoids have emerged as crucial mediators in a variety of pathophysiological conditions. Awareness of their critical functions in liver pathophysiology is only recent, probably given the low level of expression of cannabinoid receptor type 1 (CB1 receptor) and type 2 (CB2 receptor) in normal liver. However, it has been shown that non-alcoholic fatty liver disease and cirrhosis are associated to a marked upregulation of the hepatic endocannabinoid system, including increases in endocannabinoids and in hepatic CB receptors, both in humans and in rodents. Consequently, a growing number of cannabinoid-related hepatic effects are being unravelled. Hence, hepatic CB1 receptors enhance liver steatogenesis in a mouse model of high fat-induced obesity, and contribute to peripheral arterial vasodilation in cirrhosis, thereby promoting portal hypertension. In addition, CB1 and CB2 receptors elicit dual opposite effects on fibrogenesis associated to chronic liver injury, by promoting pro- and antifibrogenic effects, respectively. Therefore, endocannabinoid-based therapies may open novel therapeutic avenues in the treatment of chronic liver diseases.”

http://www.ncbi.nlm.nih.gov/pubmed/16751709

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/