Endocannabinoids in the regulation of appetite and body weight

The discovery of cannabinoid receptors, together with the development of selective cannabinoid receptor antagonists, has encouraged a resurgence of cannabinoid pharmacology. With the identification of endogenous agonists, such as anandamide, scientists have sought to uncover the biological role of endocannabinoid systems; initially guided by the long-established actions of cannabis and exogenous cannabinoids such as delta9-tetrahydrocannabinol (THC). In particular, considerable research has examined endocannabinoid involvement in appetite, eating behaviour and body weight regulation. It is now confirmed that endocannabinoids, acting at brain CB1 cannabinoid receptors, stimulate appetite and ingestive behaviours, partly through interactions with more established orexigenic and anorexigenic signals. Key structures such as the nucleus accumbens and hypothalamic nuclei are sensitive sites for the hyperphagic actions of these substances, and endocannabinoid activity in these regions varies in relation to nutritional status and feeding expression. Behavioural studies indicate that endocannabinoids increase eating motivation by enhancing the incentive salience and hedonic evaluation of ingesta. Moreover, there is strong evidence of an endocannabinoid role in energy metabolism and fuel storage. Recent developments point to potential clinical benefits of cannabinoid receptor antagonists in the management of obesity, and of agonists in the treatment of other disorders of eating and body weight regulation.     

The Endocannabinoids Anandamide and Virodhamine Modulate the Activity of the Candidate Cannabinoid Receptor GPR55

The role of cannabinoid receptors in inflammation has been the topic of many research endeavors. Despite this effort, to date the involvement of the endocannabinoid system (ECS) in inflammation remains obscure. The ambiguity of cannabinoid involvement may be explained by the existence of cannabinoid receptors, other than CB₁ and CB₂, or a consequence of interaction of endocannabinoids with other signaling systems. GPR55 has been proposed to be a cannabinoid receptor; however the interaction of the endocannabinoid system with GPR55 remains elusive. Consequently this study set about to examine the effects of the endocannabinoids, anandamide (AEA) and virodhamine, on GPR55 mediated signaling. Specifically, we assessed changes in ??-arrestin2 (??arr2) distribution and GPR55 receptor internalization following activation by lysophosphatidylinositol (LPI), the synthetic cannabinoid ligand SR141716A, and new selective synthetic GPR55 agonists. Data obtained from the experiments presented herein demonstrate that AEA and virodhamine modulate agonist-mediated recruitment of ??arr2. AEA and virodhamine act as partial agonists; enhancing the agonist effect at low concentrations and inhibiting it at high concentrations. Furthermore, both virodhamine and AEA significantly attenuated agonist-induced internalization of GPR55. These effects are attributed to the expression of GPR55, and not CB₁ and CB₂ receptors, as we have established negligible expression of CB₁ and CB₂ in these GPR55-transfected U2OS cells. The identification of select endocannabinoids as GPR55 modulators will aide in elucidating the function of GPR55 in the ECS.     

Cannabinoid receptor ligands: clinical and neuropharmacological considerations,relevant to future drug discovery and development

This review highlights some important advances that have taken place in cannabinoid research over the last four years. It focuses on novel ligands that are of interest either as experimental tools or as lead compounds for therapeutic agents and possible clinical applications for some of these ligands. The molecular targets for these compounds are various components of the system of endogenous cannabinoids (endocannabinoids) and receptors that together constitute the 'endocannabinoid system'. These are CB1 cannabinoid receptors that are present mainly on central and peripheral neurones, CB2 cannabinoid receptors that are expressed predominantly by immune cells, the biochemical mechanisms responsible for the tissue uptake or metabolism of endocannabinoids and vanilloid receptors. Other cannabinoid receptor types may also exist. Recently developed ligands include potent and selective agonists for CB1 and CB2 receptors, a potent CB2-selective antagonist/inverse agonist and inhibitors of endocannabinoid uptake or metabolism. Future research should be directed at characterising the endocannabinoid system more completely and at obtaining more conclusive clinical data about the possible beneficial effects of cannabinoids as well as their adverse effects. There is also a need for improved cannabinoid formulations/modes of administration in the clinic and advances in this area should be facilitated by the recent development of a potent water-soluble CB1/CB2 receptor agonist. A growing number of strategies for separating sought-after therapeutic effects of cannabinoid receptor agonists from the unwanted consequences of CB1 receptor activation are now emerging and these are discussed at the end of this review.     

Bidirectional cannabinoid modulation of social behavior in adolescent rats

Rationale Marijuana use in adolescents is a highly social activity, and interacting endocannabinoid and opioid systems may modulate social reward. However, cannabinoid exposure has been reported to reduce social behavior. Objectives The aim of this study was to elucidate the mechanisms underlying the paradoxical relationship between cannabinoid exposure and sociability. Materials and methods We investigated the effect of cannabinoid agonists with a different mechanism of action on social play behavior in adolescent rats. In addition, we examined whether endocannabinoid neurotransmission interacts with opioid and dopaminergic neurotransmission in the modulation of social play behavior. Results The direct CB₁ cannabinoid receptor agonist WIN55,212-2 reduced social play. However, the indirect cannabinoid agonist URB597, which inhibits the hydrolysis of the endocannabinoid anandamide, enhanced social play. This effect of URB597 depended upon stimulation of opioid and dopamine receptors. The well-known stimulatory effect of morphine on social play was attenuated by the CB₁ cannabinoid receptor antagonist SR141716A, but independent of dopamine receptor stimulation. Combined treatment with ineffective doses of URB597 and morphine increased social play. Conclusions Cannabinoid neurotransmission can both enhance and inhibit social interaction in adolescent rats depending on how the endocannabinoid system is stimulated. Activation of cannabinoid receptors throughout the brain, which occurs during cannabis use, inhibits sociability. In contrast, on-demand release of endocannabinoids facilitates social interaction, which is magnified by indirect cannabinoid agonists through an interaction with opioid and dopaminergic neurotransmission. These results shed light on the paradoxical relationship between cannabis exposure and sociability and suggest that endocannabinoid degradation inhibitors hold promise for the treatment of social dysfunctions.     

Cannabinoid receptor ligands: clinical and neuropharmacological considerations, relevant to future drug discovery and development

This review highlights some important advances that have taken place in cannabinoid research over the last four years. It focuses on novel ligands that are of interest either as experimental tools or as lead compounds for therapeutic agents and possible clinical applications for some of these ligands. The molecular targets for these compounds are various components of the system of endogenous cannabinoids (endocannabinoids) and receptors that together constitute the 'endocannabinoid system'. These are CB(1) cannabinoid receptors that are present mainly on central and peripheral neurones, CB(2) cannabinoid receptors that are expressed predominantly by immune cells, the biochemical mechanisms responsible for the tissue uptake or metabolism of endocannabinoids and vanilloid receptors. Other cannabinoid receptor types may also exist. Recently developed ligands include potent and selective agonists for CB(1) and CB(2) receptors, a potent CB(2)-selective antagonist/inverse agonist and inhibitors of endocannabinoid uptake or metabolism. Future research should be directed at characterising the endocannabinoid system more completely and at obtaining more conclusive clinical data about the possible beneficial effects of cannabinoids as well as their adverse effects. There is also a need for improved cannabinoid formulations/modes of administration in the clinic and advances in this area should be facilitated by the recent development of a potent water-soluble CB(1)/CB(2) receptor agonist. A growing number of strategies for separating sought-after therapeutic effects of cannabinoid receptor agonists from the unwanted consequences of CB(1) receptor activation are now emerging and these are discussed at the end of this review.     

Neuropharmacology of the endocannabinoid signaling system-molecular mechanisms, biological actions and synaptic plasticity

The endocannabinoid signaling system is composed of the cannabinoid receptors; their endogenous ligands, the endocannabinoids; the enzymes that produce and inactivate the endocannabinoids; and the endocannabinoid transporters. The endocannabinoids are a new family of lipidic signal mediators, which includes amides, esters, and ethers of long-chain polyunsaturated fatty acids. Endocannabinoids signal through the same cell surface receptors that are targeted by Delta(9)-tetrahydrocannabinol (Delta(9)THC), the active principles of cannabis sativa preparations like hashish and marijuana. The biosynthetic pathways for the synthesis and release of endocannabinoids are still rather uncertain. Unlike neurotransmitter molecules that are typically held in vesicles before synaptic release, endocannabinoids are synthesized on demand within the plasma membrane. Once released, they travel in a retrograde direction and transiently suppress presynaptic neurotransmitter release through activation of cannabinoid receptors. The endocannabinoid signaling system is being found to be involved in an increasing number of pathological conditions. In the brain, endocannabinoid signaling is mostly inhibitory and suggests a role for cannabinoids as therapeutic agents in central nervous system (CNS) disease. Their ability to modulate synaptic efficacy has a wide range of functional consequences and provides unique therapeutic possibilities. The present review is focused on new information regarding the endocannabinoid signaling system in the brain. First, the structure, anatomical distribution, and signal transduction mechanisms of cannabinoid receptors are described. Second, the synthetic pathways of endocannabinoids are discussed, along with the putative mechanisms of their release, uptake, and degradation. Finally, the role of the endocannabinoid signaling system in the CNS and its potential as a therapeutic target in various CNS disease conditions, including alcoholism, are discussed.     

Endocannabinoids and food consumption: comparisons with benzodiazepine and opioid palatability-dependent appetite

The endocannabinoid system consists of several endogenous lipids, including anandamide and 2-arachidonoyl-glycerol (2-AG), and constitute a retrograde signalling system, which modulates neurotransmitter release and synaptic plasticity. Specific brain-type cannabinoid receptors (CB₁) are widely distributed in the central nervous system, and are localized presynaptically. Mounting evidence, reviewed here, indicates that cannabinoids can act to increase food consumption, and cannabinoid CB₁ receptor antagonists/inverse agonists reduce food intake and suppress operant responding for food rewards. Hence, endocannabinoids provide the first example of a retrograde signalling system, which is strongly implicated in the control of food intake. Benzodiazepine and opioid palatability-dependent appetite are well-established processes supported by several sources of convergent evidence; they provide pharmacological benchmarks against which to evaluate the endocannabinoids. To date, evidence that endocannabinoids specifically modulate palatability as an affective evaluative process is insufficient and not compelling. Endocannabinoids may have important clinical utility in the treatment of human obesity and forms of eating disorders.     

The endocannabinoid system as an emerging target of pharmacotherapy

The recent identification of cannabinoid receptors and their endogenous lipid ligands has triggered an exponential growth of studies exploring the endocannabinoid system and its regulatory functions in health and disease. Such studies have been greatly facilitated by the introduction of selective cannabinoid receptor antagonists and inhibitors of endocannabinoid metabolism and transport, as well as mice deficient in cannabinoid receptors or the endocannabinoid-degrading enzyme fatty acid amidohydrolase. In the past decade, the endocannabinoid system has been implicated in a growing number of physiological functions, both in the central and peripheral nervous systems and in peripheral organs. More importantly, modulating the activity of the endocannabinoid system turned out to hold therapeutic promise in a wide range of disparate diseases and pathological conditions, ranging from mood and anxiety disorders, movement disorders such as Parkinson's and Huntington's disease, neuropathic pain, multiple sclerosis and spinal cord injury, to cancer, atherosclerosis, myocardial infarction, stroke, hypertension, glaucoma, obesity/metabolic syndrome, and osteoporosis, to name just a few. An impediment to the development of cannabinoid medications has been the socially unacceptable psychoactive properties of plant-derived or synthetic agonists, mediated by CB(1) receptors. However, this problem does not arise when the therapeutic aim is achieved by treatment with a CB(1) receptor antagonist, such as in obesity, and may also be absent when the action of endocannabinoids is enhanced indirectly through blocking their metabolism or transport. The use of selective CB(2) receptor agonists, which lack psychoactive properties, could represent another promising avenue for certain conditions. The abuse potential of plant-derived cannabinoids may also be limited through the use of preparations with controlled composition and the careful selection of dose and route of administration. The growing number of preclinical studies and clinical trials with compounds that modulate the endocannabinoid system will probably result in novel therapeutic approaches in a number of diseases for which current treatments do not fully address the patients' need. Here, we provide a comprehensive overview on the current state of knowledge of the endocannabinoid system as a target of pharmacotherapy.     

Cannabinoids

Since the discovery of an endogenous cannabinoid system, research into the pharmacology and therapeutic potential of cannabinoids has steadily increased. Two subtypes of G-protein coupled cannabinoid receptors, CB(1) and CB(1), have been cloned and several putative endogenous ligands (endocannabinoids) have been detected during the past 15 years. The main endocannabinoids are arachidonoyl ethanolamide (anandamide) and 2-arachidonoyl glycerol (2-AG), derivatives of arachidonic acid, that are produced "on demand" by cleavage of membrane lipid precursors. Besides phytocannabinoids of the cannabis plant, modulators of the cannabinoid system comprise synthetic agonists and antagonists at the CB receptors and inhibitors of endocannabinoid degradation. Cannabinoid receptors are distributed in the central nervous system and many peripheral tissues, including immune system, reproductive and gastrointestinal tracts, sympathetic ganglia, endocrine glands, arteries, lung and heart. There is evidence for some non-receptor dependent mechanisms of cannabinoids and for endocannabinoid effects mediated by vanilloid receptors. Properties of CB receptor agonists that are of therapeutic interest include analgesia, muscle relaxation, immunosuppression, anti-inflammation, antiallergic effects, improvement of mood, stimulation of appetite, antiemesis, lowering of intraocular pressure, bronchodilation, neuroprotection and antineoplastic effects. The current main focus of clinical research is their efficacy in chronic pain and neurological disorders. CB receptor antagonists are under investigation for medical use in obesity and nicotine addiction. Additional potential was proposed for the treatment of alcohol and heroine dependency, schizophrenia, conditions with lowered blood pressure, Parkinson's disease and memory impairment in Alzheimer's disease.     

Pro-drugs for indirect cannabinoids as therapeutic agents

Medicinal cannabis, cannabis extracts, and other cannabinoids are currently in use or under clinical trial investigation for the control of nausea, emesis and wasting in patients undergoing chemotherapy, the control of neuropathic pain and arthritic pain, and the control of the symptoms of multiple sclerosis. The further development of medicinal cannabinoids has been challenged with problems. These include the psychoactivity of cannabinoid CB1 receptor agonists and the lack of availability of highly selective cannabinoid receptor full agonists (for the CB1 or CB2 receptor), as well as problems of pharmacokinetics. Global activation of cannabinoid receptors is usually undesirable, and so enhancement of local endocannabinoid receptor activity with indirect cannabimimetics is an attractive strategy for therapeutic modulation of the endocannabinoid system. However, existing drugs of this type tend to be metabolized by the same enzymes as their target endocannabinoids and are not yet available in a form that is clinically useful. A potential solution to these problems may now have been suggested by the discovery that paracetamol (acetaminophen) exerts its analgesic (and probably anti-pyretic) effects by its degradation into an anandamide (an endocannabinoid) reuptake inhibitor (AM404) within the body, thus classifying it as pro-drug for an indirect cannabimimetic. Given the proven efficacy and safety of paracetamol, the challenge now is to develop related drugs, or entirely different substrates, into pro-drug indirect cannabimimetics with a similar safety profile to paracetamol but at high effective dose titrations.     

Endocannabinoid tone versus constitutive activity of cannabinoid receptors

This review evaluates the cellular mechanisms of constitutive activity of the cannabinoid (CB) receptors, its reversal by inverse agonists, and discusses the pitfalls and problems in the interpretation of the research data. The notion is presented that endogenously produced anandamide (AEA) and 2-arachidonoylglycerol (2-AG) serve as autocrine or paracrine stimulators of the CB receptors, giving the appearance of constitutive activity. It is proposed that one cannot interpret inverse agonist studies without inference to the receptors' environment vis-à-vis the endocannabinoid agonists which themselves are highly lipophilic compounds with a preference for membranes. The endocannabinoid tone is governed by a combination of synthetic pathways and inactivation involving transport and degradation. The synthesis and degradation of 2-AG is well characterized, and 2-AG has been strongly implicated in retrograde signalling in neurons. Data implicating endocannabinoids in paracrine regulation have been described. Endocannabinoid ligands can traverse the cell's interior and potentially be stored on fatty acid-binding proteins (FABPs). Molecular modelling predicts that the endocannabinoids derived from membrane phospholipids can laterally diffuse to enter the CB receptor from the lipid bilayer. Considering that endocannabinoid signalling to CB receptors is a much more likely scenario than is receptor activation in the absence of agonist ligands, researchers are advised to refrain from assuming constitutive activity except for experimental models known to be devoid of endocannabinoid ligands.     

"The tools of the trade"--an overview of the pharmacology of the endocannabinoid system

The endocannabinoid system can be manipulated pharmacologically in a variety of ways, including directly acting agonists and inverse agonists, and indirectly acting compounds which affect the synthesis, cellular accumulation and metabolism of the two main endocannabinoids, anandamide and 2-arachidonoylglycerol. In this overview, the most commonly used compounds are discussed, primarily with respect to their targets of action and to their selectivities vis a vis "off targets". For direct acting compounds such as cannabinoid receptor agonists, it is suggested that the use of several compounds with different chemical structures at relevant doses or concentrations is likely to minimise the risk of misinterpreting an "off target" effect as being an action mediated by cannabinoid receptors. For indirectly acting compounds, the same reasoning applies, and in the case of compounds affecting the accumulation of anandamide, it is important to recognize that the molecular target of these compounds is far from clear. Nonetheless, judicious use of the array of pharmacological tools currently available, and combination of these tools with RNA interference techniques and the use of genetically modified animals, provides a powerful approach with which to characterize the endocannabinoid system in the body.     

The therapeutic potential of drugs that target cannabinoid receptors or modulate the tissue levels or actions of endocannabinoids

There are at least 2 types of cannabinoid receptor, CB(1) and CB(2), both G protein coupled. CB(1) receptors are expressed predominantly at nerve terminals and mediate inhibition of transmitter release, whereas CB(2) receptors are found mainly on immune cells, their roles including the modulation of cytokine release and of immune cell migration. Endogenous agonists for cannabinoid receptors also exist. These "endocannabinoids" are synthesized on demand and removed from their sites of action by cellular uptake and intracellular enzymic hydrolysis. Endocannabinoids and their receptors together constitute the endocannabinoid system. This review summarizes evidence that there are certain central and peripheral disorders in which increases take place in the release of endocannabinoids onto their receptors and/or in the density or coupling efficiency of these receptors and that this upregulation is protective in some disorders but can have undesirable consequences in others. It also considers therapeutic strategies by which this upregulation might be modulated to clinical advantage. These strategies include the administration of (1) a CB(1) and/or CB(2) receptor agonist or antagonist that does or does not readily cross the blood brain barrier; (2) a CB(1) and/or CB(2) receptor agonist intrathecally or directly to some other site outside the brain; (3) a partial CB(1) and/or CB(2) receptor agonist rather than a full agonist; (4) a CB(1) and/or CB(2) receptor agonist together with a noncannabinoid, for example, morphine or codeine; (5) an inhibitor or activator of endocannabinoid biosynthesis, cellular uptake, or metabolism; (6) an allosteric modulator of the CB(1) receptor; and (7) a CB(2) receptor inverse agonist.     

The role of endocannabinoids in pain modulation and the therapeutic potential of inhibiting their enzymatic degradation

The need for new pain therapies that provide greater relief without unwanted side-effects drives the search for new drug targets. The identification of endogenous lipid ligands for the two known cannabinoid receptors (CB(1) and CB(2)) has led to numerous studies investigating the role of these endocannabinoids in pain processes. The two most widely studied endocannabinoids are anandamide (AEA; arachidonoyl ethanolamide) and 2-arachidonoylglycerol (2-AG), but there are also a number of structurally related endogenous lipid signaling molecules that are agonists at cannabinoid and noncannabinoid receptors. These lipid signaling molecules are not stored in synaptic vesicles, but are synthesized and released on-demand and act locally, as they are rapidly inactivated. This suggests that there may be therapeutic potential in modulating levels of these ligands to only have effects in active neural pathways, thereby reducing the potential for side-effects that result from widespread systemic cannabinoid receptor activation. One approach to modulate the levels and duration of action of these lipid signaling molecules is to target the enzymes responsible for their hydrolysis. The two main enzymes responsible for hydrolysis of these lipid signaling molecules are fatty acid amide hydrolase (FAAH) and monoacylglyceride lipase (MGL). This article will discuss the role of the endocannabinoid system in the modulation of pain and will review the current understanding of the properties of the hydrolytic enzymes and the recent advances in developing inhibitors for these targets, with particular relevance to the treatment of pain.     

The biosynthesis, fate and pharmacological properties of endocannabinoids

The finding of endogenous ligands for cannabinoid receptors, the endocannabinoids, opened a new era in cannabinoid research. It meant that the biological role of cannabinoid signalling could be finally studied by investigating not only the pharmacological actions subsequent to stimulation of cannabinoid receptors by their agonists, but also how the activity of these receptors was regulated under physiological and pathological conditions by varying levels of the endocannabinoids. This in turn meant that the enzymes catalysing endocannabinoid biosynthesis and inactivation had to be identified and characterized, and that selective inhibitors of these enzymes had to be developed to be used as (1) probes to confirm endocannabinoid involvement in health and disease, and (2) templates for the design of new therapeutic drugs. This chapter summarizes the progress achieved in this direction during the 12 years following the discovery of the first endocannabinoid.     

The endocannabinoid signalling system: biochemical aspects

Knowledge of the endogenous cannabinoid system has expanded greatly during the past years. After the discovery of the cannabinoid receptors, of their endogenous agonists and of the proteins for their synthesis and inactivation, significant progress has been made towards the understanding of the role of the endocannabinoid system in vital functions. Subsequently, an increasing number of papers has been published on the biochemistry and pharmacology of endocannabinoids. This article overviews the endocannabinoid signalling system with focus on its biochemical aspects. In particular we review the mechanisms for the biosynthesis and inactivation of the endocannabinoids, as well as the various molecular targets for some of the endocannabinoids described so far.     

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

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, rimon-abant, 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.     

Expression and function of CB1 receptor in the rat striatum: localization and effects on D1 and D2 dopamine receptor-mediated motor behaviors.

Cannabinoid CB1 receptors are densely expressed on striatal projection neurons expressing dopamine D1 or D2 receptors. However, the specific neuronal distribution of CB1 receptors within the striatum is not known. Previous research has established that the endocannabinoid system controls facilitation of behavior by dopamine D2 receptors, but it is not clear if endocannabinoids also modulate D1 receptor-mediated motor behavior. In the present study, we show that cannabinoid CB1 receptor mRNA is present in striatonigral neurons expressing substance P and dopamine D1 receptors, as well as in striatopallidal neurons expressing enkephalin and dopamine D2 receptors. We explored the functional relevance of the interaction between dopamine D1 and D2 receptors and cannabinoid CB1 receptors with behavioral pharmacology experiments. Potentiation of endogenous cannabinoid signaling by the uptake blocker AM404 blocked dopamine D1 receptor-mediated grooming and D2 receptor-mediated oral stereotypies. In addition, contralateral turning induced by unilateral intrastriatal infusion of D1 receptor agonists is counteracted by AM404 and potentiated by the cannabinoid antagonist SR141716A. These results indicate that the endocannabinoid system negatively modulates D1 receptor-mediated behaviors in addition to its previously described effect on dopamine D2 receptor-mediated behaviors. The effect of AM404 on grooming behavior was absent in dopamine D1 receptor knockout mice, demonstrating its dependence on D1 receptors. This study indicates that the endocannabinoid system is a relevant negative modulator of both dopamine D1 and D2 receptor-mediated behaviors, a finding that may contribute to our understanding of basal ganglia motor disorders.     

The endocannabinoid system in the cancer therapy: an overview

The endocannabinoid system comprises the cannabinoid receptors type 1 (CB1) and type 2 (CB2), their endogenous ligands (endocannabinoids), and the proteins responsible for their biosynthesis and degradation. This ubiquitous signalling system, that has attracted a great deal of scientist interest in the past 15 years, regulates several physiological and pathological functions. In mammals, among other functions, the endocannabinoid is involved in nervous, cardiovascular, metabolic, reproductive and immune functions. Finally, yet importantly, endocannabinoids are known to exert important antiproliferative actions in a great number of tumor cells including breast, brain, skin, thyroid, prostate and colorectal. The following review describes our current knowledge on the effects of two of the most studied endocannabinoids (AEA and 2-AG) on various types of tumor and summarizes the possible mechanism of observed antitumor effects.     

Gastrointestinal endocannabinoid system: multifaceted roles in the healthy and inflamed intestine

1. The endogenous cannabinoid (endocannabinoid) system is emerging as a key modulator of intestinal physiology, influencing motility, secretion, epithelial integrity and immune function in the gut, in addition to influencing satiety and emesis. 2. Accumulating evidence suggests that the endocannabinoid system may play a pivotal role in the pathophysiology of gastrointestinal disease, particularly in the light of recent studies demonstrating an effect of endocannabinoids on the development of experimental inflammation and linkages with functional clinical disorders characterized by altered motility. 3. The predominant endocannabinoids, anandamide and 2-arachidonoylglycerol, not only mediate their effects via two recognized cannabinoid receptor subtypes, namely CB(1) and CB(2), but emerging evidence now shows they are also substrates for cyclo-oxygenase (COX)-2, generating a distinct and novel class of prostaglandin ethanolamides (prostamides) and prostaglandin glycerol esters. These compounds are bioactive and may mediate an array of biological effects distinct to those of conventional prostanoids. 4. The effects of prostamides on gastrointestinal motility, secretion, sensation and immune function have not been characterized extensively. Prostamides may play an important role in gastrointestinal inflammation, particularly given the enhanced expression of both COX-2 and endocannabinoids that occurs in the inflamed gut. 5. Further preclinical studies are needed to determine the therapeutic potential of drugs targeting the endocannabinoid system in functional and inflammatory gut disorders, to assist with the determination of feasibility for clinical translation.