Role of endocannabinoids in regulating drug dependence.

 “This review will discuss the latest knowledge of how the endocannabinoid system might be involved in treating addiction to the most common illicit drugs. Experimental models are providing increasing evidence for the pharmacological management of endocannabinoid signaling not only to block the direct reinforcing effects of cannabis, opioids, nicotine and ethanol, but also for preventing relapse to the various drugs of abuse, including opioids, cocaine, nicotine, alcohol and metamphetamine. Preclinical and clinical studies suggest that the endocannabinoid system can be manipulated by the CB1 receptor antagonist SR141716A, that might constitute a new generation of compounds for treating addiction across different classes of abused drugs.”

“In the last 25 years the neurobiological and behavioral mechanisms that lead to drug dependence have been extensively investigated but clinical treatment is still unsatisfactory and ineffective in many subjects.”

“Experimental models are now providing evidence for the pharmacological management of endocannabinoid signaling not only to block the direct reinforcing effects of cannabis, opioids, nicotine and ethanol, but also to prevent relapse to these various substances of abuse, also including cocaine and metamphetamine. The endocannabinoid system can be manipulated by SR141716A and by all the new compounds that protect AEA and 2-AG from deactivation and prolong the lifespan of these endocannabinoid substances in vivo. Rimonabant reduces the motivational effect of drug-related stimuli and drug re-exposure, probably by altering synaptic plasticity, thus providing an effective means of preventing relapse and a new tool for the treatment of drug abuse.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2656312/

Δ(9) -Tetrahydrocannabinol and N-arachidonyl glycine are full agonists at GPR18 receptors and induce migration in human endometrial HEC-1B cells.

Abstract

“BACKGROUND AND PURPOSE:

Endometriosis is a disorder in which the endometrium forms growths outside the uterus and is associated with chronic pain. Recent evidence suggests that endometrial motility plays a role in the aetiology of endometriosis. The endocannabinoid system regulates cellular migration. Given the growing involvement of the endocannabinoids in reproduction, we investigated the role of the endocannabinoid system in migration of endometrial cells.

EXPERIMENTAL APPROACH:

Migration of the human endometrial HEC-1B cells was assayed. Standard PCR techniques were used to determine the presence of the GPCR, GPR18, in HEC-1B cells, and p44/42 MAPK was assayed in stably transfected HEK293-GPR18 cells to determine receptor specificity for known cannabinoid agonists and antagonists. N-arachidonoyl ethanolamine (AEA) metabolism was measured, using HPLC/MS/MS for lipid analysis.

KEY RESULTS:

AEA, Δ(9) -tetrahydrocannabinol (Δ(9) -THC) and N-arachidonoyl glycine (NAGly) induce migration of HEC-1B cells through cannabinoid CB(1) receptor-independent mechanisms. MAPK activation in HEK293-GPR18 cells revealed novel pharmacology for known CB(1) and CB(2) receptor ligands at GPR18 receptors, including Δ(9) -THC, which activates MAPK at nanomolar concentrations, whereas WIN 55212-2, CP55940, JWH-133 and JWH-015, and arachidonyl-1-hydroxy-2-propylamide (R1-methanandamide) had no effect. Moreover, HEC-1B migration and MAPK activation by NAGly and Δ(9) -THC were antagonized by Pertussis toxin, AM251 and cannabidiol.

CONCLUSIONS AND IMPLICATIONS:

An understanding of the function and regulation of GPR18 and its molecular interactions with endogenous ligands, and how phytocannabinoids play a role with GPR18 signalling is vital if we are to comprehensively assess the function of the cannabinoid signalling system in human health and disease. LINKED ARTICLES: This article is commented on by Alexander, pp. 2411-2413 of this issue and is part of a themed section on Cannabinoids in Biology and Medicine. To view Alexander visit http://dx.doi.org/10.1111/j.1476-5381.2011.01731.x. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7.”

http://www.ncbi.nlm.nih.gov/pubmed/21595653

Cannabinoids, Endocannabinoids, and Related Analogs in Inflammation.

“This review covers reports published in the last 5 years on the anti-inflammatory activities of all classes of cannabinoids, including phytocannabinoids such as tetrahydrocannabinol and cannabidiol, synthetic analogs such as ajulemic acid and nabilone, the endogenous cannabinoids anandamide and related compounds, namely, the elmiric acids, and finally, noncannabinoid components of Cannabis that show anti-inflammatory action. It is intended to be an update on the topic of the involvement of cannabinoids in the process of inflammation. A possible mechanism for these actions is suggested involving increased production of eicosanoids that promote the resolution of inflammation. This differentiates these cannabinoids from cyclooxygenase-2 inhibitors that suppress the synthesis of eicosanoids that promote the induction of the inflammatory process.”

 

“INTRODUCTION

This review is intended to be an update on the topic of the involvement of cannabinoids in the process of inflammation. Other reviews cover certain aspects of this subject and the reader is referred to them for a discussion of earlier reports. In this review are reports published in the last 5 years on the activities of all classes of cannabinoids, including the endogenous cannabinoids such as anandamide, related compounds such as the elmiric acids (EMAs), and noncannabinoid components of Cannabis that show anti-inflammatory action. An interesting recently published example of the latter one is caryophyllene, an abundant component of Cannabis oil that shows anti-inflammatory activity and has high affinity for cannabinoid receptor 2 (CB2; 5).”

 

“Phytocannabinoids: Tetrahydrocannabinol and Cannabidiol”

 

“PLANT PREPARATIONS AND NONCANNABINOID CONSTITUENTS OF CANNABIS”

“Cannabis sativa is a complex botanical, and it is not unlikely that the therapeutic benefits of marijuana are due to some of the more than 60 cannabinoids and 200–250 noncannabinoid constituents of the plant. One noncannabinoid, the geranylated flavone cannflavin A (Fig. 5), is 30 times more potent than aspirin as an inhibitor of prostaglandin E2 . These potentially important findings have been overlooked, as most attention in marijuana research has been directed to the analgesic effects of the plant and to mechanisms of psychoactivity. A further example that this line of inquiry has remained dormant is a series of overlooked observations, which demonstrate potent anti-inflammatory actions of a crude marijuana extract and of the nonpsychoactive Cannabis constituents, CBD, cannabinol, and cannabichromene in the carrageenan paw edema model of acute inflammation in rats. Volatile oil products of the plant also have biological activity. Thus, pyrolysis products may add to the therapeutic properties of smoked marijuana. Several of the most abundant cannabinoid and noncannabinoid constituents of C. sativa are nonpsychoactive.”

“Flavonoids are ubiquitous plant phenolic compounds that consist of two aromatic rings linked by a three carbon bridge. They are attracting interest because of their antioxidant, antitumor, anti-inflammatory, and antimicrobial activities. The flavone luteolin, a constituent of C. sativa, is also found in spices and in vegetables such as celery and green pepper. When added to peripheral blood mononuclear cells in vitro, luteolin suppresses production of the inflammatory cytokines TNFα, IL-1b, and IL-6, actions that relate to a selective reduction in numbers of monocytes. Perhaps more importantly, luteolin inhibits growth of Plasmodium falciparum in vitro and protects against induction of colon cancer in mice.”

“CONCLUSIONS

Possibly the very earliest literature reference on Cannabis describes its use as an anti-inflammatory agent. The Chinese emperor Shen-nung (ca. 2000 B.C.), in a work called Pen-ts’ao Ching, noted many of the effects of Cannabis in humans. Among other properties, it was claimed that cannabis “undoes rheumatism”, suggesting possible anti-inflammatory effects. The reports described in this review of the current literature provide support for the claims made by the ancient Chinese healers. These more recent publications include relief from chronic neuropathic pain, fibromyalgia, rheumatoid arthritis, and postoperative pain. In addition, a large body of preclinical data on all classes of cannabinoids, including the endogenous examples, point to a variety of therapeutic targets for cannabinoids and important roles for the endocannabinoids in the physiology of inflammation.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2664885/

Brain’s own cannabis compound protects against inflammation

“Some clinical studies have indicated that marijuana or its active cannabinoid ingredient alleviates symptoms of the inflammatory disease multiple sclerosis (MS). Also, researchers have found that the brain’s natural “endocannabinoids” are released after brain injury and are believed to alleviate neuronal damage. However, scientists have not understood how such substances act within the brain’s own immune system.

 Now, experiments by Oliver Ullrich and colleagues have pinpointed how one of the brain’s endocannabinoids protects neurons from inflammation after such damage. They say their studies could lead to new drugs to treat the inflammation and brain degeneration from MS or other such disorders.

In an article in the January 5, 2006, issue of Neuron, the researchers reported experiments showing how the endocannabinoid anandamide (AEA) protects brain cells from inflammation. Such a role in the brain’s immune system is distinct from cannabinoids’ effects on neuronal signaling that produce the behavioral effects of marijuana.”

http://www.bio-medicine.org/biology-news/Brains-own-cannabis-compound-protects-against-inflammation-2810-1/

From endocannabinoid profiling to ‘endocannabinoid therapeutics’.

Abstract

“The discovery of the endocannabinoid signalling system, that is, of cannabinoid receptors, their endogenous ligands, known as endocannabinoids, and of endocannabinoid anabolic and catabolic enzymes, raised several questions regarding the physiopathological role of these mediators. Several of these questions were answered by investigating alterations in the levels of the most studied endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), in tissues of animal models of disorders, and in bioptic samples and biological fluids (cerebrospinal fluid and blood) of human volunteers. Subsequently, the pharmacological effects of synthetic compounds that selectively target the cannabinoid CB(1) and CB(2) receptors, and endocannabinoid anabolic and catabolic enzymes, established cause-effect relationships between pathological alterations in endocannabinoid levels and the symptoms and progress of several disorders, including emesis, obesity, metabolic disorders, hepatic diseases, pain, inflammation and neurological and neuropsychiatric disorders. These new developments are discussed in this second review on the endocannabinoids, together with the results of pre-clinical and clinical studies on the potential therapeutic use of plant-derived cannabinoids and synthetic agents that manipulate pharmacologically the action at cannabinoid receptors or the tissue levels of AEA and 2-AG.”

http://www.ncbi.nlm.nih.gov/pubmed/19497779

Endocannabinoids Measurement in Human Saliva as Potential Biomarker of Obesity

Background

“The discovery of the endocannabinoid system and of its role in the regulation of energy balance has significantly advanced our understanding of the physiopathological mechanisms leading to obesity and type 2 diabetes. New knowledge on the role of this system in humans has been acquired by measuring blood endocannabinoids. Here we explored endocannabinoids and related N-acylethanolamines in saliva and verified their changes in relation to body weight status and in response to a meal or to body weight loss.”

“The discovery of the endocannabinoid system (ECS) and of its impact on the regulation of energy homeostasis represents a significant advance in the study of obesity and type 2 diabetes [1][4].”

“The saliva is the first digestive secretion produced in response to the ingestion of food [11]. Therefore, it is reasonable to investigate whether signals and systems involved in the regulation of food intake, such as the ECS, might be present in saliva and exert a functional role. Besides, saliva offers distinctive advantages over serum or plasma as a diagnostic tool, thanks to the non-invasiveness of the collection procedure.”

“The ECS is present in human salivary glands.”

“Changes in salivary endocannabinoids and N-acylethanolamines levels in response to body weight loss.”

“Here we demonstrate that endocannabinoids and related N-acylethanolamines can be reliably detected and quantified in human saliva. Similarly to what already reported for circulating levels in the blood [7], [9], [10], the salivary concentration of AEA and OEA were significantly increased in obese, insulin-resistant subjects as compared to normal weight controls.”

“the present findings overall indicate that salivary AEA might be a useful biomarker in human obesity, in particular considering that salivary samples are easy to collect, require a non-invasive procedure advantageous when performing studies in obese subjects in whom venipuncture may be difficult, and can be repeatedly collected at home by the patient during a therapeutic intervention. This type of tool could therefore be used to better phenotype the obese population, assess responses to treatment, or to further study the physiology of the ECS in humans, by investigating salivary endocannabinoid responses under various conditions.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3409167/

Biomarkers of Endocannabinoid System Activation in Severe Obesity

BACKGROUND:

“Obesity is a worldwide epidemic, and severe obesity is a risk factor for many diseases, including diabetes, heart disease, stroke, and some cancers. Endocannabinoid system (ECS) signaling in the brain and peripheral tissues is activated in obesity and plays a role in the regulation of body weight. The main research question here was whether quantitative measurement of plasma endocannabinoids, anandamide, and related N-acylethanolamines (NAEs), combined with genotyping for mutations in fatty acid amide hydrolase (FAAH) would identify circulating biomarkers of ECS activation in severe obesity.”

CONCLUSIONS/SIGNIFICANCE:

“Significantly increased levels of the endocannabinoid anandamide and related NAEs were found in carriers of the FAAH 385 A mutant alleles compared with wild-type FAAH controls. This evidence supports endocannabinoid system activation due to the effect of FAAH 385 mutant A genotype on plasma AEA and related NAE analogs. This is the first study to document that FAAH 385 A mutant alleles have a direct effect on elevated plasma levels of anandamide and related NAEs in humans. These biomarkers may indicate risk for severe obesity and may suggest novel ECS obesity treatment strategies.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2808340/

Activation of the peripheral endocannabinoid system in human obesity.

Abstract

“Obesity is the main risk factor for the development of type 2 diabetes. Activation of the central endocannabinoid system increases food intake and promotes weight gain. Blockade of the cannabinoid type 1 (CB-1) receptor reduces body weight in animals by central and peripheral actions; the role of the peripheral endocannabinoid system in human obesity is now being extensively investigated. We measured circulating endocannabinoid concentrations and studied the expression of CB-1 and the main degrading enzyme, fatty acid amide hydrolase (FAAH), in adipose tissue of lean (n = 20) and obese (n = 20) women and after a 5% weight loss in a second group of women (n = 17). Circulating levels of anandamide and 1/2-arachidonoylglycerol were increased by 35 and 52% in obese compared with lean women (P < 0.05). Adipose tissue mRNA levels were reduced by -34% for CB-1 and -59% for FAAH in obese subjects (P < 0.05). A strong negative correlation was found between FAAH expression in adipose tissue and circulating endocannabinoids. Circulating endocannabinoids and CB-1 or FAAH expression were not affected by 5% weight loss. The expression of CB-1 and FAAH was increased in mature human adipocytes compared with in preadipocytes and was found in several human tissues. Our findings support the presence of a peripheral endocannabinoid system that is upregulated in human obesity.”

“We demonstrated that the CB-1 receptor is expressed in organs relevant to the pathogenesis of obesity in humans, so that results from mechanistic studies in animals may also be applicable to patients. Furthermore, the peripheral endocannabinoid system is activated in human obesity. The observation that endocannabinoid activation is not reversible with a 5% weight loss may suggest that this activation is a cause rather than a consequence of obesity. The physiology and pathophysiology of the peripheral adipose tissue endocannabinoid system warrant further studies.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2228268/

Cannabinoid drugs and enhancement of endocannabinoid responses: strategies for a wide array of disease states.

Abstract

“The endogenous cannabinoid system has revealed potential avenues to treat many disease states. Medicinal indications of cannabinoid drugs including compounds that result in enhanced endocannabinoid responses (EER) have expanded markedly in recent years. The wide range of indications covers chemotherapy complications, tumor growth, addiction, pain, multiple sclerosis, glaucoma, inflammation, eating disorders, age-related neurodegenerative disorders, as well as epileptic seizures, traumatic brain injury, cerebral ischemia, and other excitotoxic insults. Indeed, a great effort has led to the discovery of agents that selectively activate the cannabinoid system or that enhance the endogenous pathways of cannabinergic signaling. The endocannabinoid system is comprised of three primary components: (i) cannabinoid receptors, (ii) endocannabinoid transport system, and (iii) hydrolysis enzymes that break down the endogenous ligands. Two known endocannabinoids, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG), are lipid molecules that are greatly elevated in response to a variety of pathological events. This increase in endocannabinoid levels is suggested to be part of an on-demand compensatory response. Furthermore, activation of signaling pathways mediated by the endogenous cannabinoid system promotes repair and cell survival. Similar cell maintenance effects are elicited by EER through inhibitors of the endocannabinoid deactivation processes (i.e., internalization and hydrolysis). The therapeutic potential of the endocannabinoid system has yet to be fully determined, and the number of medical maladies that may be treated will likely continue to grow. This review will underline studies that demonstrate medicinal applications for agents that influence the endocannabinoid system.”

http://www.ncbi.nlm.nih.gov/pubmed/17022737

The Endocannabinoid System and the Brain.

Abstract

“The psychoactive constituent in cannabis, Δ(9)-tetrahydrocannabinol (THC), was isolated in the mid-1960s, but the cannabinoid receptors, CB1 and CB2, and the major endogenous cannabinoids (anandamide and 2-arachidonoyl glycerol) were identified only 20 to 25 years later. The cannabinoid system affects both central nervous system (CNS) and peripheral processes. In this review, we have tried to summarize research-with an emphasis on recent publications-on the actions of the endocannabinoid system on anxiety, depression, neurogenesis, reward, cognition, learning, and memory. The effects are at times biphasic-lower doses causing effects opposite to those seen at high doses. Recently, numerous endocannabinoid-like compounds have been identified in the brain. Only a few have been investigated for their CNS activity, and future investigations on their action may throw light on a wide spectrum of brain functions. Expected final online publication date for the Annual Review of Psychology Volume 64 is November 30, 2012. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.”

http://www.ncbi.nlm.nih.gov/pubmed/22804774