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Abstract

The term 'endocannabinoid' - originally coined in the mid-1990s after the discovery of membrane receptors for the psychoactive principle in Cannabis, Delta9-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.

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... Lipids have also emerged as important signaling molecules and secondary messengers that modulate diverse biological processes, and over the past two decades, a few signaling lipid classes have been extensively investigated in the context of mammalian physiology 3 . Examples of such well-studied signaling lipids include prostaglandins 4-6 , endocannabinoids [7][8][9][10] , and a few classes of lysophospholipids such as sphingosine 1-phosphate [11][12][13][14][15] , lysophosphatidic acid [16][17][18][19] and lysophosphatidylserine 20,21 . Given their importance in mammalian signaling pathways, dysregulation in their metabolism or signaling is linked to numerous human pathophysiological conditions, and drugs targeting their respective metabolic enzymes and cognate receptors are emerging as key therapies in the treatment of an array of human diseases 22,23 . ...
... The endocannabinoid 2-arachidonoyl-glycerol (2-AG, C20:4 MAG) is an endogenous ligand to the cannabinoid receptors in the mammalian brain, and its metabolic and signaling pathways have been very well worked out in the mammalian nervous system [8][9][10]24 . Given its central role in numerous critical processes in the mammalian nervous system, modulation of 2-AG levels in the brain together with the endocannabinoid system are being rigorously explored as potential therapeutic targets for treating a variety of neurological disorders [25][26][27] . ...
... Given its central role in numerous critical processes in the mammalian nervous system, modulation of 2-AG levels in the brain together with the endocannabinoid system are being rigorously explored as potential therapeutic targets for treating a variety of neurological disorders [25][26][27] . 2-AG belongs to the monoacylglycerol (MAG) family of signaling lipids [8][9][10] , and while lot is known with regards to the physiological processes regulated by 2-AG in mammals, the same cannot be said for the other MAG lipids. MAG lipids are biosynthesized from diacylglycerol (DAG) precursors by the action of the DAG lipases, and degraded by MAG lipases (Figure 1) [7][8][9][10] . ...
Preprint
Signaling lipids are hormone-like small biomolecules that regulate many critical facets of physiology in mammals, including humans. Given their biomedical importance, the past few decades have seen a tremendous increase in our mechanistic understanding of the physiological processes regulated by a handful of such signaling lipids (e.g.: endocannabinoids, lysophospholipids, prostaglandins). However, a significant number of signaling lipid classes still remain poorly characterized, despite their direct associations to human pathophysiology and disease. Over the past decade, the advent of chemical proteomics technologies coupled with the development of multifunctional lipid probes has rapidly expanded our knowledge in terms of the protein ligands and biological pathways that the different signaling lipids interact with and modulate respectively. While the signaling pathways regulated by the endocannabinoid 2-arachidonoyl-glycerol in mammals are extensively characterized, the same cannot be said for the other members of the monoacylglycerol (MAG) family of signaling lipids. To understand this, here, we report the synthesis of a bifunctional MAG probe, containing a photoreactive group and a biorthogonal handle. Using established chemical proteomics approaches, we profile this bifunctional MAG probe in mouse brain and mammalian cell lysates, and leveraging probe competition experiments identify hitherto unknown protein ligands for MAG lipids. Finally, we biochemically validate the neuronal calcium sensor Hippocalcin as a putative MAG protein ligand, and show for the first time, that MAG may have a role to play in calcium sensing and downstream signaling in the mammalian brain.
... The entire body is saturated with components of the endocannabinoid system (ECS), which orchestrate physiological and cognitive processes. 121,122 Within the ECS, cannabinoid receptor-1 (CB1) remains the most abundant, alongside CB2 and transient receptor potential channels. [121][122][123] Endogenous cannabinoids, including the widely studied 2-arachidonoyl glycerol and arachidonoyl ethanolamide (anandamide; AEA), alongside their respective receptors, play crucial roles in various processes, including immune system modulation, appetite, pain sensation, mood, memory, and fertility. ...
... 121,122 Within the ECS, cannabinoid receptor-1 (CB1) remains the most abundant, alongside CB2 and transient receptor potential channels. [121][122][123] Endogenous cannabinoids, including the widely studied 2-arachidonoyl glycerol and arachidonoyl ethanolamide (anandamide; AEA), alongside their respective receptors, play crucial roles in various processes, including immune system modulation, appetite, pain sensation, mood, memory, and fertility. [124][125][126][127] Exogenous cannabinoids, including but not limited to tetrahydrocannabinol (Delta-9-THC) and cannabidiol, act on these endogenous pathways, eliciting their local or systemic effects. ...
Article
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Endometriosis is a prevalent gynecological disease, leading to chronic pain and inflammation, affecting 1 in 10 individuals presumed female at birth. The diagnostic journey is often arduous, marked by neglect of the right diagnosis and prolonged wait times, significantly compromising the quality of life among those affected. This review provides a nuanced exploration of endometriosis-associated pain management, encompassing medical, surgical, and holistic approaches, all guided by accurate and refined diagnostics. Our paramount goal is to empower physicians as key figures in confronting this intricate challenge with a patient-centric approach, ultimately aiming to improve treatment and quality of life. Acknowledging each patient’s unique needs, we emphasize the importance of tailoring a spectrum of options informed by current literature and insights gleaned from our experience in a high-volume tertiary endometriosis center. It is imperative to recognize endometriosis as a complex and chronic disease, often occurring with co-morbid conditions and nuanced complexities, necessitating a long-term personalized multimodal approach for each case. In addition, incorporating principles such as patient autonomy, profound respect for diverse experiences, and practical education on treatment choices is pivotal in enhancing treatment outcomes and overall patient satisfaction.
... Thereafter, the discovery of Endocannabinoid System (ESC) began [4]. The widespread presence of this system across species and within numerous animal tissues has led to the identification of a vast array of molecular mediators of cannabinoid biological activities, along with other compounds present in the plant [5]. Therefore, the real scope of the ESC and the therapeutic potential of cannabinoids and other compounds are being redefined. ...
... First in 1988, cannabinoid receptors on the plasma membrane were identified; followed by the cloning of receptors CB1 and CB2, respectively, both of which are orphan receptors bound to protein G. And lastly, the search for their natural ligands, termed "endocannabinoids," as they were named in 1995, some years after their discovery [5]. ...
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This work is licensed under Creative Commons Attribution 4.0 License SJRR.MS.ID.000583.. Abstract Cannabis sativa L. produces a plethora of molecules with therapeutic potential, among which phytocannabinoids stand out as significant components. The search for endogenous mediators of cannabis effects in animals has led to the elucidation of cannabinoid receptors CB1/CB2, their endogenous ligands (endocannabinoids), and their enzymes responsible for their synthesis and degradation, collectively termed ''Endocannabinoid System (ECS). Cannabinoids, such as THC, contribute to both therapeutic efficacy and toxicity of the cannabis plant. Phytocannabinoids not only interact with the ECS but also engage with a diverse array of other receptors, ion membrane channels, nuclear receptors (orphan GPCRs, PPARs, and LGICs), endogenous ligands akin to endocannabinoids, metabolic enzymes, and other target molecules. These mediators, although described within other systems or families, may play a pivotal role in mediating the effects of cannabis products constituting an-ome broader than the ECS, referred to as the Endocannabinoidome (eCBome) by some authors. Understanding the role of the eCBome in health and disease, as well as its modulation, presents an interesting target for the development of therapeutic strategies. This review provides an overview of the historical and current knowledge of the endocannabinoidome and its exogenous modulation as a therapeutic approach.
... Endocannabinoids are a group of lipid mediators that act as endogenous ligands to those receptors that are engaged by the psychoactive constituents of Cannabis sativa and Cannabis indica and have been both characterised as important neuromodulatory and immunomodulatory agents [126]. The so-called "endocannabinoid (eCB) system" includes the two major eCBs, i.e., N-arachidonoylethanolamine (AEA, also known as anandamide) and 2-arachidonoylglycerol (2-AG), their two main receptors, i.e., CB1 and CB2, as well as the enzymes that control biosynthesis (i.e., Nacylphosphatidylethanolamine-hydrolyzing phospholipase D [NAPE-PLD], and sn-1-DAG lipase (DAGL)) and degradation (i.e., fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL)) [90,126]. ...
... Endocannabinoids are a group of lipid mediators that act as endogenous ligands to those receptors that are engaged by the psychoactive constituents of Cannabis sativa and Cannabis indica and have been both characterised as important neuromodulatory and immunomodulatory agents [126]. The so-called "endocannabinoid (eCB) system" includes the two major eCBs, i.e., N-arachidonoylethanolamine (AEA, also known as anandamide) and 2-arachidonoylglycerol (2-AG), their two main receptors, i.e., CB1 and CB2, as well as the enzymes that control biosynthesis (i.e., Nacylphosphatidylethanolamine-hydrolyzing phospholipase D [NAPE-PLD], and sn-1-DAG lipase (DAGL)) and degradation (i.e., fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL)) [90,126]. ...
Article
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The present review provides a comprehensive examination of the intricate dynamics between α-synuclein, a protein crucially involved in the pathogenesis of several neurodegenerative diseases, including Parkinson’s disease and multiple system atrophy, and endogenously-produced bioactive lipids, which play a pivotal role in neuroinflammation and neurodegeneration. The interaction of α-synuclein with bioactive lipids is emerging as a critical factor in the development and progression of neurodegenerative and neuroinflammatory diseases, offering new insights into disease mechanisms and novel perspectives in the identification of potential biomarkers and therapeutic targets. We delve into the molecular pathways through which α-synuclein interacts with biological membranes and bioactive lipids, influencing the aggregation of α-synuclein and triggering neuroinflammatory responses, highlighting the potential of bioactive lipids as biomarkers for early disease detection and progression monitoring. Moreover, we explore innovative therapeutic strategies aimed at modulating the interaction between α-synuclein and bioactive lipids, including the development of small molecules and nutritional interventions. Finally, the review addresses the significance of the gut-to-brain axis in mediating the effects of bioactive lipids on α-synuclein pathology and discusses the role of altered gut lipid metabolism and microbiota composition in neuroinflammation and neurodegeneration. The present review aims to underscore the potential of targeting α-synuclein-lipid interactions as a multifaceted approach for the detection and treatment of neurodegenerative and neuroinflammatory diseases.
... Topical administration has been therefore used to overcome this setback and to increase safety, while retaining efficacy in the treatment of skin disorders, as exemplified by asivatrep in atopic dermatitis ( Fig. 1) [13] and resiniferatoxin (RTX) in osteoarthritic pain. CB1 and CB2 belong to the cannabinoid receptor family of G protein coupled receptors (GPCRs) and are the biological targets of Δ 9 -tetrahydrocannabinol (THC), the main psychoactive component in Cannabis sativa [14,15]. CB1 is highly expressed in central nervous system, mediates psychoactive effects, and modulates nociceptive pain [16], whereas CB2 is mainly located in immune cells with anti-inflammatory effects that indirectly contribute to anti-nociception of pain [17]. ...
... The Passerini reaction between the isocyanide (5, 7, 11, 13 and the commercially available cyclopropyl isocyanide 14), the carboxylic acid (15)(16)(17)(18)(19)(20)(21) and formaldehyde was carried out as outlined in Scheme 3, affording the corresponding α-acyloxycarboxamides 22-56 with yields ranging from 18 to 82 % (Tables 1 and 2). To prepare compounds 22-42, a final cleavage of the TBDMS group with tetra-n-butylammonium fluoride (TBAF) in the presence of acetic acid to prevent ester hydrolysis was used. ...
... Its importance is highlighted by its extensive distribution throughout the body and its involvement in several physiological processes, including pain, hunger, mood, and immune system control [35]. The ECS is made up of G protein-coupled cannabinoid receptors CB 1 and CB 2 [36], their endogenous ligands such as classical endocannabinoids (e.g., anandamide or N-arachidonoylethanolamine and 2-arachidonoylglycerol) and endocannabinoid-like compounds (e.g., PEA, oleoylethanolamide-OEA, and stearoylethanolamide-SEA) [37], and the metabolic enzymes responsible for endocannabinoid synthesis and degradation [38]. The orphan G-protein-coupled receptor GPR55 and two more receptor classes have been introduced to this system as cannabinoid ligand targets: TRPV1 [39] and PPAR nuclear receptors [40]. ...
... Furthermore, CB 1 receptors are found in the gastrointestinal system, where they regulate digestion processes and hunger regulation. The location of CB 1 receptors in the CNS and peripheral tissues explains their role in a variety of processes, including mood regulation, pain modulation, and hunger management [38]. CB 2 receptors are widely expressed in immune cells such as macrophages, T cells, and B cells, and in the immune system's peripheral organs, including the spleen, tonsils, and bone marrow. ...
Article
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Palmitoylethanolamide (PEA) is an endocannabinoid-like bioactive lipid mediator belonging to the family of N-acylethanolamines, most abundantly found in peanuts and egg yolk. When the gastrointestinal (GI) effects of PEA are discussed, it must be pointed out that it affects intestinal motility but also modulates gut microbiota. This is due to anti-inflammatory, antioxidant, analgesic, antimicrobial, and immunomodulatory features. Additionally, PEA has shown beneficial effects in several GI diseases, particularly irritable bowel syndrome and inflammatory bowel diseases, as various studies have shown, and it is important to emphasize its relative lack of toxicity, even at high dosages. Unfortunately, there is not enough endogenous PEA to treat disturbed gut homeostasis, even though it is produced in the GI tract in response to inflammatory stimuli, so exogenous intake is mandatory to achieve homeostasis. Intake of PEA could be through animal and/or vegetable food, but bearing in mind that a high dosage is needed to achieve a therapeutic effect, it must be compensated through dietary supplements. There are still open questions pending to be answered, so further studies investigating PEA’s effects and mechanisms of action, especially in humans, are crucial to implementing PEA in everyday clinical practice.
... In 1990, the first ECS receptor, CB1R, an "orphan" GPCR, was discovered [10], and then in 1993, the second endocannabinoid receptor, CB2R, located mainly on blood cells and immune tissues, was characterized [11]. ...
Article
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The endocannabinoid system (ECS), composed of receptors, endocannabinoids, and enzymes that regulate biosynthesis and degradation, plays a fundamental role in the physiology and pathology of the gastrointestinal tract, particularly in the small and large intestine and liver. Specifically, cannabinoid receptor type 1 (CB1R) and cannabinoid receptor type 2 (CB2R), located principally in the nervous system and immune cells, orchestrate processes such as intestinal motility, intestinal and hepatic inflammation, and energy metabolism, respectively. The main endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), influence appetite, body weight regulation, and inflammatory states and thus have implications in obesity, non-alcoholic fatty liver disease (NAFLD) and irritable bowel syndrome (IBS). Recent studies have highlighted the therapeutic potential of targeting the ECS to modulate gastrointestinal and metabolic diseases. In particular, peripheral CB1R antagonists and CB2R agonists have shown efficacy in treating intestinal inflammation, reducing hepatic steatosis, and controlling IBS symptoms. Moreover, the ECS is emerging as a potential target for the treatment of colorectal cancer, acting on cell proliferation and apoptosis. This review highlights the opportunity to exploit the endocannabinoid system in the search for innovative therapeutic strategies, emphasizing the importance of a targeted approach to optimize treatment efficacy and minimize side effects.
... Cannabis Sativa with a better safety profile in comparison to other cannabinoids, bearing non addictive properties (Di Marzo et al., 2004;Pacher et al., 2018;Wang et al., 2023). CBD acts directly on the endocannabinoid system (ECS) through CB 1 and CB 2 receptors, with a low affinity for both receptors (Pisanti et al., 2017). ...
... Tetrahydrocannabinol (THC), the primary psychoactive component of Cannabis sativa, has been shown to alleviate pain, inflammation, cancers, etc., by acting as a partial agonist at both CB1 and CB2 receptors [11][12][13]. Preclinical studies have shown that THC can alleviate inflammation and promote tissue healing in models of colitis [14]. However, its therapeutic application is often limited by behavioural side effects such as anxiety, tolerance and cognitive impairment, which restrict its clinical utility [15][16][17]). ...
Article
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Background/Objectives: Current inflammatory bowel disease (IBD) treatments focus on symptomatic relief, highlighting the need for innovative approaches. Dysregulation of the cannabinoid 1 (CB1) receptor, part of the endocannabinoid system, is linked to colitis. While tetrahydrocannabinol (THC) alleviates colitis via CB1 activation, its psychotropic effects limit clinical use. ZCZ011, a CB1R allosteric modulator, and cannabidiol (CBD), a non-psychoactive cannabinoid, offer alternatives. This study investigated combining sub-therapeutic THC doses with ZCZ011 or CBD in a murine model of dextran sodium sulphate (DSS)-induced colitis. Methods: Acute colitis was induced with 4% DSS for 7 days, followed by 3 days of water. Chronic colitis was modelled over 24 days with alternating DSS concentrations. The combination of 2.5 mg/kg THC with 20 mg/kg ZCZ011 or 10 mg/kg CBD was evaluated. Key markers were assessed to determine efficacy and safety, including disease activity index (DAI), inflammation, cytokine levels, GLP-1, and organ health. Results: DSS-induced colitis resulted in increased DAI scores, cytokines, organ inflammation and dysregulation of GLP-1 and ammonia. THC at 10 mg/kg significantly improved colitis markers but was ineffective at 2.5 and 5 mg/kg. ZCZ011 alone showed transient effects. However, combining 2.5 mg/kg THC with either 20 mg/kg ZCZ011 or 10 mg/kg CBD significantly alleviated colitis markers, restored colon integrity and reestablished GLP-1 homeostasis. This combination also maintained favourable haematological and biochemical profiles, including a notable reduction in colitis-induced elevated ammonia levels. Conclusions: This study demonstrates the synergistic potential of low-dose THC combined with CBD or ZCZ011 as a novel, effective and safer therapeutic strategy for ulcerative colitis.
... In several studies on hematological malignancies, the CB2 receptor has been the primary target due to its selective localization on immune cells. However, the underlying molecular anticancer mechanism of most cannabinoids remains poorly understood [48,49]. THC showed dosedependent induction of apoptosis in leukemia cells (Jurkat and Sup-T1 cell lines) through the binding of CB2 receptors [35]. ...
Article
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Several cannabis plant-derived compounds, especially cannabinoids, exhibit therapeutic potential in numerous diseases and conditions. In particular, THC and CBD impart palliative, antiemetic, as well as anticancer effects. The antitumor effects include inhibition of cancerous cell growth and metastasis and induction of cell death, all mediated by cannabinoid interaction with the endocannabinoid system (ECS). However, the exact molecular mechanisms are still poorly understood. In addition, their effects on leukemia have scarcely been investigated. The current work aimed to assess the antileukemic effects of CBN and CBG on an acute monocytic leukemia cell line, the THP-1. THP-1 cell viability, morphology and cell cycle analyses were performed to determine potential cytotoxic, antiproliferative, and apoptotic effects of CBN and CBG. Western blotting was carried out to measure the expression of the proapoptotic p53. Both CBN and CBG inhibited cell growth and induced THP-1 cell apoptosis and cell cycle arrest in a dose- and time-dependent manner. CBN and CBG illustrated different dosage effects on THP-1 cells in the MTT assay (CBN > 40 μΜ, CBG > 1 μM) and flow cytometry (CBN > 5 μM, CBG > 40 μM), highlighting the cannabinoids’ antileukemic activity. Our study hints at a direct correlation between p53 expression and CBG or CBN doses exceeding 50 μM, suggesting potential activation of p53-associated signaling pathways underlying these effects. Taken together, CBG and CBN exhibited suppressive, cell death-inducing effects on leukemia cells. However, further in-depth research will be needed to explore the molecular mechanisms driving the anticancer effects of CBN and CBG in the leukemia setting.
... Interest in the therapeutic benefits of cannabis and specific cannabinoids has grown significantly since the 1990s, largely driven by an increased understanding of the endocannabinoid system (ECS) [1,2]. In recent years there has been a global trend towards relaxing regulatory restrictions. ...
Article
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Background Cannabinoids have been of increasing interest mainly due to their putative efficacy in a wide array of psychiatric, psychosomatic, and neurological conditions. Aims This systematic review aims to synthesize results from randomized placebo-controlled trials regarding the efficacy and the dosage of cannabinoids as therapeutics in psychiatric disorders in children, adolescents, and young adults. Methods All publications up to June 30th, 2024, were included from PubMed and Embase. Eligibility criteria in accordance with the PRISMA-guidelines was applied. RCTs providing pre- and post-treatment parameters on cannabinoid therapies for mental disorders in comparison to controls in an age range from 0 to 25 years were included. Effect sizes were calculated as Hedges’ g for primary outcomes, and a multilevel random-effects meta-analysis was conducted to account for dependent outcomes from same study populations. Results We identified 7603 records, of which 8 independent clinical trials (reported in 9 publications) met the pre-established eligibility criteria, comprising 474 unique participants (245 treatment, 229 control). Analysis of 13 primary outcomes (of 7 clinical trials) revealed a modest positive overall effect for symptom improvement or normalization of brain physiology (Hedges’ g = 0.308, 95% CI: 0.167, 0.448). Autism spectrum disorder studies showed the most consistent evidence (g = 0.264, 95% CI: 0.107, 0.421), while other conditions showed wider confidence intervals. Age-stratified analysis showed that adult populations (mean age 23.3 years, n = 5 outcomes) demonstrated higher effect sizes (g = 0.463, SD = 0.402) compared to pediatric populations (mean age 11.8 years, n = 8 outcomes; g = 0.318, SD = 0.212). Whole plant preparations (g = 0.328, 95% CI: 0.083, 0.573) and pharmaceutical cannabinoids (g = 0.292, 95% CI: 0.069, 0.515) showed comparable effects. CBD dosages ranged from 17.5 mg to 600 mg per day, with no significant correlation between dosage and effect size (ρ = -0.014, p = 0.963). Mild to moderate side effects were reported, but no serious adverse events. Risk of bias assessment ranged from low (n = 3) to high (n = 5). Conclusion While meta-analysis of effect sizes for primary outcomes revealed modest positive effects, particularly for autism spectrum disorders, the current evidence remains insufficient to broadly recommend cannabinoids for treating mental disorders in youth populations. Larger, controlled studies with standardized outcomes are needed to establish definitive clinical recommendations.
... The historical roots of cannabis use can be traced back to ancient China, where it found application in religious ceremonies, for spiritual and medicinal purposes to prevent and treat diseases due to its psychotropic effects [1] [2] [3] [4]. The earliest records of therapeutic use date back to Chinese medicine around 2300 BC. ...
Article
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Cannabis sativa L.-based food supplement products in pharmacies and para pharmacies in Portugal increased by 84 % between 2021 and 2022, arousing consumers' curiosity. However, information about these products is limited, and consumers are not aware of the restrictions in current European regulations. This study aims to understand Portuguese consumers' perceptions of cannabis products and identify the distribution channels and market strategy. A cross-sectional investigation on the consumption of non-medicinal products derived from cannabis occurred using a survey that aimed to collect data covering four main research questions: consumer information, consumed products, level of satisfaction, and used channels for purchasing products. Applying an original questionnaire aimed at the public via email and social networks, 176 responses were collected, where a high degree of satisfaction with taking cannabis-based products was evident, with sleep disorders and the promotion of well-being as the reasons (48,5 %) that led to the majority of respondents to seek out these products. Health professionals are already recommending cannabis-derived products; however, most respondents are unable to differentiate a food supplement from a medicine. Online purchase was the respondents' favourite choice, and respondents (93 %) were unaware of the properties of food supplements in general. Consumers ignore that the parts of the cannabis plant, whose active ingredients they expect to have a greater capacity to promote well-being, namely cannabinoids, are not authorized by the European Food Safety Authority (EFSA) to be marketed in foods or dietary supplements. Results also show that the influence of media in Portugal is significant in the choice of products, together with the lack of information on cannabis-based supplements and medicines, highlighting the need for a pro-consumer review, and promoting conscious and informed choices. Thus, we propose creating a Community Knowledge on Food Supplements linking academics, stakeholders, and authorities.
... The Journal of Headache and Pain (2024) 25:200 systems, modulation of neuronal activity and network function in the mature nervous system, and energy balance [14][15][16][17]. There are multiple different aspects of this signaling system, this includes endogenous ligands 2-arachidonoylglycerol (2-AG) and anandamide (AEA) and enzymes monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH) that serve as principal catabolic enzymes, as well as cannabinoid receptors 1 and 2 (CB 1 R and CB 2 R) [5,[18][19][20]. Additionally, dysregulation of this system has been implicated in some overlapping symptomologies with headache, such as learning and memory processes, and the development of anxiety [21,22]. ...
Article
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Background Headache is a pain disorder present in populations world-wide with a higher incidence in females. Specifically, the incidences of medication overuse headache (MOH) have increased worldwide. Comorbidities of MOH include photosensitivity, anxiety, “brain fog”, and decreased physical activity. The FDA-approved long-lasting selective β2-adrenergic receptor agonist, formoterol, is currently approved for use in severe asthma and chronic obstructive pulmonary disease. Recently, interest in repurposing formoterol for use in other disorders including Alzheimer’s disease, and neuropathic pain after spinal cord injury and traumatic brain injury has gained traction. Thus, revisiting known side-effects of formoterol, like headache and anxiety, could inform treatment paradigms. The endocannabinoid (eCB) system is implicated in the etiology of preclinical headache, with observed decreases in the circulating levels of endogenous cannabinoids, referred to as Clinical Endocannabinoid Deficiency. As cross-talk between the eCB system and adrenergic receptors has been reported, this study investigated the role of the eCB system and ability of formoterol to induce headache-like periorbital allodynic behavior. Methods Female 8-week-old C57Bl/6J mice were treated daily with formoterol (0.3 mg/kg, i.p.) for up to 42-days, during which they were assessed for periorbital allodynia, open field/novel object recognition, and photosensitivity. At the end of the study, the periaqueductal grey (PAG), a brain region known to contribute to both headache induction and maintenance, was collected and subjected to LC-MS to quantify endocannabinoid levels. Results Mice exhibited periorbital allodynia at nearly all time points tested and photosensitivity from 28-days onward. Levels of endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), along with cannabinoid receptor 1 (CB1R) expression were altered by both age and upon treatment with formoterol. Administration of FAAH/MAGL inhibitors, to target the eCB system, and a non-selective cannabinoid receptor agonist, WIN 55,212 reversed the formoterol-induced periorbital allodynia. Conclusions These results suggest that formoterol is dysregulates eCB tone to drive headache-like periorbital allodynic behaviors. These results could help inform preventative treatment options for individuals receiving formoterol, as well as provide information on the interaction between the eCB and adrenergic system. Graphical Abstract
... Cannabis sativa L. is one of the oldest cultivated plants, with evidence of human use dating back thousands of years. It has been employed as a source of fiber, food and oil and used for religious purposes [1][2][3][4][5]. The cannabinoids discovered in Cannabis sativa, such as Δ-9tetrahydrocannabinol (THC), cannabidiol (CBD), cannabinol (CBN), cannabigerol (CBG) and cannabichromen (CBC), represent a diverse group of bioactive compounds that interact with the human endocannabinoid system, each exhibiting distinct pharmacological effects, ranging from psychoactivity and pain relief to anti-inflammatory and neuroprotective properties, making them subjects of increasing scientific and medical interest. ...
Article
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Cannabinoids represent a highly researched group of plant-derived ingredients. The substantial investment of funds from state and commercial sources has facilitated a significant increase in knowledge about these ingredients. Cannabinoids can be classified into three principal categories: plant-derived phytocannabinoids, synthetic cannabinoids and endogenous cannabinoids, along with the enzymes responsible for their synthesis and degradation. All of these compounds interact biologically with type 1 (CB1) and/or type 2 (CB2) cannabinoid receptors. A substantial body of evidence from in vitro and in vivo studies has demonstrated that cannabinoids and inhibitors of endocannabinoid degradation possess anti-inflammatory, antioxidant, antitumour and antifibrotic properties with beneficial effects. This review, which spans the period from 1940 to 2024, offers an overview of the potential therapeutic applications of natural and synthetic cannabinoids. The development of these substances is essential for the global market of do-it-yourself drugs to fully exploit the promising therapeutic properties of cannabinoids.
... A significantly higher amylase and lipase activities among marijuana smokers compared to the control group observed in this study aligns with previous research indicating that marijuana use can influence enzyme activity due to its interaction with the endocannabinoid system. This interaction plays a role in regulating various physiological processes, including digestion [12,13]. ...
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Marijuana consumption is prevalent among young adults in Nigeria, and its effects on various physiological systems are of growing concern. This study investigates the impact of marijuana use on digestive enzymes, specifically serum amylase and lipase, to understand its potential implications on digestive health. This cross-sectional study was conducted in 120 participants comprising of 60 marijuana smokers and 60 non-smokers. Sociodemographic and lifestyle data were collected through structured questionnaires. Serum amylase and lipase activity levels were measured by spectrophotometric method and compared between the two groups. Statistical analysis was performed to assess differences and correlations. The study revealed that marijuana smokers had significantly higher serum amylase and lipase activities compared to non-smokers. Lipase activity correlated positively (r=0.425, p=0.019) with duration of marijuana use. Amylase activity was higher among males than females (r=-0.40, p=0.028). No significant correlation was found between the quantity of marijuana consumed and enzyme activities. Chronic marijuana consumption was associated with increased serum amylase and lipase activities, indicating potential alterations in pancreatic function. These findings suggest that marijuana use may have adverse effects on digestive health, warranting further investigation into the long-term implications. It is recommended that healthcare providers monitor digestive enzyme activities in marijuana users to detect early signs of pancreatic dysfunction.
... 2 Based on preclinical data, compounds that inhibit the cellular accumulation of anandamide exhibit significant therapeutic potential for treating multiple sclerosis, pain management, and cancer. 3,4 Extracellular anandamide is eliminated through a process involving cellular uptake followed by metabolism. ...
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Cannabinoids interact with cannabinoid receptors, influencing diverse central nervous system (CNS) and peripheral functions, including anxiety, depression, and cognition. CB1 and CB2 receptors modulate signaling cascades via G-protein coupling, with anandamide acting as an endogenous ligand for CB1 receptors. LY-2183240, a putative endocannabinoid transport blocker, elevates brain anandamide levels, showing therapeutic potential in pain management and alcohol-related behaviors. LY-2183240 enhances neuronal excitability and is classified as a new psychoactive substance (NPS). However, its precise cellular mechanisms within the CNS remain poorly understood. In this study, the effect of LY-2183240 on cortical neurons and reward-seeking behavior is investigated. Our results indicate enhanced neuronal excitability and reward-seeking behavior induction by LY-2183240, shedding light on its pharmacological profile and NPS-associated risks. Our research underscores the importance of further understanding the cellular mechanisms of LY-2183240 to inform regulatory efforts and mitigate public health risks.
... The endocannabinoid system has emerged as a promising novel therapeutic target in inflammatory diseases, cancer types, metabolic, cardiovascular, gastrointestinal diseases and urogenital system diseases [25][26][27][28]. The endocannabinoid system is expressed in the female reproductive system [29]. ...
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... . The ECS is a complex signaling network comprised of canonical receptors (CNR1 and CNR2) and endocannabinoid (EC) ligands, along with a non-canonical extended signaling network of ligands and enzymes extensively reviewed elsewhere (Di Marzo et al., 2004). CNR1 and CNR2 are primarily expressed in nerve tissues, immune cells, and reproductive tissues, where they regulate various physiological processes, including pain perception, immune responses, and reproductive functions (Zou and Kumar, 2018). ...
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... In this regard, seminal research has highlighted the role of heightened inflammatory environment in the mediobasal hypothalamus in driving the ageing process throughout the body, establishing a connection between hyperactive hypothalamic microglia, enhanced the neuroinflammatory inhibitor of nuclear factor-κB kinase subunit-β (IKKβ)/NF-κB pathway, decreased GnRH mRNA expression, and systemic ageing propagation in mice . Conversely, inhibiting IKKβ/NF-κB signaling reduced microglial activity, increased hypothalamic GnRH levels, and extended longevity in mice, and GnRH administration countered the age-related neurogenesis decline , slowed down the ageing process in peripheral organs, increasing skin thickness, bones mass and reducing muscle weakness (Di Marzo et al., 2004;Tang and Cai, 2013). This suggests that, besides its reproductive function, GnRH operates in both the central nervous system and the periphery to modulate systemic ageing. ...
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Cannabinoids are compounds found in and derived from the Cannabis plants that have become increasingly recognised as significant modulating factors of physiological mechanisms and inflammatory reactions of the organism, thus inevitably affecting maintenance of homeostasis. Medical Cannabis popularity has surged since its legal regulation growing around the world. Numerous promising discoveries bring more data on cannabinoids’ pharmacological characteristics and therapeutic applications. Given the current surge in interest in the medical use of cannabinoids, there is an urgent need for an effective method of their administration. Surpassing low bioavailability, low water solubility, and instability became an important milestone in the advancement of cannabinoids in pharmaceutical applications. The numerous uses of cannabinoids in clinical practice remain restricted by limited administration alternatives, but there is hope when biodegradable polymers are taken into account. The primary objective of this review is to highlight the wide range of indications for which cannabinoids may be used, as well as the polymeric carriers that enhance their effectiveness. The current review described a wide range of therapeutic applications of cannabinoids, including pain management, neurological and sleep disorders, anxiety, and cancer treatment. The use of these compounds was further examined in the area of dermatology and cosmetology. Finally, with the use of biodegradable polymer-based drug delivery systems (DDSs), it was demonstrated that cannabinoids can be delivered specifically to the intended site while also improving the drug’s physicochemical properties, emphasizing their utility. Nevertheless, additional clinical trials on novel cannabinoids’ formulations are required, as their full spectrum therapeutical potential is yet to be unravelled.
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Endometriosis (EM), characterized by the presence of endometrial-like tissue outside the uterus, is the leading cause of chronic pelvic pain and infertility in females of reproductive age. Despite its high prevalence, the molecular mechanisms underlying EM pathogenesis remain poorly understood. The endocannabinoid system (ECS) is known to influence several cardinal features of this complex disease including pain, vascularization, and overall lesion survival, but the exact mechanisms are not known. Utilizing CNR1 knockout (k/o), CNR2 k/o, and wild-type (WT) mouse models of EM, we reveal the contributions of ECS and these receptors in disease initiation, progression, and immune modulation. Particularly, we identified EM-specific T cell dysfunction in the CNR2 k/o mouse model of EM. We also demonstrate the impact of decidualization-induced changes on ECS components and the unique disease-associated transcriptional landscape of ECS components in EM. Imaging Mass Cytometry (IMC) analysis revealed distinct features of the microenvironment between CNR1, CNR2, and WT genotypes in the presence or absence of decidualization. This study, for the first time, provides an in-depth analysis of the involvement of the ECS in EM pathogenesis and lays the foundation for the development of novel therapeutic interventions to alleviate the burden of this debilitating condition.
Preprint
Endometriosis (EM), characterized by the presence of endometrial-like tissue outside the uterus, is the leading cause of chronic pelvic pain and infertility in females of reproductive age. Despite its high prevalence, the molecular mechanisms underlying EM pathogenesis remain poorly understood. The endocannabinoid system (ECS) is known to influence several cardinal features of this complex disease including pain, vascularization, and overall lesion survival, but the exact mechanisms are not known. Utilizing CNR1 knockout (k/o), CNR2 k/o and wild type (WT) mouse models of EM, we reveal contributions of ECS and these receptors in disease initiation, progression, and immune modulation. Particularly, we identified EM-specific T cell dysfunction in the CNR2 k/o mouse model of EM. We also demonstrate the impact of decidualization-induced changes on ECS components, and the unique disease-associated transcriptional landscape of ECS components in EM. Imaging Mass Cytometry (IMC) analysis revealed distinct features of the microenvironment between CNR1, CNR2, and WT genotypes in the presence or absence of decidualization. This study, for the first time provides an in-depth analysis of the involvement of the ECS in EM pathogenesis and lays the foundation for the development of novel therapeutic interventions to alleviate the burden of this debilitating condition.
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The primary psychoactive ingredient in cannabis, Δ^9-tetrahydrocannabinol (Δ^9-THC), affects the brain mainly by activating a specific receptor (CB1). CB1 is expressed at high levels in many brain regions, and several endogenous brain lipids have been identified as CB1 ligands. In contrast to classical neurotransmitters, endogenous cannabinoids can function as retrograde synaptic messengers: They are released from postsynaptic neurons and travel backward across synapses, activating CB1 on presynaptic axons and suppressing neurotransmitter release. Cannabinoids may affect memory, cognition, and pain perception by means of this cellular mechanism.
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Human reproduction is a rather inefficient process, yet the molecular reasons for this inefficiency remain unknown. IVF and embryo transfer (IVF–embryo transfer) also results in a high frequency of implantation failures and early spontaneous abortions. Here we show that the anandamide (AEA)-degrading enzyme, fatty acid amide hydrolase (FAAH), had significantly lower activity (46 17 versus 161 74 pmol/min per mg protein) and protein content (0.10 0.03 versus 0.23 0.06 units) in lymphocytes of IVF–embryo transfer patients who failed to achieve an ongoing pregnancy than in those who become pregnant, and this was paralleled by a significant increase in blood AEA (4.0 2.2 pmol/ml and 0.9 1.0 pmol/ml respectively). The blood levels of the other endocannabinoid, 2-arachidonoylglycerol, or of the AEA congener, N-palmitoylethanolamine, which are metabolized by enzymes different from FAAH, was not different between the pregnant and nonpregnant women, nor was there any difference in the activity of the AEA membrane transporter or the amounts of cannabinoid receptors in lymphocytes. Taken together with the reported negative effects of AEA on embryo implantation, this study indicates that low FAAH activity and subsequent increased AEA levels in blood might be one of the causes of implantation failure or pregnancy loss, thereby leading to a better understanding of the pathophysiological and therapeutic implications of endocannabinoids in human fertility.
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Two cannabinoid receptors have been identified: CB1, present in the central nervous system (CNS) and to a lesser extent in other tissues, and CB2, present outside the CNS, in peripheral organs. There is evidence for the presence of CB2-like receptors in peripheral nerve terminals. We report now that we have synthesized a CB2-specific agonist, code-named HU-308. This cannabinoid does not bind to CB1\ (Ki>10\ mu M), but does so efficiently to CB2\ (Ki=22.7± 3.9\ nM); it inhibits forskolin-stimulated cyclic AMP production in CB2-transfected cells, but does so much less in CB1-transfected cells. HU-308 shows no activity in mice in a tetrad of behavioral tests, which together have been shown to be specific for tetrahydrocannabinol (THC)-type activity in the CNS mediated by CB1. However, HU-308 reduces blood pressure, blocks defecation, and elicits anti-inflammatory and peripheral analgesic activity. The hypotension, the inhibition of defecation, the anti-inflammatory and peripheral analgesic effects produced by HU-308 are blocked (or partially blocked) by the CB2 antagonist SR-144528, but not by the CB1 antagonist SR-141716A. These results demonstrate the feasibility of discovering novel nonpsychotropic cannabinoids that may lead to new therapies for hypertension, inflammation, and pain.
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Background: Preliminary studies suggested that delta-9-tetrahydrocannabinol (THC), the major psychoactive ingredient of Cannabis sativa L., might be effective in the treatment of Tourette syndrome (TS). This study was performed to investigate for the first time under controlled conditions, over a longer-term treatment period, whether THC is effective and safe in reducing tics in TS. Method: In this randomized, double-blind, placebo-controlled study, 24 patients with TS, according to DSM-III-R criteria, were treated over a 6-week period with up to 10 mg/day of THC. Tics were rated at 6 visits (visit 1, baseline; visits 2-4, during treatment period; visits 5-6, after withdrawal of medication) using the Tourette Syndrome Clinical Global Impressions scale (TS-CGI), the Shapiro Tourette- Syndrome Severity Scale (STSSS), the Yale Global Tic Severity Scale (YGTSS), the self-rated Tourette Syndrome Symptom List (TSSL), and a videotape-based rating scale. Results: Seven patients dropped out of the study or had to be excluded, but only 1 due to side effects. Using the TS-CGI, STSSS, YGTSS, and video rating scale, we found a significant difference (p < .05) or a trend toward a significant difference (p < .05) between THC and placebo groups at visits 2, 3, and/or 4. Using the TSSL at 10 treatment days (between days 16 and 41) there was a significant difference (p < .05) between both groups. ANOVA as well demonstrated a significant difference (p = .037). No serious adverse effects occurred. Conclusion: Our results provide more evidence that THC is effective and safe in the treatment of tics. It, therefore, can be hypothesized that the central cannabinoid receptor system might play a role in TS pathology.
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In Fig. 2Fig. 2 the incorrect structure was given for 2-arachidonoylglycerol, and in Fig. 3Fig. 3 the incorrect structure was given for arachidonic acid. The correct structures are shown below.Fig. 22-ArachidonoylglycerolView Large Image | Download PowerPoint SlideFig. 3Arachidonic acidView Large Image | Download PowerPoint SlideWe apologize to the authors and readers.
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GW Pharmaceuticals is undertaking a major research programme in the UK to develop and market distinct cannabis-based prescription medicines [THC:CBD, High THC, High CBD] in a range of medical conditions. The cannabis for this programme is grown in a secret location in the UK.It is expected that the product will be marketed in the US in late 2003. GW's cannabis-based products include selected phytocannabinoids from cannabis plants, including D9 tetrahydrocannabinol (THC) and cannabidiol (CBD). The company is investigating their use in three delivery systems, including sublingual spray, sublingual tablet and inhaled (but not smoked) dosage forms. The technology is protected by patent applications. Four different formulations are currently being investigated, including High THC, THC:CBD (narrow ratio), THC:CBD (broad ratio) and High CBD. GW is also developing a specialist security technology that will be incorporated in all its drug delivery systems. This technology allows for the recording and remote monitoring of patient usage to prevent any potential abuse of its cannabis-based medicines.GW plans to enter into agreements with other companies following phase III development, to secure the best commercialisation terms for its cannabis-based medicines. In June 2003, GW announced that exclusive commercialisation rights for the drug in the UK had been licensed to Bayer AG. The drug will be marketed under the Sativex® brand name. This agreement also provides Bayer with an option to expand their license to include the European Union and certain world markets. GW was granted a clinical trial exemption certificate by the Medicines Control Agency to conduct clinical studies with cannabis-based medicines in the UK. The exemption includes investigations in the relief of pain of neurological origin and defects of neurological function in the following indications: multiple sclerosis (MS), spinal cord injury, peripheral nerve injury, central nervous system damage, neuroinvasive cancer, dystonias, cerebral vascular accident and spina bifida, as well as for the relief of pain and inflammation in rheumatoid arthritis and also pain relief in brachial plexus injury. The UK Government stated that it would be willing to amend the Misuse of Drugs Act 1971 to permit the introduction of a cannabis-based medicine.GW stated in its 2002 Annual Report that it was currently conducting five phase III trials of its cannabis derivatives, including a double-blind, placebo-controlled trial with a sublingual spray containing High THC in more than 100 patients with cancer pain in the UK. Also included is a phase III trial of THC:CBD (narrow ratio) being conducted in patients with severe pain due to brachial plexus injury, as are two more phase III trials of THC:CBD (narrow ratio) targeting spasticity and bladder dysfunction in multiple sclerosis patients. Another phase III trial of THC:CBD (narrow ratio) in patients with spinal cord injury is also being conducted. Results from the trials are expected during 2003.Three additional trials are also in the early stages of planning. These trials include a phase I trial of THC:CBD (broad ratio) in patients with inflammatory bowel disease, a phase I trial of High CBD in patients with psychotic disorders such as schizophrenia, and a preclinical trial of High CBD in various CNS disorders (including epilepsy, stroke and head injury).GW Pharmaceuticals submitted an application for approval of cannabis-based medicines to UK regulatory authorities in March 2003. Originally GW hoped to market cannabis-based prescription medicines by 2004, but is now planning for a launch in the UK towards the end of 2003.Several trials for GW's cannabis derivatives have also been completed, including four randomised, double-blind, placebo-controlled phase III clinical trials conducted in the UK. The trials were initiated by GW in April 2002, to investigate the use of a sublingual spray containing THC:CBD (narrow ratio) in the following medical conditions: pain in spinal cord injury, pain and sleep in MS and spinal cord injury, neuropathic pain in MS and general neuropathic pain (presented as allodynia). Results from these trials show that THC:CBD (narrow ratio) caused statistically significant reductions in neuropathic pain in patients with MS and other conditions. In addition, improvements in other MS symptoms were observed as well.Phase II studies of THC:CBD (narrow ratio) have also been completed in patients with MS, spinal cord injury, neuropathic pain and a small number of patients with peripheral neuropathy secondary to diabetes mellitus or AIDS. A phase II trial of THC:CBD (broad ratio) has also been completed in a small number of patients with rheumatoid arthritis, as has a trial of High CBD in patients with neurogenic symptoms. A phase II trial has also been evaluated with High THC in small numbers of
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ANANDAMIDE (N-arachidonoyl-ethanolamine) was recently identified as a brain arachidonate derivative that binds to and activates cannabinoid receptors1–4, yet the mechanisms underlying formation, release and inactivation of this putative messenger molecule are still unclear. Here we report that anandamide is produced in and released from cultured brain neurons in a calcium ion-dependent manner when the neurons are stimulated with membrane-depolarizing agents. Anandamide formation occurs through phos-phodiesterase-mediated cleavage of a novel phospholipid precursor, N-arachidonoyl-phosphatidylethanolamine. A similar mechanism also governs the formation of a family of anandamide congeners, whose possible roles in neuronal signalling remain unknown. Our results and those of others5,6indicate therefore that multiple biochemical pathways may participate in anandamide formation in brain tissue. The life span of extracellular anandamide is limited by a rapid and selective process of cellular uptake, which is accompanied by hydrolytic degradation to ethanolamine and arachidonate. Our results thus strongly support the proposed role of anandamide as an endogenous neuronal messenger.
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We have tested our prediction that AM630 is a CB2 cannabinoid receptor ligand and also investigated whether L759633 and L759656, are CB2 receptor agonists. Binding assays with membranes from CHO cells stably transfected with human CB1 or CB2 receptors using [3H]-CP55940, confirmed the CB2-selectivity of L759633 and L759656 (CB2/CB1 affinity ratios=163 and 414 respectively) and showed AM630 to have a Ki at CB2 receptors of 31.2 nM and a CB2/CB1 affinity ratio of 165. In CB2-transfected cells, L759633 and L759656 were potent inhibitors of forskolin-stimulated cyclic AMP production, with EC50 values of 8.1 and 3.1 nM respectively and CB1/CB2 EC50 ratios of >1000 and >3000 respectively. AM630 inhibited [35S]-GTPγS binding to CB2 receptor membranes (EC50=76.6 nM), enhanced forskolin-stimulated cyclic AMP production in CB2-transfected cells (5.2 fold by 1 μM), and antagonized the inhibition of forskolin-stimulated cyclic AMP production in this cell line induced by CP55940. In CB1-transfected cells, forskolin-stimulated cyclic AMP production was significantly inhibited by AM630 (22.6% at 1 μM and 45.9% at 10 μM) and by L759633 at 10 μM (48%) but not 1 μM. L759656 (10 μM) was not inhibitory. AM630 also produced a slight decrease in the mean inhibitory effect of CP55940 on cyclic AMP production which was not statistically significant. We conclude that AM630 is a CB2-selective ligand that behaves as an inverse agonist at CB2 receptors and as a weak partial agonist at CB1 receptors. L759633 and L759656 are both potent CB2-selective agonists. British Journal of Pharmacology (1999) 126, 665–672; doi:10.1038/sj.bjp.0702351
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The stimulus-induced biosynthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG) in intact mouse J774 macrophages and the inactivation of 2-AG by the same cells or by rat circulating macrophages was studied. By using gas chromatography-mass spectrometry, we found that ionomycin (5 µm) and lipopolysaccharide (LPS, 200 µg·mL−1) cause a 24-fold and 2.5-fold stimulation of 2-AG levels in J774 cells, respectively, thus providing unprecedented evidence that this cannabimimetic metabolite can be synthesized by macrophages. In J774 cells, LPS also induced a 7.8-fold increase of the levels of the other endocannabinoid, anandamide, and, in rat circulating macrophages, an almost twofold increase of 2-AG levels. Extracellular [3H]2-AG was cleared from the medium of intact J774 macrophages (t1/2 = 19–28 min) and esterified to phospholipids, diacylglycerols and triglycerides or hydrolyzed to [3H]arachidonic acid and glycerol. These catabolic processes were attenuated differentially by various enzyme inhibitors. Rat circulating macrophages were shown to contain enzymatic activities for the hydrolysis of 2-AG, including: (a) fatty acid amide hydrolase (FAAH), the enzyme responsible for anandamide breakdown and previously shown to catalyse also 2-AG hydrolysis, and (b) a 2-AG hydrolase activity different from FAAH and down-regulated by LPS. High levels of FAAH mRNA were found in circulating macrophages but not platelets, which, however, contain a 2-AG hydrolase. Both platelets and macrophages were shown to express the mRNA for the CB1 cannabinoid receptor. A macrophage 2-AG hydrolase with apparent Km = 110 µm and Vmax = 7.9 nmol·min−1·(mg protein)−1 was partially characterized in J774 cells and found to exhibit an optimal pH of 6–7 and little or no sensitivity to typical FAAH inhibitors. These findings demonstrate for the first time that macrophages participate in the homeostasis of the hypotensive and immunomodulatory endocannabinoid 2-AG through metabolic mechanisms that are subject to regulation.
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(−)-Cannabidiol (CBD) is a non-psychotropic component of Cannabis with possible therapeutic use as an anti-inflammatory drug. Little is known on the possible molecular targets of this compound. We investigated whether CBD and some of its derivatives interact with vanilloid receptor type 1 (VR1), the receptor for capsaicin, or with proteins that inactivate the endogenous cannabinoid, anandamide (AEA). CBD and its enantiomer, (+)-CBD, together with seven analogues, obtained by exchanging the C-7 methyl group of CBD with a hydroxy-methyl or a carboxyl function and/or the C-5′ pentyl group with a di-methyl-heptyl (DMH) group, were tested on: (a) VR1-mediated increase in cytosolic Ca2+ concentrations in cells over-expressing human VR1; (b) [14C]-AEA uptake by RBL-2H3 cells, which is facilitated by a selective membrane transporter; and (c) [14C]-AEA hydrolysis by rat brain membranes, which is catalysed by the fatty acid amide hydrolase. Both CBD and (+)-CBD, but not the other analogues, stimulated VR1 with EC50=3.2 – 3.5 μM, and with a maximal effect similar in efficacy to that of capsaicin, i.e. 67 – 70% of the effect obtained with ionomycin (4 μM). CBD (10 μM) desensitized VR1 to the action of capsaicin. The effects of maximal doses of the two compounds were not additive. (+)-5′-DMH-CBD and (+)-7-hydroxy-5′-DMH-CBD inhibited [14C]-AEA uptake (IC50=10.0 and 7.0 μM); the (−)-enantiomers were slightly less active (IC50=14.0 and 12.5 μM). CBD and (+)-CBD were also active (IC50=22.0 and 17.0 μM). CBD (IC50=27.5 μM), (+)-CBD (IC50=63.5 μM) and (−)-7-hydroxy-CBD (IC50=34 μM), but not the other analogues (IC50>100 μM), weakly inhibited [14C]-AEA hydrolysis. Only the (+)-isomers exhibited high affinity for CB1 and/or CB2 cannabinoid receptors. These findings suggest that VR1 receptors, or increased levels of endogenous AEA, might mediate some of the pharmacological effects of CBD and its analogues. In view of the facile high yield synthesis, and the weak affinity for CB1 and CB2 receptors, (−)-5′-DMH-CBD represents a valuable candidate for further investigation as inhibitor of AEA uptake and a possible new therapeutic agent. British Journal of Pharmacology (2001) 134, 845–852; doi:10.1038/sj.bjp.0704327
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We have studied the effect of cannabinoid agonists (CP 55,940 and cannabinol) on intestinal motility in a model of intestinal inflammation (induced by oral croton oil in mice) and measured cannabinoid receptor expression, endocannabinoids (anandamide and 2-arachidonylglycerol) and anandamide amidohydrolase activity both in physiological and pathophysiological states. CP 55,940 (0.03 – 10 nmol mouse−1) and cannabinol (10 – 3000 nmol mouse−1) were more active in delaying intestinal motility in croton oil-treated mice than in control mice. These inhibitory effects were counteracted by the selective cannabinoid CB1 receptor antagonist SR141716A (16 nmol mouse−1). SR141716A (1 – 300 nmol mouse−1), administered alone, increased intestinal motility to the same extent in both control and croton oil-treated mice Croton oil-induced intestinal inflammation was associated with an increased expression of CB1 receptor, an unprecedented example of up-regulation of cannabinoid receptors during inflammation. High levels of anandamide and 2-arachidonylglycerol were detected in the small intestine, although no differences were observed between control and croton oil-treated mice; by contrast anandamide amidohydrolase activity increased 2 fold in the inflamed small intestine. It is concluded that inflammation of the gut increases the potency of cannabinoid agonists possibly by ‘up-regulating’ CB1 receptor expression; in addition, endocannabinoids, whose turnover is increased in inflamed gut, might tonically inhibit intestinal motility. British Journal of Pharmacology (2001) 134, 563–570; doi:10.1038/sj.bjp.0704293
Article
The levels of N-arachidonoylethanolamine (anandamide), an endogenous cannabinoid-receptor ligand, and a relevant molecule, N-arachidonoylphosphatidylethanolamine (N-arachidonoylPtdEtn), in rat brain were investigated using a newly developed sensitive analytical method. We found that rat brain contains small but significant amounts of these two types of N-arachidonoyl lipids (4.3 pmol/g tissue and 50.2 pmol/g tissue, respectively). Then, we investigated how N-arachidonoylethanolamine (anandamide) is produced in the brain. We found that anandamide can be formed enzymatically via two separate synthetic pathways in the brain: enzymatic condensation of free arachidonic acid and ethanolamine; and formation of N-arachidonoylPtdEtn from PtdEtn and arachidonic acid esterified at the 1-position of phosphatidyl-choline (PtdCho), and subsequent release of anandamide from N-arachidonoylPtdEtn through the action of a phosphodiesterase. We confirmed that rat brain contains both the enzyme activities and lipid substrates involved in these reactions. Several lines of evidence strongly suggest that the second pathway, rather than the first one, meets the requirements and conditions for the synthesis of various species of N-acylethanolamine including anandamide in the brain.