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A simple and sustainable propylphosphonic anhydride (T3P)-assisted methodology for the synthesis of N-acyl tryptamines, an interesting class of gut microbiota-derived endocannabinoid-like lipid mediators, was proposed. This protocol is characterized by great operational simplicity, and all products were obtained at room temperature, without the use of an inert atmosphere and by using limited amounts of non-halogenated solvents. Finally, the possibility to realize the reaction under mechanochemical conditions was explored with interesting results. [ABSTRACT FROM AUTHOR]

The synthesis of some N-(3-acyloxyacyl)glycines, an interesting class of bioactive gut microbiota metabolites, is described. This procedure involves seven reaction steps using the commercially available Meldrum's acid to obtain highly pure products, in normal or deuterated form. The key point of the synthetic strategy was the use of commendamide t-butyl ester as a synthetic intermediate, a choice that allowed the removal of the protecting group at the end of the synthetic procedure without degrading of the other ester bond present in the molecule. The developed synthetic sequence is particularly simple, uses readily available reagents and involves a limited number of purifications by chromatographic column, with a reduction in the volume of solvent and energy used. [ABSTRACT FROM AUTHOR]

The endocannabinoidome (eCBome) is defined as an ensemble of (1) lipid mediators bearing chemical and, to some extent, biochemical and functional similarity with the two endogenous ligands of cannabinoid type-1 and type-2 (CB1 and CB2, respectively) receptors, that is, the endocannabinoids (eCBs) I N i -arachidonoyl-ethanolamine (anandamide, AEA) and 2-arachidonoyl-glycerol (2-AG); (2) the molecular targets for these mediators; and (3) their anabolic and catabolic enzymes.[1] By definition, the eCBome thus includes the eCBs as well as several families of eCB-like molecules, and proteins controlling their levels or mediating their actions. A microbiome-dependent gut-brain pathway regulates motivation for exercise. Effect of gut microbiota on depressive-like behaviors in mice is mediated by the endocannabinoid system. [Extracted from the article]

The discovery of the endocannabinoidome (eCBome) is evolving gradually with yet to be elucidated functional lipid mediators and receptors. The diet modulates these bioactive lipids and the gut microbiome, both working in an entwined alliance. Mounting evidence suggests that, in different ways and with a certain specialisation, lipid signalling mediators such as N-acylethanolamines (NAEs), 2-monoacylglycerols (2-MAGs), and N-acyl-amino acids (NAAs), along with endocannabinoids (eCBs), can modulate physiological mechanisms underpinning appetite, food intake, macronutrient metabolism, pain sensation, blood pressure, mood, cognition, and immunity. This knowledge has been primarily utilised in pharmacology and medicine to develop many drugs targeting the fine and specific molecular pathways orchestrating eCB and eCBome activity. Conversely, the contribution of dietary NAEs, 2-MAGs and eCBs to the biological functions of these molecules has been little studied. In this review, we discuss the importance of (Wh) olistic (E)ndocannabinoidome-Microbiome-Axis Modulation through (N) utrition (WHEN), in the management of obesity and related disorders. [ABSTRACT FROM AUTHOR]

The discovery of the endocannabinoidome (eCBome) is evolving gradually with yet to be elucidated functional lipid mediators and receptors. The diet modulates these bioactive lipids and the gut microbiome, both working in an entwined alliance. Mounting evidence suggests that, in different ways and with a certain specialisation, lipid signalling mediators such as N-acylethanolamines (NAEs), 2-monoacylglycerols (2-MAGs), and N-acyl-amino acids (NAAs), along with endocannabinoids (eCBs), can modulate physiological mechanisms underpinning appetite, food intake, macronutrient metabolism, pain sensation, blood pressure, mood, cognition, and immunity. This knowledge has been primarily utilised in pharmacology and medicine to develop many drugs targeting the fine and specific molecular pathways orchestrating eCB and eCBome activity. Conversely, the contribution of dietary NAEs, 2-MAGs and eCBs to the biological functions of these molecules has been little studied. In this review, we discuss the importance of (Wh) olistic (E)ndocannabinoidome-Microbiome-Axis Modulation through (N) utrition (WHEN), in the management of obesity and related disorders. [ABSTRACT FROM AUTHOR]

Palmitoylethanolamide (PEA) has emerged as a potential nutraceutical, because this compound is naturally produced in many plant and animal food sources, as well as in cells and tissues of mammals, and endowed with important neuroprotective, anti-inflammatory and analgesic actions. Several efforts have been made to identify the molecular mechanism of action of PEA and explain its multiple effects both in the central and the peripheral nervous system. Here, we provide an overview of the pharmacology, efficacy and safety of PEA in neurodegenerative disorders, pain perception and inflammatory diseases. The current knowledge of new formulations of PEA with smaller particle size (i.e. micronized and ultra-micronized) when given alone or in combination with antioxidant flavonoids (i.e. luteolin) and stilbenes (i.e. polydatin) is also reviewed.Linked Articles: This article is part of a themed section on Principles of Pharmacological Research of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.11/issuetoc. [ABSTRACT FROM AUTHOR]

The endocannabinoid system (ECS) is composed of two G protein-coupled receptors (GPCRs), the cannabinoid CB1 and CB2 receptors, and the two main endogenous lipid ligands of such receptors (also known as the “endocannabinoids”), anandamide and 2-arachidonoyl-glycerol. The ECS is a pleiotropic signalling system involved in all aspects of mammalian physiology and pathology, and for this reason it represents a potential target for the design and development of new therapeutic drugs. However, the endocannabinoids as well as some of their congeners also interact with a much wider range of receptors, including members of the Transient Receptor Potential (TRP) channels, Peroxisome Proliferator-Activated Receptors (PPARs), and other GPCRs. Indeed, following the discovery of the endocannabinoids, endocannabinoid-related lipid mediators, which often share the same metabolic pathways of the endocannabinoids, have also been identified or rediscovered. In this review article, we discuss the role of endocannabinoids and related lipids during physiological functions, as well as their involvement in some of the most common neurological disorders. [ABSTRACT FROM AUTHOR]

A series of 31 arylboronic acids designed on the basis of the pharmacophore model for a variety of TRPV1 antagonists was prepared and tested on FAAH and TRPV1 channel. Four of them, that is, compounds 3c , 4a , 5a , b acted as dual FAAH/TRPV1 blockers with IC 50 values between 0.56 and 8.11 μM whereas ten others (compounds 1c , f – i , 2c – f , 4b ) inhibited FAAH and activated/desensitized TRPV1. [ABSTRACT FROM AUTHOR]

Chronic diseases are due to deviations of fundamental physiological systems, with different pathologies being characterised by similar malfunctioning biological networks. The ensuing compensatory mechanisms may weaken the body's dynamic ability to respond to further insults and reduce the efficacy of conventional single target treatments. The multitarget, systemic, and prohomeostatic actions emerging for plant cannabinoids exemplify what might be needed for future medicines. Indeed, two combined cannabis extracts were approved as a single medicine (Sativex ® ), while pure cannabidiol, a multitarget cannabinoid, is emerging as a treatment for paediatric drug-resistant epilepsy. Using emerging cannabinoid medicines as an example, we revisit the concept of polypharmacology and describe a new empirical model, the ‘therapeutic handshake’, to predict efficacy/safety of compound combinations of either natural or synthetic origin. [ABSTRACT FROM AUTHOR]

The article discusses cannabinoid medicines. Topics including Tetrahydrocannabinol (THC) and cannabidiol (CBD) are primarily studied, particularly because high-grade Cannabis subspecies can produce over 20 percent yield of either compound; THC action in humans is dependent on the CB1 cannabinoid receptor which is the most abundant G protein–coupled receptor (GPCR) in the brain; and CBD is thought to have anti-inflammatory and tissue-protective effects.

Regulatory authorities admit clinical studies with an initial enrichment phase to select patients that respond to treatment before randomization (Enriched Design Studies; EDSs). The trial period aims to prevent long-term drug exposure risks in patients with limited chances of improvement while optimizing costs. In EDSs for symptom control therapies providing early improvements and without a wash-out period, it is difficult to show further improvements and thus large therapeutic gains versus placebo. Moreover, in trials with cannabinoids, the therapeutic gains can be further biased in the postenrichment randomized phase because of carryover and other effects. The aims of the present review article are to examine the placebo effects in the enrichment and postenrichment phases of an EDS with Δ9-tetrahydrocannabinol and cannabidiol ( THC/ CBD) oromucosal spray in patients with multiple sclerosis ( MS) spasticity and to discuss the possible causes of maintained efficacy after randomization in the placebo-allocated patients. The overall mean therapeutic gain of THC/ CBD spray over placebo in resistant MS spasticity after 16 weeks can be estimated as a ~1.27-point improvement on the spasticity 0-10 Numerical Rating Scale ( NRS; ~−20.1% of the baseline NRS score). We conclude that careful interpretation of the results of EDSs is required, especially when cannabinoid-based medications are being investigated. [ABSTRACT FROM AUTHOR]

Ageing is characterized by the progressive impairment of physiological functions and increased risk of developing debilitating disorders, including chronic inflammation and neurodegenerative diseases. These disorders have common molecular mechanisms that can be targeted therapeutically. In the wake of the approval of the first cannabinoid-based drug for the symptomatic treatment of multiple sclerosis, we examine how endocannabinoid (eCB) signalling controls - and is affected by - normal ageing and neuroinflammatory and neurodegenerative disorders. We propose a conceptual framework linking eCB signalling to the control of the cellular and molecular hallmarks of these processes, and categorize the key components of endocannabinoid signalling that may serve as targets for novel therapeutics. [ABSTRACT FROM AUTHOR]

Ageing is characterized by the progressive impairment of physiological functions and increased risk of developing debilitating disorders, including chronic inflammation and neurodegenerative diseases. These disorders have common molecular mechanisms that can be targeted therapeutically. In the wake of the approval of the first cannabinoid-based drug for the symptomatic treatment of multiple sclerosis, we examine how endocannabinoid (eCB) signalling controls--and is affected by--normal ageing and neuroinflammatory and neurodegenerative disorders. We propose a conceptual framework linking eCB signalling to the control of the cellular and molecular hallmarks of these processes, and categorize the key components of endocannabinoid signalling that may serve as targets for novel therapeutics. [ABSTRACT FROM AUTHOR]

Simple Summary: Dysbiosis, which is an imbalance of gut microbial composition and function, can be caused by several external as well as internal factors, contributing to the onset of human and animal disorders, not limited to the gastrointestinal tract. Accordingly, the mechanisms leading to disease development involve a crucial interaction between the gut microbiota, their metabolic products, and the host. The expanded endocannabinoid system, also known as the "endocannabinoidome", includes endocannabinoids (e.g., anandamide) and endocannabinoid-like mediators (e.g., palmitoylethanolamide), their receptors and metabolic enzymes. Dysregulation of this newly recognized endogenous system is also involved in several diseases. It is becoming increasingly apparent that a link between the endocannabinoidome and the gut microbiome exists. Here, we review some of the latest discoveries related to the functional link between these two complex systems and the disorders emerging from the malfunctioning of such a mutual interaction: for example, idiopathic inflammation, chronic enteropathies, metabolic disease and certain neuroinflammatory disorders. It is expected that in the near future new nutritional tools will emerge based on the expanding knowledge in this cutting-edge field. There is growing evidence that perturbation of the gut microbiome, known as "dysbiosis", is associated with the pathogenesis of human and veterinary diseases that are not restricted to the gastrointestinal tract. In this regard, recent studies have demonstrated that dysbiosis is linked to the pathogenesis of central neuroinflammatory disorders, supporting the existence of the so-called microbiome-gut-brain axis. The endocannabinoid system is a recently recognized lipid signaling system and termed endocannabinoidome monitoring a variety of body responses. Accumulating evidence demonstrates that a profound link exists between the gut microbiome and the endocannabinoidome, with mutual interactions controlling intestinal homeostasis, energy metabolism and neuroinflammatory responses during physiological conditions. In the present review, we summarize the latest data on the microbiome-endocannabinoidome mutual link in health and disease, focalizing the attention on gut dysbiosis and/or altered endocannabinoidome tone that may distort the bidirectional crosstalk between these two complex systems, thus leading to gastrointestinal and metabolic diseases (e.g., idiopathic inflammation, chronic enteropathies and obesity) as well as neuroinflammatory disorders (e.g., neuropathic pain and depression). We also briefly discuss the novel possible dietary interventions based not only on probiotics and/or prebiotics, but also, and most importantly, on endocannabinoid-like modulators (e.g., palmitoylethanolamide) for intestinal health and beyond. [ABSTRACT FROM AUTHOR]

Abstract: Apart from the psychotropic compound Δ9-tetrahydrocannabinol (THC), evidence suggests that other non-psychotropic phytocannabinoids are also of potential clinical use. This study aimed at elucidating the effect of major non-THC phytocannabinoids on the fate of adult neural stem progenitor cells (NSPCs), which are an essential component of brain function in health as well as in pathology. We tested three compounds: cannabidiol, cannabigerol, and cannabichromene (CBC), and found that CBC has a positive effect on the viability of mouse NSPCs during differentiation in vitro. The expression of NSPC and astrocyte markers nestin and Glial fibrillary acidic protein (GFAP), respectively, was up- and down-regulated, respectively. CBC stimulated ERK1/2 phosphorylation; however, this effect had a slower onset in comparison to typical MAPK stimulation. A MEK inhibitor, U0126, antagonized the up-regulation of nestin but not the down-regulation of GFAP. Based on a previous report, we studied the potential involvement of the adenosine A1 receptor in the effect of CBC on these cells and found that the selective adenosine A1 receptor antagonist, DPCPX, counteracted both ERK1/2 phosphorylation and up-regulation of nestin by CBC, indicating that also adenosine is involved in these effects of CBC, but possibly not in CBC inhibitory effect on GFAP expression. Next, we measured ATP levels as an equilibrium marker of adenosine and found higher ATP levels during differentiation of NSPCs in the presence of CBC. Taken together, our results suggest that CBC raises the viability of NSPCs while inhibiting their differentiation into astroglia, possibly through up-regulation of ATP and adenosine signalling. [Copyright &y& Elsevier]

Abstract: The exploitation of preparations of Cannabis sativa to combat pain seems to date back to time immemorial, although their psychotropic effects, which are at the bases of their recreational use and limit their therapeutic use, are at least as ancient. Indeed, it has always been different to tease apart the unwanted central effects from the therapeutic benefits of Δ9-tetrahydrocannabinol (THC), the main psychotropic component of cannabis. The discovery of the cannabinoid receptors and of their endogenous ligands, the endocannabinoids, which, unlike THC, play a pro-homeostatic function in a tissue- and time-selective manner, offered the opportunity to develop new analgesics from synthetic inhibitors of endocannabinoid inactivation. The advantages of this approach over direct activation of cannabinoid receptors as a therapeutic strategy against neuropathic and inflammatory pain are discussed here along with its potential complications. These latter have been such that clinical success has been achieved so far more rapidly with naturally occurring THC or endocannabinoid structural analogues acting at a plethora of cannabinoid-related and -unrelated molecular targets, than with selective inhibitors of endocannabinoid enzymatic hydrolysis, thus leading to revisit the potential usefulness of “multi-target” versus “magic bullet” compounds as new analgesics. [Copyright &y& Elsevier]

Abstract: The endocannabinoid system (ECS), comprising two G protein-coupled receptors (the cannabinoid receptors 1 and 2 [CB1 and CB2] for marijuana''s psychoactive principle ∆9-tetrahydrocannabinol [∆9-THC]), their endogenous small lipid ligands (namely anandamide [AEA] and 2-arachidonoylglycerol [2-AG], also known as endocannabinoids), and the proteins for endocannabinoid biosynthesis and degradation, has been suggested as a pro-homeostatic and pleiotropic signaling system activated in a time- and tissue-specific way during physiopathological conditions. In the brain activation of this system modulates the release of excitatory and inhibitory neurotransmitters and of cytokines from glial cells. As such, the ECS is strongly involved in neuropsychiatric disorders, particularly in affective disturbances such as anxiety and depression. It has been proposed that synthetic molecules that inhibit endocannabinoid degradation can exploit the selectivity of endocannabinoid action, thus activating cannabinoid receptors only in those tissues where there is perturbed endocannabinoid turnover due to the disorder, and avoiding the potential side effects of direct CB1 and CB2 activation. However, the realization that endocannabinoids, and AEA in particular, also act at other molecular targets, and that these mediators can be deactivated by redundant pathways, has recently led to question the efficacy of such approach, thus opening the way to new multi-target therapeutic strategies, and to the use of non-psychotropic cannabinoids, such as cannabidiol (CBD), which act via several parallel mechanisms, including indirect interactions with the ECS. The state of the art of the possible therapeutic use of endocannabinoid deactivation inhibitors and phytocannabinoids in mood disorders is discussed in this review article. [Copyright &y& Elsevier]

The psychoactive component of the cannabis resin and flowers, delta9-tetrahydrocannabinol (THC), was first isolated in 1964, and at least 70 other structurally related 'phytocannabinoid' compounds have since been identified. The serendipitous identification of a G-protein-coupled cannabinoid receptor at which THC is active in the brain heralded an explosion in cannabinoid research. Elements of the endocannabinoid system (ECS) comprise the cannabinoid receptors, a family of nascent lipid ligands, the 'endocannabinoids' and the machinery for their biosynthesis and metabolism. The function of the ECS is thus defined by modulation of these receptors, in particular, by two of the best-described ligands, 2-arachidonoyl glycerol and anandamide (arachidonylethanolamide). Research on the ECS has recently aroused enormous interest not only for the physiological functions, but also for the promising therapeutic potentials of drugs interfering with the activity of cannabinoid receptors. Many of the former relate to stress-recovery systems and to the maintenance of homeostatic balance. Among other functions, the ECS is involved in neuroprotection, modulation of nociception, regulation of motor activity, neurogenesis, synaptic plasticity and the control of certain phases of memory processing. In addition, the ECS acts to modulate the immune and inflammatory responses and to maintain a positive energy balance. This theme issue aims to provide the reader with an overview of ECS pharmacology, followed by discussions on the pivotal role of this system in the modulation of neurogenesis in the developing and adult organism, memory processes and synaptic plasticity, as well as in pathological pain and brain ageing. The volume will conclude with discussions that address the proposed therapeutic applications of targeting the ECS for the treatment of neurodegeneration, pain and mental illness. [ABSTRACT FROM AUTHOR]

The endocannabinoid system was revealed following the understanding of the mechanism of action of marijuana's major psychotropic principle, Δ9-tetrahydrocannabinol, and includes two G-protein-coupled receptors (GPCRs; the cannabinoid CB1 and CB2 receptors), their endogenous ligands (the endocannabinoids, the best studied of which are anandamide and 2-arachidonoylglycerol (2-AG)), and the proteins that regulate the levels and activity of these receptors and ligands. However, other minor lipid metabolites different from, but chemically similar to, anandamide and 2-AG have also been suggested to act as endocannabinoids. Thus, unlike most other GPCRs, cannabinoid receptors appear to have more than one endogenous agonist, and it has been often wondered what could be the physiological meaning of this peculiarity. In 1999, it was proposed that anandamide might also activate other targets, and in particular the transient receptor potential of vanilloid type-1 (TRPV1) channels. Over the last decade, this interaction has been shown to occur both in peripheral tissues and brain, during both physiological and pathological conditions. TRPV1 channels can be activated also by another less abundant endocannabinoid, N-arachidonoyldopamine, but not by 2-AG, and have been proposed by some authors to act as ionotropic endocannabinoid receptors. This article will discuss the latest discoveries on this subject, and discuss, among others, how anandamide and 2-AG differential actions at TRPV1 and cannabinoid receptors contribute to making this signalling system a versatile tool available to organisms to fine-tune homeostasis. [ABSTRACT FROM AUTHOR]

Starting from the well-documented effects of marijuana smoking on heart rate and blood pressure, the cardiovascular effects of Δ9-tetrahydrocannabinol (THC, the main psychotropic ingredient of Cannabis) and endocannabinoids [THC endogenous counterparts that activate cannabinoid receptor type 1 (CB1) and 2 (CB2)] have been thoroughly investigated. These studies were mostly aimed at establishing the molecular bases of the hypotensive actions of THC, endocannabinoids and related molecules, but also evaluated their therapeutic potential in cardiac injury protection, metabolic cardiovascular risk factors and atherosclerotic plaque vulnerability. The results of these investigations, reviewed here, also served to highlight some of the most peculiar aspects of endocannabinoid signaling, such as redundancy in endocannabinoid targets and the often dualistic role of CB1 and CB2 receptors during pathological conditions. [ABSTRACT FROM AUTHOR]

Studies of the endocannabinoid system in the CNS have been mostly focused on endocannabinoid receptors and inactivating mechanisms. Until recently, very little was known about the role of biosynthetic enzymes in endocannabinoid signaling. New data from the recent development of pharmacological and genetic tools for the study of these enzymes point to their fundamental role in determining where and when endocannabinoids function, and raise the possibility of new intriguing and previously unsuspected concepts in the general strategy of endocannabinoid signaling. However, even with these new tools, the cross-talk between anandamide and 2-arachidonoylglycerol biosynthesis makes it difficult to dissect one from the other, and data will need to be interpreted with this in mind. [ABSTRACT FROM AUTHOR]

Abstract: Evidence suggests that dietary long chain polyunsaturated fatty acids (LCPUFAs), and particularly those belonging to the n-3 family, may influence the brain fatty acid profile and, thereby, the biosynthesis of endocannabinoids in rodents. However, the doses used are usually quite high and not comparable with human intake. Recently, we have shown that relatively low doses of dietary n-3 LCPUFAs (4 weeks), in the form of either fish or krill oil, balanced for EPA and DHA content, and against a control diet with no EPA and DHA and similar contents of oleic, linoleic and α-linolenic acids, lower the concentrations of the endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), in the visceral adipose tissue, and of AEA in the liver and heart, of obese Zucker rats. This, in turn, is associated with lower levels of arachidonic acid in membrane phospholipids and with amelioration of some metabolic syndrome parameters. We investigated here whether in Zucker rats, under the same conditions, fish and krill oil are also able to influence LCPUFA and endocannabinoid profiles in brain. Only krill oil was able to increase significantly DHA levels in brain phospholipids, with no changes in arachidonic acid. DHA increase was associated with lower levels of 2-AG in the brain, whereas AEA and its congeners, N-palmitoylethanolamine and N-oleoylethanolamine, were unchanged. We conclude that, despite the strong impact of dietary n-3 fatty acid on endocannabinoid levels previously observed in peripheral tissues, in the brain only 2-AG is affected by dietary krill oil, suggesting that the beneficial effect of the latter on the metabolic syndrome is mostly exerted by modifying peripheral endocannabinoids. Nevertheless, possible effects of dietary krill oil in the brain through modification of 2-AG levels deserve further investigation. [Copyright &y& Elsevier]

When compared with other modifiable cardiovascular risk factors, such as hypertension, dyslipidemia and smoking, obesity remains a surprisingly puzzling condition to prevent and treat. The history of the development of anti-obesity drugs has known more defeats than even partial victories. With very few drugs on the market, and bad publicity related to adverse events, obesity remains an almost completely unmet challenge for the pharmaceutical industry. In light of past experience with endocannabinoid-system antagonists, such as rimonabant, we propose that a major paradigm shift in clinical practice might be necessary to justify the use of pharmacotherapy for obesity. Furthermore, we suggest that the criteria currently used by regulatory authorities to evaluate and approve anti-obesity drugs should be rigorously re-examined. Finally, we discuss how pharmacological approaches that aim to counteract overactivity of the endocannabinoid system should be revisited in the future to treat visceral (intra-abdominal) obesity and its metabolic consequences. [ABSTRACT FROM AUTHOR]

Abstract: The endocannabinoid signalling system includes: (1) at least two G-protein-coupled receptors, known as the cannabinoid CB1 and CB2 receptors and discovered following studies on the mechanism of action of Δ9-tetrahydrocannabinol, the major psychoactive principle of the hemp plant Cannabis sativa; (2) the endogenous agonists at these receptors, known as endocannabinoids, of which anandamide and 2-arachidonoylglycerol are the best known; and (3) proteins and enzymes for the regulation of endocannabinoid levels and action at receptors. The endocannabinoid system is quite widespread in mammalian tissues and cells and appears to play a pro-homeostatic role by being activated following transient or chronic perturbation of homeostasis, and by regulating in a local way the levels and action of other chemical signals. Compounds that selectively manipulate the action and levels of endocannabinoids at their targets have been and are being developed, and represent templates for potential new therapeutic drugs. [Copyright &y& Elsevier]

The endocannabinoid system (ECS) is a complex physiologic system that affects metabolic pathways. A dysregulated ECS has been demonstrated in animal models of obesity and the expression of the cannabinoid type 1 (CB1) receptor in both brain and peripheral tissues suggests that selective antagonism at this receptor could target multiple tissues involved in metabolic homeostasis. In clinical trials with obese patients, treatment with the CB1 receptor antagonist rimonabant was associated with clinically meaningful weight loss, as well as improved serum lipids and glycemic control. The biological basis for the metabolic effects of rimonabant (SR141716) appears to involve the modulation of metabolism through antagonism at a single receptor with several target organs. [Copyright &y& Elsevier]

On sensory neurons, the capsaicin receptor TRPV1 (transient receptor potential, vanilloid subfamily, member 1) functions as a molecular integrator of noxious stimuli and represents a novel target for analgesic drugs. The presence of TRPV1 in the brain is now well established but, despite intensive research, its function is only beginning to be understood. New evidence implies an unexpected role for hippocampal TRPV1 in neuropsychiatric disorders. For instance, it was hypothesized that the effects of the cannabinoid-receptor antagonist rimonabant on mood might be due to its capability to antagonize TRPV1 receptors at high doses. Most studies, however, imply a positive (e.g. anxiolytic) outcome for TRPV1 antagonism. With potent small-molecule TRPV1 antagonists undergoing clinical trials, the effect of brain TRPV1 blockade might determine the future of this class of novel analgesic drugs. Clearly, more research is needed to delineate the biological role of brain TRPV1 receptors. [Copyright &y& Elsevier]

As our understanding of the endocannabinoids improves, so does the awareness of their complexity. During pathological states, the levels of these mediators in tissues change, and their effects vary from those of protective endogenous compounds to those of dysregulated signals. These observations led to the discovery of compounds that either prolong the lifespan of endocannabinoids or tone down their action for the potential future treatment of pain, affective and neurodegenerative disorders, gastrointestinal inflammation, obesity and metabolic dysfunctions, cardiovascular conditions and liver diseases. When moving to the clinic, however, the pleiotropic nature of endocannabinoid functions will require careful judgement in the choice of patients and stage of the disorder for treatment. [ABSTRACT FROM AUTHOR]

Abstract: Endogenous cannabinoids modulate the activity of dopamine reward pathways and may play a role in the development of behavioural sensitization to psychostimulants. Here, we investigated the effects of the CB1 cannabinoid receptor antagonist AM251 on amphetamine-induced locomotor sensitization in mice. Furthermore, we measured post-mortem monoamine concentrations in nucleus accumbens and hippocampus after termination of the behavioural tests. The results can be summarized as follows: Mice pre-treated with AM251 (3 mg/kg; i.p.) showed less sensitivity to the psychomotor stimulant as well as locomotor sensitizing effects of amphetamine (2 mg/kg; i.p.) resembling previous results obtained with CB1 receptor-deficient animals. Furthermore, the behavioural effects of AM251 were paralleled by increased dopamine concentration in nucleus accumbens and increased serotonin concentration/turnover rate in hippocampus, respectively. The present data indicate that under normal conditions activation of the CB1 receptor facilitates those adaptive responses elicited by repeated psychostimulant administration and resulting in sensitization, possibly by reducing dopamine biosynthesis and serotonin turnover in the nucleus accumbens and hippocampus. [Copyright &y& Elsevier]

Fatty acid amide hydrolase (FAAH) is a hydrolytic enzyme that recognizes as substrates and inactivates the two most studied endocannabinoids, anandamide and 2-arachidonoylglycerol (2-AG). Following the observation that endocannabinoids produced by tissues during pathological conditions often have protective roles, FAAH inhibitors have been proposed as therapeutic drugs. Yet it has been suggested that FAAH functions in vivo only as an anandamide-degrading enzyme because its pharmacological and genetic inactivation is usually accompanied by elevation of anandamide, but not 2-AG, levels. We believe, however, that this concept needs to be revisited in light of reports that, under certain experimental conditions, FAAH inhibitors also elevate 2-AG tissue levels in vivo and, more recently, that FAAH inactivation in the striatum instead reduces 2-AG concentrations through upregulation of anandamide levels, activation of transient receptor potential vanilloid 1 receptors and inhibition of 2-AG biosynthesis. [Copyright &y& Elsevier]

Abstract: The activity of the endocannabinoid system, in terms of the levels of the endocannabinoids and of cannabinoid receptors, or of the functional coupling of the latter to a biological response, undergoes to remodelling during pathological conditions. In the CNS, these changes, depending also on the nature of the disorder, can be transient or long-lasting, occur only in those tissues involved in the pathological condition and usually aim at restoring the physiological homeostasis by reducing excitotoxicity, inflammation and neuronal death. However, during chronic disorders, prolonged activation of the endocannabinoid system might also contribute to the symptoms of the pathology. Whilst acute changes of the tissue levels of the endocannabinoids reflect the “on demand” nature of their biosynthesis and release, and hence are effected mostly through regulation of the biosynthetic enzymes, chronic changes seem to be mostly due to longer-lasting alterations in the expression of anabolic and catabolic enzymes. The possibility of obtaining therapeutic advantage from endocannabinoid plasticity in neuropsychiatric and neurological disorders is discussed in this review article. [Copyright &y& Elsevier]

Cannabis sativa has been known, used, and misused by mankind for centuries, and yet only over the last two decades has research stemming from the chemical constituents specific to this plant, the cannabinoids, started to provide fundamental insights into animal physiology and pathology, resulting in the development of new therapeutics. The discovery of the endocannabinoid system, and its targeting with two new pharmaceutical preparations now on the market in several countries, represent the most recent example of how studies on medicinal plants and on the mechanism of their biological effects can reveal, through a chain of breakthroughs, new systems of endogenous signals and physiological phenomena that can become the source of novel strategies for unmet therapeutic challenges. [Copyright &y& Elsevier]

In the present study, we used electrophysiological, biochemical, and confocal microscopy techniques, to investigate the functional role of transient receptor potential vanilloid type 1 (TRPV1) and cannabinoid type 1 receptors (CB1-R) in the substantia nigra pars compacta (SNpc) and their stimulation by the endocannabinoid N-arachidonoyl-dopamine (NADA). Liquid chromatography–mass spectrometry analyses revealed that a NADA-like compound is produced in substantia nigra slices, in conditions of hyperactivity. Moreover, the functional role of both TRPV1 and CB1-R in modulating synaptic transmission in this area was suggested by confocal microscopy data, showing TRPV1 and CB1-R immunoreactivity in punctate structures, probably representing synaptic contacts on cell bodies of the SNpc. In patch-clamp recordings from dopamine (DA) neurons of the SNpc, we found that NADA increases or reduces glutamatergic transmission onto DA neurons by activating TRPV1 and CB1 receptors, respectively, whereas it decreases GABAergic transmission via CB1 stimulation. Facilitation of glutamate release through TRPV1 was blocked in the presence of a selective blocker of the putative endocannabinoid membrane transporter (EMT), indicating that NADA needs to be taken up by cells to interact with this receptor. In line with these data, biochemical results demonstrated that NADA selectively acted at CB1-R when its re-uptake was blocked. Altogether these data demonstrate a significant role exerted by the endocannabinoid/endovanilloid NADA in the regulation of synaptic transmission to DA neurons of the SNpc. Moreover, they highlight a key function of the EMT transporter in promoting the stimulation of TRPV1 or CB1-R, thus favoring facilitation or inhibition of glutamate synaptic release.Neuropsychopharmacology (2007) 32, 298–308. doi:10.1038/sj.npp.1301118; published online 7 June 2006 [ABSTRACT FROM AUTHOR]

Two receptors have been cloned to date for the psychotropic compound Δ9-tetrahydrocannabinol, and termed cannabinoid CB1 and CB2 receptors. Their endogenous ligands, the endocannabinoids, have also been identified. CB1 receptors and endocannabinoids are present in brain structures controlling energy intake and in peripheral cells (hepatocytes, adipocytes, pancreatic islet cells) regulating energy homeostasis. CB2 receptors are more abundant in lymphocytes and macrophages, and participate in immune and inflammatory reactions. Metabolic hormones and peptides regulate the levels of the endocannabinoids and, hence, the activity of cannabinoid receptors in several tissues in a seemingly coordinated way. The endocannabinoids, particularly after stress and brief food deprivation, act in turn as local modulators of the expression and action of neurotransmitters, hormones and adipokines involved in metabolic control. Endocannabinoid overactivity seems to accompany metabolic and eating disorders and to contribute to the development of abdominal obesity, dyslipidemia and hyperglycemia. Accordingly, clinical trials have shown that CB1 receptor antagonists are efficacious at reducing not only food intake, but also abdominal adiposity and its metabolic sequelae. [Copyright &y& Elsevier]

Abstract: Although most commonly associated with actions at cannabinoid CB1 receptors on the extracellular surface of the plasma membrane, the endocannabinoid anandamide (AEA) is also transported into the cell, by the putative anandamide membrane transporter (AMT), and activates the vanilloid receptor 1 (TRPV1) at an intracellular site. AEA is then inactivated by fatty acid amide hydrolase (FAAH). As systemic administration of TRPV1 ligands reduces locomotor activity in normal rodents, we hypothesised that activation of TRPV1 by endocannabinoids could play a role in the control of voluntary movement and that such actions could be regulated by AMT and FAAH. Motor activity was assessed in normal, in reserpine-treated, and in reserpine-treated rats treated with L-DOPA. In normal rats, the TRPV1 agonist capsaicin (1mg/kg) or the FAAH inhibitor URB597 (10mg/kg) caused a significant reduction in movement in both the horizontal (locomotion) and vertical (rearing) planes (−45% and −53% respectively with capsaicin; −33% and −37% for URB597). Capsaicin-induced hypolocomotion was attenuated by the TRPV1 antagonist, capsazepine. There was no effect of capsaicin, URB597 or the AMT inhibitor OMDM-2 on motor activity in reserpine-treated rats. L-DOPA treatment of reserpine-treated rats elicited high levels of motor activity in both the horizontal and vertical planes. Horizontal activity was attenuated by capsaicin (1mg/kg, −60%), but not by URB597 (10mg/kg) or OMDM-2 (5mg/kg). Vertical activity was attenuated by capsaicin (1mg/kg, −61%) and by URB597 (10mg/kg, −54%), but not by OMDM-2. These data suggest that activation of the TRPV1 system can suppress spontaneous locomotion in normal animals and modulates several L-DOPA-induced behaviours in reserpine-treated rats. [Copyright &y& Elsevier]

British scientists have played a leading role in the long history of cannabinoid and endocannabinoid research. Such research has progressed from the first crucial evaluation of the medicinal properties of Cannabis sativa in the Western world to pioneering studies of the chemical constituents of this plant, the development of in vitro biological assays to study cannabinoids, the identification of the mechanism of action of cannabinoids, the discovery of endocannabinoids and the assessment of their therapeutic implications. Stemming from the many innovative ideas and achievements of these researchers, I provide a personal view of where these studies have led us thus far and where they are likely to take us in the future. [Copyright &y& Elsevier]

Although used for more than 4000 years for recreational and medicinal purposes, Cannabis and its best-known pharmacologically active constituents, the cannabinoids, became a protagonist in medical research only recently. This revival of interest is explained by the finding in the 1990s of the mechanism of action of the main psychotropic cannabinoid, Δ9-tetrahydrocannabinol (THC), which acts through specific membrane receptors, the cannabinoid receptors. The molecular characterization of these receptors allowed the development of synthetic molecules with cannabinoid and noncannabinoid structure and with higher selectivity, metabolic stability, and efficacy than THC, as well as the development of antagonists that have already found pharmaceutical application. The finding of endogenous agonists at these receptors, the endocannabinoids, opened new therapeutic possibilities through the modulation of the activity of cannabinoid receptors by targeting the biochemical mechanisms controlling endocannabinoid tissue levels. [ABSTRACT FROM AUTHOR]

Abstract: After 7 years from its cloning, the transient receptor potential vanilloid type-1 (TRPV1) channel remains the sole membrane receptor mediating the pharmacological effects of the hot chilli pepper pungent component, capsaicin, and of the Euphorbia toxin, resiniferatoxin. Yet, this ion channel represents one of the most complex examples of how the activity of a protein can be regulated. Among the several chemicophysical stimuli that can modulate TRPV1 permeability to cations, endogenous lipids appear to play a major role, either as allosteric effectors or as direct agonists, or both. Furthermore, the capability of some mediators, such as the endocannabinoid anandamide, or the eicosanoid precursors 12- and 5-hydroperoxy-eicosatetraenoic acids, to activate TRPV1 receptors provides a striking example of the “site-dependent” and “metabolic” functional plasticity, respectively, typical of bioactive lipids. In this article, the multi-faceted and most recently discovered aspects of TRPV1 regulation are reviewed, with particular emphasis on the interaction between these membrane channels and some lipid molecules. [Copyright &y& Elsevier]

Marijuana and its major psychotropic component,?9-tetrahydrocannabinol, stimulate appetite and increase body weight in wasting syndromes, suggesting that the CB1 cannabinoid receptor and its endogenous ligands, the endocannabinoids, are involved in controlling energy balance. The endocannabinoid system controls food intake via both central and peripheral mechanisms, and it may also stimulate lipogenesis and fat accumulation. Here we discuss the multifaceted regulation of energy homeostasis by endocannabinoids, together with its applications to the treatment of eating disorders and metabolic syndromes. [ABSTRACT FROM AUTHOR]

The term 'endocannabinoid'-originally coined in the mid-1990s after the discovery of membrane receptors for the psychoactive principle in Cannabis,?9-tetrahydrocannabinol and their endogenous ligands-now indicates a whole signalling system that comprises cannabinoid receptors, endogenous ligands and enzymes for ligand biosynthesis and inactivation. This system seems to be involved in an ever-increasing number of pathological conditions. With novel products already being aimed at the pharmaceutical market little more than a decade since the discovery of cannabinoid receptors, the endocannabinoid system seems to hold even more promise for the future development of therapeutic drugs. We explore the conditions under which the potential of targeting the endocannabinoid system might be realized in the years to come. [ABSTRACT FROM AUTHOR]

Endovanilloids are defined as endogenous ligands of the transient receptor potential vanilloid type 1 (TRPV1) protein, a nonselective cation channel that belongs to the large family of TRP ion channels, and is activated by the pungent ingredient of hot chilli peppers, capsaicin. TRPV1 is expressed in some nociceptor efferent neurons, where it acts as a molecular sensor of noxious heat and low pH. However, the presence of these channels in various regions of the central nervous system, where they are not likely to be targeted by these noxious stimuli, suggests the existence of endovanilloids. Three different classes of endogenous lipids have been found recently that can activate TRPV1, i.e. unsaturated N-acyldopamines, lipoxygenase products of arachidonic acid and the endocannabinoid anandamide with some of its congeners. To classify a molecule as an endovanilloid, the compound should be formed or released in an activity-dependent manner in sufficient amounts to evoke a TRPV1-mediated response by direct activation of the channel. To control TRPV1 signaling, endovanilloids should be inactivated within a short time-span. In this review, we will discuss, for each of the proposed endogenous ligands of TRPV1, their ability to act as endovanilloids in light of the criteria mentioned above. [ABSTRACT FROM AUTHOR]

To date, N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol are the best studied endocannabinoids and are thought to act as retrograde messengers in the central nervous system (CNS). By activating presynaptic cannabinoid CB1 receptors, they can reduce glutamate release in dorsal and ventral striatum (nucleus accumbens) and alter synaptic plasticity, thereby modulating neurotransmission in the basal ganglia and in the mesolimbic reward system. In this review, we will focus on the role of the endocannabinoid system within these neuronal pathways and describe its effect on dopaminergic transmission and vice versa. The endocannabinoid system is unlikely to directly affect dopamine release, but can modify dopamine transmission trough trans-synaptic mechanisms, involving γ-aminobutyric acid (GABA)-ergic and glutamatergic synapses, as well as by converging signal transduction cascades of the cannabinoid and dopamine receptors. The dopamine and endocannabinoid systems exert a mutual control on each other. Cannabinergic signalling may lead to release of dopamine, which can act via dopamine D1-like receptors as a negative feedback mechanism to counteract the effects of activation of the cannabinoid CB1 receptor. On the other hand, dopaminergic signalling via dopamine D2-like receptors may lead to up-regulation of cannabinergic signalling, which is likely to represent a negative feedback on dopaminergic signalling. The consequences of these interactions become evident in pathological conditions in which one of the two systems is likely to be malfunctioning. We will discuss neurological and psychiatric disorders such as Parkinson''s and Huntington''s disease, drug addiction and schizophrenia. Furthermore, the possible role of the endocannabinoid system in disorders not necessarily depending on the dopaminergic system, such as eating disorders and anxiety, will be described. [Copyright &y& Elsevier]

Investigates the function and the endogenous stimulation of vanilloid receptor-1 (VR1) in dopaminergic neurons of the substantia nigra pars compacta. Evidence of VR1 function in the substantia nigra; Electrophysiological characteristics of the dopaminergic neurons; Calcium dependence of VR1-mediated excitatory effects.

Recent work has addressed the role of vanilloid receptor type 1 (VR1) in pain perception. VR1 activity is regulated both directly and indirectly by endogenous factors. For example, protein kinase C sensitizes human VR1 to mild decreases in pH, which are commonly encountered during inflammation, and renders the endocannabinoid anandamide a more potent ‘endovanilloid’. Bradykinin and nerve growth factor release VR1 from the inhibitory control of phosphatidylinositol (4,5)-bisphosphate and anti-VR1 serum ameliorates thermal allodynia and hyperalgesia in diabetic mice. There is strong evidence that not only the sensitivity but also the density of expression of VR1 is enhanced during inflammatory conditions. These observations provide an empirical foundation which could explain the reduced inflammatory hyperalgesia in VR1 knockout mice, and they imply an important role for endovanilloid signaling via VR1 in the development of ongoing pain in humans that occurs in most inflammatory conditions. Conversely, downregulation of VR1 expression and/or activity is a promising therapeutic strategy for novel analgesic drugs. [ABSTRACT FROM AUTHOR]

Reports on studies undertaken to determine the effect of endogenous cannabinoid receptor ligands on cancer cells. Findings of treatment of human breast cell cancer lines with sub-micromolar concentrations of endocannabinoids; Examination whether cancer therapies can target the endocannabinoid system; Necessity of more basic clinical research to assess ability of cannabinoids to act like other therapeutic drugs.

Focuses on the role of compound anandamide, an endogenous ligand of cannabinoid receptors, in activating receptors specific for capsaicin, known as vanilloid type 1 receptors (VR1). Regulatory factors that enhance the activation of VR1; Details on the regulation of VR1 activity; Role of anandamide membrane transporter.

Presents a study which investigates whether leptin may similarly regulate hypothalamic endocannabinoids in mice. Experiment where mice were injected with leptin; Indication from findings that endocannabinoids in the hypothalamus may tonically activate CB1 receptors to maintain food intake and form part of the neural circuitry regulated by leptin.

Deals with a study that proposed the endocannabinoid anandamide to function as an endogenous agonist at the vanilloid receptor-like protein (VR1). Heterogeneity of vanilloid actions; Capsaicin congeners and proteins of the endogenous cannabinoid system; Discussion on anandamide as an endogenous ligand for VR1 in sensory neurons; Distribution of VR1 in the brain.

Background and purpose: Preclinical studies of amyotrophic lateral sclerosis (ALS) have shown altered endocannabinoid (eCB) signalling that may contribute to the disease. Results from human studies are sparse and inconclusive. The aim of this study was to determine the association between serum levels of eCBs or their congeners, the so‐called endocannabinoidome, and disease status and activity in ALS patients. Methods: Serum concentrations of 2‐arachidonoylglycerol and N‐arachidonoylethanolamine (AEA), and AEA congeners palmitoylethanolamide (PEA), oleoylethanolamide (OEA), eicosapentaenoylethanolamide (EPEA), 2‐docosahexaenoylglycerol (2‐DHG) and docosahexaenoylethanolamide (DHEA) were measured in samples from 65 ALS patients, 32 healthy controls (HCs) and 16 neurological disease controls (NALS). A subset of 46 ALS patients underwent a longitudinal study. Disease activity and progression were correlated with eCB and congener levels. Results: Most circulating mediators were higher in ALS than HCs (all p < 0.001), but not NALS. Across clinical stages, ALS patients showed increased levels of PEA, OEA and EPEA (all p < 0.02), which were confirmed by the longitudinal study (all p < 0.03). Serum PEA and OEA levels were independent predictors of survival and OEA levels were higher in patients complaining of appetite loss. Cluster analysis revealed two distinct profiles of circulating mediators associated with corresponding patterns of disease activity (severe vs. mild). Patients belonging to the 'severe' cluster showed significantly higher levels of OEA and PEA and lower levels of 2‐DHG compared to NALS and HCs. Conclusion: Circulating endocannabinoidome profiles are indicative of disease activity, thus possibly paving the way to a personalized, rather than a 'one‐fits‐all', therapeutic approach targeting the endocannabinoidome. [ABSTRACT FROM AUTHOR]

Discusses the similarity between endocannabinoids and the psychoactive substance in marijuana and the role for endocannabinoids in the modulation of neurotransmitter action and release. Discussion on endocannabinoids and the endogenous cannabinoid system; How the brain makes and disposes of endocannabinoids; Cannabinoid-receptor-mediated actions of endocannabinoids in neurones and astrocytes.