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Review article: Endocannabinoids and their receptors in the enteric nervous system
Abstract
The therapeutic actions of cannabinoids have been known for centuries. In the last 25 years this area of research has grown exponentially with the discovery of specific cannabinoid receptors and endogenous ligands.
In the enteric nervous system of gastrointestinal tract, cannabinoid receptors are located on enteric nerve terminals where they exert inhibitory actions on neurotransmission to reduce motility and secretion. Endogenous cannabinoids are present in the enteric nervous system, as are the degradative enzymes necessary to inhibit their action. The cellular mechanism of action of endocannabinoids has not been established in the enteric nervous system. Endocannabinoids not only act at cannabinoid receptors, but potentially also at vanilloid and 5-HT3 receptors, both of which are expressed in the gastrointestinal tract. The interactions between endocannabinoids and these other important receptor systems have not been extensively investigated.
A greater understanding of the endocannabinoid system in the enteric nervous system could lead to advances with important therapeutic potential in the treatment of gastrointestinal disorders such as irritable bowel syndrome, inflammatory bowel disease, secretory diarrhoea and gastro-oesophageal reflux disease.
... The ECS components are widely expressed in the GI tract. The presence of CB1 receptors, the most predominant in the intestines, was confirmed in the enteric neurons [156], myocytes [157], and epithelial cells [158]. It should be emphasized that intestinal CB1 receptors participate in epithelial regeneration [159] and therefore play a crucial role in the maintenance of the intestinal barrier integrity [158]. ...
... CB2 receptors are present in the GI tract, but their expression is lower in comparison to CB1 receptors [14,156]. Similarly to CB1 receptors, LPS-or DSS-induced colitis does not alter the mRNA expression of CB2 receptors, but these receptors do play an important role during intestinal inflammation. ...
... For example, it was shown that LPS increased the expression of c-fos in rat ileal EGCs and enteric neurons, and this was attenuated by CB2 agonists. Since enteric neurons do express CB2 receptors under inflammatory conditions, LPS activation of EGCs could be secondary to CB2-mediated neuronal activation [156]. ...
The enteric nervous system (ENS) is a part of the autonomic nervous system that intrinsically innervates the gastrointestinal (GI) tract. Whereas enteric neurons have been deeply studied, the enteric glial cells (EGCs) have received less attention. However, these are immune-competent cells that contribute to the maintenance of the GI tract homeostasis through supporting epithelial integrity, providing neuroprotection, and influencing the GI motor function and sensation. The endogenous cannabinoid system (ECS) includes endogenous classical cannabinoids (anandamide, 2-arachidonoylglycerol), cannabinoid-like ligands (oleoylethanolamide (OEA) and palmitoylethanolamide (PEA)), enzymes involved in their metabolism (FAAH, MAGL, COX-2) and classical (CB1 and CB2) and non-classical (TRPV1, GPR55, PPAR) receptors. The ECS participates in many processes crucial for the proper functioning of the GI tract, in which the EGCs are involved. Thus, the modulation of the EGCs through the ECS might be beneficial to treat some dysfunctions of the GI tract. This review explores the role of EGCs and ECS on the GI tract functions and dysfunctions, and the current knowledge about how EGCs may be modulated by the ECS components, as possible new targets for cannabinoids and cannabinoid-like molecules, particularly those with potential nutraceutical use.
... Cannabinoid receptors regulate gastrointestinal tract (GIT) motility and secretion, sensation, emesis, satiety, and inflammation (Hornby and Prouty 2004;Izzo 2004;Duncan et al. 2005aDuncan et al. , 2008Storr and Sharkey 2007;Wright et al. 2008;Sharkey and Wiley 2016;Lee et al. 2016;Di Patrizio 2016). ...
... CB1R-immunoreactivity (IR) is also expressed by enteric neurons (Kulkarni-Narla and Brown 2000;Van Sickle et al. 2001;Coutts et al. 2002;Duncan et al. 2005a;Galiazzo et al. 2018), enteroendocrine cells (EECs), and lamina propria cells (Adami et al. 2002;Hornby and Prouty 2004;Galiazzo et al. 2018) of several mammalian species. CB2R may be expressed by GIT macrophages, plasma cells, mast cells, dendritic cells, lymphocytes, epithelial cells, and enteric glial cells (Facci et al. 1995;Wright et al. 2005Wright et al. , 2008Duncan et al. 2005bDuncan et al. , 2008Svensson et al. 2010;Ke et al. 2016;Galiazzo et al. 2018). ...
... Faint CB1R immunoreactive neurons were observed in the cat enteric neurons; this data is consistent with the findings observed in many other species, such as rodents, ferrets, dogs, and humans (Kulkarni-Narla and Brown 2000;Van Sickle et al. 2001;Coutts et al. 2002;Storr et al. 2004;Duncan et al. 2005a;Wright et al. 2005;Marquez et al. 2009;Galiazzo et al. 2018;Grill et al. 2019). In rodents, CB1R is mainly expressed by cholinergic excitatory motor neurons. ...
A growing body of literature indicates that activation of cannabinoid receptors may exert beneficial effects on gastrointestinal inflammation and visceral hypersensitivity. The present study aimed to immunohistochemically investigate the distribution of the canonical cannabinoid receptors CB1 (CB1R) and CB2 (CB2R) and the putative cannabinoid receptors G protein-coupled receptor 55 (GPR55), nuclear peroxisome proliferator-activated receptor alpha (PPARα), transient receptor potential ankyrin 1 (TRPA1), and serotonin receptor 5-HT1a 5-HT1aR) in tissue samples of the gastrointestinal tract of the cat. CB1R-immunoreactivity (CB1R-IR) was observed in gastric epithelial cells, intestinal enteroendocrine cells (EECs) and goblet cells, lamina propria mast cells (MCs), and enteric neurons. CB2R-IR was expressed by EECs, enterocytes, and macrophages. GPR55-IR was expressed by EECs, macrophages, immunocytes, and MP neurons. PPARα-IR was expressed by immunocytes, smooth muscle cells, and enteroglial cells. TRPA1-IR was expressed by enteric neurons and intestinal goblet cells. 5-HT1a receptor-IR was expressed by gastrointestinal epithelial cells and gastric smooth muscle cells. Cannabinoid receptors showed a wide distribution in the feline gastrointestinal tract layers. Although not yet confirmed/supported by functional evidences, the present research might represent an anatomical substrate potentially useful to support, in feline species, the therapeutic use of cannabinoids during gastrointestinal inflammatory diseases.
... Cannabis or its constituents exert their effects through CB1 and CB2 receptors, found throughout the GI system (liver, pancreas, stomach, small and large intestines (Fig. 2) (2-AG) [10,27]. Other endocannabinoids include noladin ether, virodhamine and N-arachidonoyl dopamine [28]. ...
... Functions of the CB1 and CB2 receptors are ascertained by their locations in the organ systems. In the gut, CB1 receptors are found in the myenteric plexus (responsible for motor control of the GI tract) and submucosal plexus (responsible for secretomotor and vasomotor actions of the gut) [27]. CB2 receptors are present in the immune cells, such as plasma cells and macrophages, in the lamina propria of the GI tract [31] and are also thought to be present in peripheral nerve terminals [32]. ...
... Activation of CB1 and CB2 receptors produces anti-emetic, anti-motility, and anti-inflammatory effects through inhibition of adenylyl cyclase with the reduced cAMP formation (Gi/o coupled), thus blocking neurotransmitter release from a presynaptic neuron by CB1 and pro-inflammatory cytokine release by CB2 [34,35]. CB1 also inhibits the activation of N-and P/Q type intracellular calcium channels, decreasing calcium release, but activates inward-rectifying potassium and potassium-A channels and mitogen-activated protein kinase; together, all these mechanisms help modulate pain [27,28] ( Table 1). When cannabinoids bind to the prejunctional CB1 receptors, a reduction in excitatory neurotransmission causes decreased gut motility and secretion [36]. ...
For many centuries, cannabis (marijuana) has been used for both recreational and medicinal purposes. Currently, there are about 192 million cannabis users worldwide, constituting approximately 3.9% of the global population. Cannabis comprises more than 70 aromatic hydrocarbon compounds known as cannabinoids. Endogenous circulating cannabinoids, or endocannabinoids, such as anandamide and 2-arachidonoyl-glycerol, their metabolizing enzymes (fatty acid amide hydrolase and monoacylglycerol lipase) and 2 G-protein coupled cannabinoid receptors, CB1 and CB2, together represent the endocannabinoid system and are present throughout the human body. In the gastrointestinal (GI) tract, the activated endocannabinoid system reduces gut motility, intestinal secretion and epithelial permeability, and induces inflammatory leukocyte recruitment and immune modulation through the cannabinoid receptors present in the enteric nervous and immune systems. Because of the effects of cannabinoids on the GI tract, attempts have been made to investigate their medicinal properties, particularly for GI disorders such as pancreatitis, hepatitis, and inflammatory bowel diseases (IBD). The effects of cannabis on IBD have been elucidated in several small observational and placebo-controlled studies, but with varied results. The small sample size and short follow-up duration in these studies make it difficult to show the clear benefits of cannabis in IBD. However, cannabis is now being considered as a potential drug for inflammatory GI conditions, particularly IBD, because of its spreading legalization in the United States and other countries and the growing trend in its use. More high-quality controlled studies are warranted to elucidate the mechanism and benefits of cannabis use as a possible option in IBD management.
... 15,48,52 Of particular relevance, CB 1 is expressed in the enteric nervous system (ENS) and the autonomic and central nervous systems (CNS) and is one of the most abundant GPCRs in the brain. 53 In the GI tract, CB 1 is expressed presynaptically on all classes of enteric neurons, except nitric oxide synthase-expressing inhibitory motor neurons. 52,53 It is also found on the terminals of primary afferent nerves innervating the gut and on glucose-dependent insulinotropic polypeptide (K cells) and cholecystokinin (I cells) enteroendocrine cells in the upper small intestine. ...
... 53 In the GI tract, CB 1 is expressed presynaptically on all classes of enteric neurons, except nitric oxide synthase-expressing inhibitory motor neurons. 52,53 It is also found on the terminals of primary afferent nerves innervating the gut and on glucose-dependent insulinotropic polypeptide (K cells) and cholecystokinin (I cells) enteroendocrine cells in the upper small intestine. 54,55 Activation of the CB 1 receptor on enteric nerves leads to a decrease in neurotransmitter release into the synapse and therefore a depression of excitatory neurotransmission in the ENS. ...
The maintenance of intestinal homeostasis is fundamentally important to health. Intestinal barrier function and immune regulation are key determinants of intestinal homeostasis and are therefore tightly regulated by a variety of signaling mechanisms. The endocannabinoid system is a lipid mediator signaling system widely expressed in the gastrointestinal tract. Accumulating evidence suggests the endocannabinoid system is a critical nexus involved in the physiological processes that underlie the control of intestinal homeostasis. In this review we will illustrate how the endocannabinoid system is involved in regulation of intestinal permeability, fluid secretion and immune regulation. We will also demonstrate a reciprocal regulation between the endocannabinoid system and the gut microbiome. The role of the endocannabinoid system is complex and multifaceted, responding to both internal and external factors while also serving as an effector system for the maintenance of intestinal homeostasis.
... CB receptors have been described throughout the gastrointestinal tract and are endogenously activated by anandamide (AEA) and 2-arachidonylglycerol (2-AG). These ligands cause reduce gastrointestinal secretion, motility and blood flow [14]. Activation of cannabinoid receptors also enhances central hunger responses ('munchies') [15]. ...
... Pathophysiology 2022, x, FOR PEER REVIEW 5 trointestinal tract and are endogenously activated by anandamide (AEA) and 2-arachidonylglycerol (2-AG). These ligands cause reduce gastrointestinal secretion, motility and blood flow [14]. Activation of cannabinoid receptors also enhances central hunger responses ('munchies') [15]. ...
Legalization/decriminalization of cannabis will increase the numbers of patients who have had recent exposure to recreational or medical cannabis. Currently, little has been reported about potential interactions between cannabis use and Propofol anesthesia e.g., for oropharyngeal procedures. We describe three cases of ‘cannabis-induced hypersalivation after propofol’ (CHAP) and present our institutions’ experience with this unique pharmacological combination. Increased hypersalivation may complicate procedures and represent a procedural risk of suffocation. We evaluate possible pharmacological interactions that might underlie this phenomenon and consider management options going forward.
... Dans le tractus gastro-intestinal, les récepteurs aux cannabinoïdes régulent notamment la motilité, la sécrétion, les vomissements, la satiété et l'inflammation (DiPatrizio, 2016;Duncan et al., 2005Duncan et al., , 2008Galiazzo et al., 2018;Izzo, 2004;Sharkey & Wiley, 2016;Storr & Sharkey, 2007;Wright et al., 2008). CB1R est notamment exprimé par les neurones du système nerveux entérique des rongeurs, du cobaye, du porc, et du furet (Coutts et al., 2002;Duncan et al., 2005;Kulkarni-Narla & Brown, 2000;Van Sickle et al., 2001). ...
... Dans le tractus gastro-intestinal, les récepteurs aux cannabinoïdes régulent notamment la motilité, la sécrétion, les vomissements, la satiété et l'inflammation (DiPatrizio, 2016;Duncan et al., 2005Duncan et al., , 2008Galiazzo et al., 2018;Izzo, 2004;Sharkey & Wiley, 2016;Storr & Sharkey, 2007;Wright et al., 2008). CB1R est notamment exprimé par les neurones du système nerveux entérique des rongeurs, du cobaye, du porc, et du furet (Coutts et al., 2002;Duncan et al., 2005;Kulkarni-Narla & Brown, 2000;Van Sickle et al., 2001). CB2R peut être exprimé par les macrophages, les plasmocytes, les mastocytes, les cellules dendritiques, les lymphocytes, les cellules musculaires lisses, les cellules épithéliales et les neurones entériques Facci et al., 1995;Ke et al., 2016;Svensson et al., 2010;Wright et al., 2008). ...
L’obésité est une pathologie dont la fréquence est en constante augmentation. Elle correspond à un excès de tissu adipeux (TA) dont les fonctions peuvent être altérées. Parmi les dérégulations métaboliques, il peut exister une hyperactivation du système endocannabinoïde (SEC). Ce système, composé de récepteurs aux cannabinoïdes (CB1R et CB2R), de leurs ligands endogènes (EndoCannabinoïdes – ECs) et des enzymes impliquées dans leur biosynthèse et leur dégradation, est présent dans le système nerveux central ainsi que dans divers tissus périphériques.Le blocage des CB1R par le Rimonabant, premier antagoniste commercialisé en 2006, s’est révélé être une approche thérapeutique efficace en réduisant la prise alimentaire, la masse corporelle et en améliorant significativement les paramètres métaboliques. Néanmoins, les troubles psychiatriques sévères associés, consécutifs aux effets centraux, ont valu à ce composé d’être retiré du marché 2 ans plus tard.Depuis, l’utilisation d’antagonistes ne franchissant pas la barrière hémato-encéphalique a permis de démontrer que l’inactivation des CB1R périphériques était suffisante pour diminuer le risque cardio-métabolique chez la souris obèse. Compte tenu du rôle central joué par le TA dans l’étiologie des pathologies associées à l’obésité, il apparait important de préciser la relation existante entre le SEC et le métabolisme adipocytaire. Dans ce contexte, ces travaux de thèse ont pour objectifs de préciser le rôle des ECs sur l’activité lipolytique adipocytaire, d’évaluer les capacités sécrétoires des différents dépôts de TA et d’étudier l’impact d’agonistes et d’antagonistes des CB1R sur l’adipogenèse. Une dernière partie, est consacrée à la caractérisation de l’activité biologique de nouveaux antagonistes des CB1R.Tout d’abord, l’étude des conséquences de la modulation du SEC sur l’activité lipolytique a permis de démontrer que l’activation des CB1R, en stimulant la voie de signalisation PI3K/Akt, conduit à une diminution de la lipolyse. Les résultats suggèrent également que les ECs produits par le TA, pourraient alimenter le pool d’ECs circulants et être à l’origine d’effets exocrines néfastes.L’étude de la production des ECs in vitro, par des explants de TA viscéral et sous-cutané chez la souris et chez l’Homme obèses, a confirmé la modification des capacités sécrétoires en ECs. Ces résultats préliminaires valident une approche méthodologique originale qui nous permet d’envisager une exploration plus poussée des mécanismes de la production des ECs.Par ailleurs, le rôle des ECs sur la différenciation de cellules souches issues de la fraction stroma-vasculaire de TA sain et pathologique de souris a été étudié. Des essais préliminaires ont permis de suggérer l’existence d’un lien entre différenciation adipocytaire et activité des CB1R.Enfin, les études de caractérisation de nouveaux antagonistes des CB1R ont démontré des effets intéressants des molécules JM-00266 et HR-0133 sur la masse corporelle et le métabolisme glucido-lipidique. Toutefois, l’optimisation, le développement et la caractérisation de ces nouveaux types d’antagonistes à des fins thérapeutiques apparait essentiel dans la lutte contre l’obésité et ses complications.Mots clés : Obésité, Système Endocannabinoïde, Tissu Adipeux, Métabolisme glucido-lipidique
... THC binds to cannabinoid type 1 (CB1) and type 2 (CB2) receptors in human tissues. The CB1 receptor is highly localized to neuronal tissue whereas CB2 receptors are expressed primarily by immune cells [16,17]. The exact mechanism of the antiemetic action of THC is unknown, though several theories exist regarding how the CB1 subtype of cannabinoid receptors may be involved in the development of CHS [18][19][20][21][22][23]. ...
... Toxicological analysis of hospital admission blood detected THC and its metabolites, in addition to presence of haloperidol, and ondansetron, reflective of the medications that she was given two days before her final ED visit. Genetic studies identified a pathogenic variant in the MYBPC3 gene (heterozygous deletion of exons [13][14][15][16][17][18][19][20][21][22][23] which is predominantly associated with autosomal dominant hypertrophic cardiomyopathy. Genetic testing furthermore identified a variant of unknown significance in the RYR2 gene (c.7234G ...
We report the death of a 22-year-old woman, with a 3½ year history of cyclic vomiting and cannabis use since age 14, who developed torsades de pointes cardiac arrythmia while being treated in the emergency room for nausea and vomiting. Resuscitation restored spontaneous cardiac circulation, however, due to post-cardiac arrest anoxic brain injury, she never regained consciousness and was declared brain dead 4 days later. Postmortem examination confirmed hypoxic-ischemic encephalopathy, in keeping with the in-hospital diagnosis of brain death. The heart was anatomically normal but showed signs of acute post-cardiopulmonary arrest reperfusion injury. As a consequence of limited survival in hospital in a neuro-vegetative state, early bronchopneumonia and isolated pulmonary thromboemboli were seen. Toxicological studies confirmed cannabis use, in addition to the presence of haloperidol and ondansetron. Genetic studies were performed to rule out a possible channelopathy and revealed a mutation in the MYBPC3 and RYR2 genes. Death in this woman with cannabinoid hyperemesis syndrome was attributed to a fatal cardiac arrhythmia complicating vomiting-induced hypokalemia and treatment with QT interval prolonging and potentially arrhythmogenic medications, with the identified cardiac genetic mutations listed as contributing factors. The emphasis of this report is a) to raise awareness that death can occur due to cyclic vomiting, b) provide a brief but practical overview of cannabinoid hyperemesis syndrome, c) describe the findings from our postmortem examination and come to the most reasonable cause and mechanism of death, d) comment on the risk factors associated with torsades de pointes cardiac arrythmia, and e) conclude that a complete postmortem examination is needed to exclude an anatomical or toxicological cause of death in cannabinoid hyperemesis syndrome, a disabling but preventable disorder.
... Studies have revealed that cannabinoids reduce the production of gastric and intestinal fluid and inhibit gastrointestinal contraction/mobility by activating CB 1 receptors. 52,53 Meanwhile, the CB 1 receptor antagonist rimonabant counteracts the long-lasting decrease in rat gastric contractility evoked by intravenously administered THC. 54 Besides, the inhibition of certain hydrolases of endocannabinoids by phytocannabinoids may also mediate the activation of CB receptors. ...
... First, in addition to being localized within the gut, CB 1 receptors are also present on peripheral nerve fibers within the brain−gut axis as well as mesolimbic and brainstem neurons involved in the reward mechanisms of food intake. 53 Thereby, cannabinoids exert their orexigenic effects via the mesolimbic pathway, directly stimulating the finding and consumption of food. 61 As a consequence, short-term use of THC products stimulates the appetite and palatability of food, increases the rates of energy uptake and storage, decreases the latency between meals, and decreases resting metabolic rates, while the results could be reversed via peripherally restricted CB1 receptor antagonists. ...
Cannabis is an excellent natural source of fiber and various bioactive cannabinoids. So far, at least 120 cannabinoids have been identified, and more novel cannabinoids are gradually being unveiled by detailed cannabis studies. However, cannabinoids in both natural and isolated forms are especially vulnerable to oxygen, heat, and light. Therefore, a diversity of cannabinoids is associated with their chemical instability to a large extent. The research status of structural conversion of cannabinoids is introduced. On the other hand, the use of drug-type cannabis and the phytocannabinoids thereof has been rapidly popularized and plays an indispensable role in both medical therapy and daily recreation. The recent legalization of edible cannabis further extends its application into the food industry. The varieties of legal edible cannabis products in the current commercial market are relatively monotonous due to rigorous restrictions under the framework of Cannabis Regulations and infancy of novel developments. Meanwhile, patents/studies related to the safety and quality assurance systems of cannabis edibles are still rare and need to be developed. Furthermore, along with cannabinoids, many phytochemicals such as flavonoids, lignans, terpenoids, and polysaccharides exist in the cannabis matrix, and these may exhibit prebiotic/probiotic properties and improve the composition of the gut microbiome. During metabolism and excretion, the bioactive phytochemicals of cannabis, mostly the cannabinoids, may be structurally modified during enterohepatic detoxification and gut fermentation. However, the potential adverse effects of both acute and chronic exposure to cannabinoids and their vulnerable groups have been clearly recognized. Therefore, a comprehensive understanding of the chemistry, metabolism, toxicity, commercialization, and regulations regarding cannabinoid edibles is reviewed and updated in this contribution.
... Concerning the endocannabinoid-like mediators, growing interest is driven by palmitoylethanolamide (PEA) and cannabidiol (CBD) [6,21]. Growing research regarding this topic indicates that activation of the cannabinoid and cannabinoid-related receptors, mediated by endogenous or plant-derived cannabinoids, may influence GIT motility and secretion, with a reduction in inflammation and visceral pain [17,[22][23][24][25][26][27]. ...
... In the GIT, cannabinoid receptors regulate motility, secretion, emesis, food intake, and inflammation [15,17,24,26]. In this paper, the authors focused their attention on the presence of the ECS in the ileal MP of pigs, with particular emphasis on both the cannabinoid receptors, namely CB1R and CB2R, and the cannabinoid-related receptors TRPV1, TRPA1, and 5-HT1aR by carrying out immunohistochemical analysis. ...
An important piece of evidence has shown that molecules acting on cannabinoid receptors influence gastrointestinal motility and induce beneficial effects on gastrointestinal inflammation and visceral pain. The aim of this investigation was to immunohistochemically localize the distribution of canonical cannabinoid receptor type 1 (CB1R) and type 2 (CB2R) and the cannabinoid-related receptors transient potential vanilloid receptor 1 (TRPV1), transient potential ankyrin receptor 1 (TRPA1), and serotonin receptor 5-HT1a (5-HT1aR) in the myenteric plexus (MP) of pig ileum. CB1R, TRPV1, TRPA1, and 5-HT1aR were expressed, with different intensities in the cytoplasm of MP neurons. For each receptor, the proportions of the immunoreactive neurons were evaluated using the anti-HuC/HuD antibody. These receptors were also localized on nerve fibers (CB1R, TRPA1), smooth muscle cells of tunica muscularis (CB1R, 5-HT1aR), and endothelial cells of blood vessels (TRPV1, TRPA1, 5-HT1aR). The nerve varicosities were also found to be immunoreactive for both TRPV1 and 5-HT1aR. No immunoreactivity was documented for CB2R. Cannabinoid and cannabinoid-related receptors herein investigated showed a wide distribution in the enteric neurons and nerve fibers of the pig MP. These results could provide an anatomical basis for additional research, supporting the therapeutic use of cannabinoid receptor agonists in relieving motility disorders in porcine enteropathies.
... Endocannabinoids include anandamide (AEA) and 2-arachidonoylglycerol (2-AG), along with naturally occurring acylethanolamides (AEs), such as palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) Ückert et al., 2017). The "classical" CB receptors, CB 1 and CB 2 are located in brain regions as well as in peripheral tissues, mainly on enteric neurons, nerve fibres and terminals in the enteric nervous system (ENS) (Duncan et al., 2005;Lalanne et al., 2017). The CB 1 receptors affect the neurotransmitter release in both central nervous system (CNS) and the ENS. ...
... compound tetrahydrocannabinol (THC) decrease the production of gastric acid (Duncan et al., 2005;Elia et al., 2015). On this basis, CB ligands could be employed in the treatment of the GI disorders, such as irritable bowel syndrome (IBS) (Zgair et al., 2017). ...
The endocannabinoid system (ECS) plays a crucial role in numerous physiological processes in the central and peripheral nervous systems. In the gastrointestinal (GI) tract, selective cannabinoid (CB) receptor agonists exert potent inhibitory actions on motility and pain signalling. In the present study, we used mouse models of diarrhea, hypermotility, and abdominal pain to examine whether a novel synthetic CB1 receptor agonist AM9405 [(2-(2,6-dihydroxy-4-(2-methyloctan-2-yl)phenyl)-1,3-dimethyl-1H-benzo[d]imidazol-3-ium bromide); also known as GAT379] exhibits effects of potential therapeutic relevance. AM9405 significantly slowed mouse intestinal motility in physiological conditions. Moreover, AM9405 reversed hypermotility and reduced pain in mouse models mimicking symptoms of functional GI disorders, such as stress-induced diarrhoea and writhing test. Interestingly, some of the effects of AM9405 were blocked by a 5-HT3 antagonist suggesting interaction with 5-HT3 receptors. In our study we show that combining CB1 agonism with 5-HT3 agonism may alter physiological functions and experimental pathophysiologies in a manner that make such compounds promising drugs for the future treatment of functional GI disorders.
... In the gastrointestinal tract (GIT), cannabinoid receptors regulate motility, secretion, sensation, emesis, satiety, and inflammation (Izzo 2004;Duncan et al. 2005aDuncan et al. , b, 2008Storr and Sharkey 2007;Wright et al. 2008;Sharkey and Wiley 2016;Lee et al. 2016;Di Patrizio 2016). The CB1 receptor is expressed by neurons of the enteric nervous system (ENS) of rodents (Duncan et al. 2005a, b), guinea-pig (Coutts et al. 2002), pig (Kulkarni-Narla et al. 2000), and ferret (Van Sickle et al. 2001). ...
... The observation of CB1 receptor immunolabelling of enteric neurons is consistent with data observed in pig, guinea-pig, rat, mouse, and ferret ENS (Kulkarni-Narla and Brown 2000;Van Sickle et al. 2001;Coutts et al. 2002;Storr et al. 2004;Duncan et al. 2005a), in which the CB1 receptor was mainly expressed by cholinergic excitatory motor neurons. In humans, the activity of the CB1 receptor was functionally demonstrated in the ileum by Croci et al. (1998) and CB1 receptor immunoreactivity has been described in enteric neurons and nerve fibres (Wright et al. 2005;Marquez et al. 2009). ...
The endocannabinoid system (ECS) is composed of cannabinoid receptors, their endogenous ligands, and the enzymes involved in endocannabinoid turnover. Modulating the activity of the ECS may influence a variety of physiological and pathophysiological processes. A growing body of evidence indicates that activation of cannabinoid receptors by endogenous, plant-derived, or synthetic cannabinoids may exert beneficial effects on gastrointestinal inflammation and visceral pain. The present ex vivo study aimed to investigate immunohistochemically the distribution of cannabinoid receptors CB1, CB2, G protein-coupled receptor 55 (GPR55), and peroxisome proliferation activation receptor alpha (PPARα) in the canine gastrointestinal tract. CB1 receptor immunoreactivity was observed in the lamina propria and epithelial cells. CB2 receptor immunoreactivity was expressed by lamina propria mast cells and immunocytes, blood vessels, and smooth muscle cells. Faint CB2 receptor immunoreactivity was also observed in neurons and glial cells of the submucosal plexus. GPR55 receptor immunoreactivity was expressed by lamina propria macrophages and smooth muscle cells. PPARα receptor immunoreactivity was expressed by blood vessels, smooth muscle cells, and glial cells of the myenteric plexus. Cannabinoid receptors showed a wide distribution in the gastrointestinal tract of the dog. Since cannabinoid receptors have a protective role in inflammatory bowel disease, the present research provides an anatomical basis supporting the therapeutic use of cannabinoid receptor agonists in relieving motility disorders and visceral hypersensitivity in canine acute or chronic enteropathies.
... Additionally, CBD activates transient ion receptor ion channels (TRPV1, TRVP2) [24][25][26][27][28][29], peroxisome proliferating activated receptor α (PPAR α), and PPAR γ, inhibits GPR55 [28][29][30], and increases endocannabinoid anandamide (AEA) concentration by blocking its hydrolysis [31]. Many of the listed receptors are expressed in the gastrointestinal tract [32][33][34][35][36]. Although many receptors are involved in cannabinoid effects on cancers, we did not prioritize the action of specific receptors on tested colorectal cancer cell lines. ...
Platinum-derived chemotherapy medications are often combined with other conventional therapies for treating different tumors, including colorectal cancer. However, the development of drug resistance and multiple adverse effects remain common in clinical settings. Thus, there is a necessity to find novel treatments and drug combinations that could effectively target colorectal cancer cells and lower the probability of disease relapse. To find potential synergistic interaction, we designed multiple different combinations between cisplatin, cannabidiol, and intermittent serum starvation on colorectal cancer cell lines. Based on the cell viability assay, we found that combinations between cannabidiol and intermittent serum starvation, cisplatin and intermittent serum starvation, as well as cisplatin, cannabidiol, and intermittent serum starvation can work in a synergistic fashion on different colorectal cancer cell lines. Furthermore, we analyzed differentially expressed genes and affected pathways in colorectal cancer cell lines to understand further the potential molecular mechanisms behind the treatments and their interactions. We found that synergistic interaction between cannabidiol and intermittent serum starvation can be related to changes in the transcription of genes responsible for cell metabolism and cancer’s stress pathways. Moreover, when we added cisplatin to the treatments, there was a strong enrichment of genes taking part in G2/M cell cycle arrest and apoptosis.
... Research has shown that marijuana acts on the cannabinoid CB1 and CB2 receptors in the enteric nervous and immune systems of the gastrointestinal tract [4]. Its effects reduce gut motility, intestinal secretion and epithelial permeability, and induce inflammatory leukocyte recruitment and immune modulation [5]. However, there are very few clinical trials examining the effect of marijuana use on disease management in IBD [6][7][8]. ...
Background
As marijuana use is rising among patients with inflammatory bowel disease (IBD), so is interest in its potential use as a therapeutic agent. We sought to survey IBD patients regarding marijuana use, self-reported impact on IBD symptoms, and perceptions of safety.
Methods
A multicenter anonymous survey was administered to patients with IBD between October 2020 and June 2021. The 70-question survey collected demographic variables, clinical variables, attitudes about marijuana, and perceptions of its safety and efficacy in IBD. Participants were classified by their marijuana use: “rarely/never,” “current,” and “former”. Percentage and chi-square tests were used to compare categorical variables between the 3 groups, and means and 2-group ANOVA were used for continuous variables.
Results
Of 181 patients surveyed, 166 were eligible for the study. Of these, 70 (42.2%) participants were rare/never marijuana users, 44 (26.5%) were current users, and 52 (31.3%) were former users. Fifty-three percent thought marijuana would help with IBD inflammation and 80% thought it would help with IBD pain. Over 70% of patients from all groups thought marijuana had a low-to-moderate risk of harm, and 69.6% of the participants who never or rarely used marijuana thought marijuana was addictive, compared to 20.5% of the current users and 44% of the former marijuana users.
Conclusions
While many patients thought marijuana use helps with IBD-related pain and inflammation, many expressed concerns about addiction to marijuana and a possible risk of harm. Further studies are needed to examine the benefit and harm of marijuana in IBD.
... 44,45 The control of intestinal motility, secretion, epithelial permeability, and immunology are also accomplished by the modulation of CB1R and CB2R expressed in the ENS and resident cells. 47,48 The activation of CB1R in the ENS is mainly related to the negative control of cholinergic neurotransmission, with consequent inhibition of the action of this neurotransmitter on muscarinic receptors and a reduction in intestinal smooth muscle contractions (Fig. 3, part b). [49][50][51] Activation of CB2R by the agonist JWH-133 in rats promotes a reduction in the speed of food passage through the gastrointestinal tract, as a consequence of the decrease in muscle contractions. ...
The components of the endogenous cannabinoid system are widely expressed in the gastrointestinal tract contributing to local homeostasis. In general, cannabinoids exert inhibitory actions in the gastrointestinal tract, inducing anti-inflammatory, antiemetic, antisecretory, and antiproliferative effects. Therefore, cannabinoids are interesting pharmacological compounds for the treatment of several acute intestinal disorders, such as dysmotility, emesis, and abdominal pain. Likewise, the role of cannabinoids in the treatment of chronic intestinal diseases, such as irritable bowel syndrome and inflammatory bowel disease, is also under investigation. Patients with chronic intestinal inflammatory diseases present impaired quality of life, and mental health issues are commonly associated with long-term chronic diseases. The complex pathophysiology of these diseases contributes to difficulties in diagnosis and, therefore, in the choice of a satisfactory treatment. Thus, this article reviews the involvement of the cannabinoid system in chronic inflammatory diseases that affect the gastrointestinal tract and highlights possible therapeutic approaches related to the use of cannabinoids.
... With regard to the GI tract, cannabinoid and cannabinoid-related receptors showed wide distribution in several mammals, including mice, pigs, ferrets, dogs, cats, horses and human beings [85][86][87][88][89][90][91][92][93][94][95][96][97][98]. In canine and feline species, CB1 receptor immunolabeling is mainly observed on enteric neurons, nerve fibers, gastric parietal cells, epithelial cells (including goblet cells and enteroendocrine cells) [90,[96][97][98]. ...
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.
... Their activation by both exogenous cannabinoids and arachidonic acid-derived endocannabinoids also leads to increased appetite, promotion of food intake and weight gain (52)(53)(54). CB1 also inhibits the activation of N-and P/ Q type intracellular calcium channels, decreasing calcium release, but activates inward-rectifying potassium and potassium-A channels and mitogen-activated protein kinase (55,56). When cannabinoids bind to the prejunctional CB1 receptors, reduced excitatory neurotransmission causes decreased gut motility and secretion (57). ...
Inflammatory bowel disease (IBD) is a general term used to describe a group of chronic inflammatory conditions of the gastrointestinal tract of unknown etiology, including two primary forms: Crohn’s disease (CD) and ulcerative colitis (UC). The endocannabinoid system (ECS) plays an important role in modulating many physiological processes including intestinal homeostasis, modulation of gastrointestinal motility, visceral sensation, or immunomodulation of inflammation in IBD. It consists of cannabinoid receptors (CB1 and CB2), transporters for cellular uptake of endocannabinoid ligands, endogenous bioactive lipids (Anandamide and 2-arachidonoylglycerol), and the enzymes responsible for their synthesis and degradation (fatty acid amide hydrolase and monoacylglycerol lipase), the manipulation of which through agonists and antagonists of the system, shows a potential therapeutic role for ECS in inflammatory bowel disease. This review summarizes the role of ECS components on intestinal inflammation, suggesting the advantages of cannabinoid-based therapies in inflammatory bowel disease.
... Both types of CB receptors are present within the gut, but they are variously expressed and distributed in epithelial cells, lamina propria, smooth muscle cells, and enteric nervous plexuses. In the GIT, both CB1 and CB2 receptors are highly expressed in the enteric nervous plexuses, especially myenteric and submucosal ones [86]. The CB1 receptors are mainly present in excitatory motor neurons, interneurons, and intrinsic primary afferent neurons [87,88]. ...
Despite the multiple preventive measures and treatment options, colorectal cancer holds a significant place in the world’s disease and mortality rates. The development of novel therapy is in critical need, and based on recent experimental data, cannabinoids could become excellent candidates. This review covered known experimental studies regarding the effects of cannabinoids on intestinal inflammation and colorectal cancer. In our opinion, because colorectal cancer is a heterogeneous disease with different genomic landscapes, the choice of cannabinoids for tumor prevention and treatment depends on the type of the disease, its etiology, driver mutations, and the expression levels of cannabinoid receptors. In this review, we describe the molecular changes of the endocannabinoid system in the pathologies of the large intestine, focusing on inflammation and cancer.
... Endocannabinoids play important role in the enteric nervous system of gastrointestinal tract, where CB receptors are localized on the enteric nerve terminals. In the enteric nervous system, endocannabinoids exert inhibitory actions on neurotransmission to reduce motility and secretion [76], however, this mechanism is mediated mostly via CB 1 receptors [77]. In the nervous system, CB receptors are distributed on peripheral terminals of primary afferent neurons, where play role in pain modulation: upon activation, modulate transducer ion channels and regulate neuron excitability [78]. ...
Over the last several decades, the percentage of patients suffering from different forms of arthritis has increased due to the ageing population and the increasing risk of civilization diseases, e.g. obesity, which contributes to arthritis development. Osteoarthritis and rheumatoid arthritis are estimated to affect 50–60% of people over 65 years old and cause serious health and economic problems. Currently, therapeutic strategies are limited and focus mainly on pain attenuation and maintaining joint functionality. First-line therapies are nonsteroidal anti-inflammatory drugs; in more advanced stages, stronger analgesics, such as opioids, are required, and in the most severe cases, joint arthroplasty is the only option to ensure joint mobility. Cannabinoids, both endocannabinoids and synthetic cannabinoid receptor (CB) agonists, are novel therapeutic options for the treatment of arthritis-associated pain. CB1 receptors are mainly located in the nervous system; thus, CB1 agonists induce many side effects, which limit their therapeutic efficacy. On the other hand, CB2 receptors are mainly located in the periphery on immune cells, and CB2 modulators exert analgesic and anti-inflammatory effects in vitro and in vivo. In the current review, novel research on the cannabinoid-mediated analgesic effect on arthritis is presented, with particular emphasis on the role of the CB2 receptor in arthritis-related pain and the suppression of inflammation.Graphic abstract
... Besides, certain pathways directly involved in pain transmission were enriched, including Morphine addiction and Retrograde endocannabinoid signaling. Endocannabinoids are involved in controlling motility, secretion and intestinal inflammation [36]. The endocannabinoid system in DRG neurons mediate ...
Background
Irritable bowel syndrome (IBS) is the most common functional gastrointestinal disease characterized by chronic abdominal discomfort and pain. The mechanisms of abdominal pain, as a relevant symptom, in IBS are still unclear. We aimed to explore the key genes and neurobiological changes specially involved in abdominal pain in IBS.
Methods
Gene expression data (GSE36701) was downloaded from Gene Expression Omnibus database. Fifty-three rectal mucosa samples from 27 irritable bowel syndrome with diarrhea (IBS-D) patients and 40 samples from 21 healthy volunteers as controls were included. Differentially expressed genes (DEGs) between two groups were identified using the GEO2R online tool. Functional enrichment analysis of DEGs was performed on the DAVID database. Then a protein–protein interaction network was constructed and visualized using STRING database and Cytoscape.
Results
The microarray analysis demonstrated a subset of genes ( CCKBR, CCL13, ACPP, BDKRB2, GRPR, SLC1A2, NPFF, P2RX4, TRPA1, CCKBR, TLX2, MRGPRX3, PAX2, CXCR1 ) specially involved in pain transmission. Among these genes, we identified GRPR, NPFF and TRPA1 genes as potential biomarkers for irritating abdominal pain of IBS patients.
Conclusions
Overexpression of certain pain-related genes ( GRPR, NPFF and TRPA1 ) may contribute to chronic visceral hypersensitivity, therefore be partly responsible for recurrent abdominal pain or discomfort in IBS patients. Several synapses modification and biological process of psychological distress may be risk factors of IBS.
... Besides, certain pathways directly involved in pain transmission were enriched, including Morphine addiction and Retrograde endocannabinoid signaling. Endocannabinoids are involved in controlling motility, secretion and intestinal inflammation [36]. The endocannabinoid system in DRG neurons mediate stress-induced visceral hypersensitivity in a mouse model of IBS [37]. ...
Background: Irritable bowel syndrome (IBS) is the most common functional gastrointestinal disease characterized by chronic abdominal discomfort and pain. The mechanisms of abdominal pain, as a relevant symptom, in IBS are still unclear. We aimed to explore the key genes and neurobiological changes specially involved in abdominal pain in IBS.
Methods: Gene expression data (GSE36701) was downloaded from Gene Expression Omnibus (GEO) database. Fifty-three rectal mucosa samples from 27 Irritable Bowel Syndrome with diarrhea (IBS-D) patients and 40 samples from 21 healthy volunteers (HV) as controls were included. Differentially expressed genes (DEGs) between two groups were identified using the GEO2R online tool. Functional enrichment analysis of DEGs was performed on the DAVID database. Then a protein-protein interaction (PPI) network was constructed and visualized using STRING database and Cytoscape.
Results: The microarray analysis demonstrated a subset of genes (CCKBR, CCL13, ACPP, BDKRB2, GRPR, SLC1A2, NPFF, P2RX4, TRPA1, CCKBR, TLX2, MRGPRX3, PAX2, CXCR1) specially involved in pain transmission. Among these genes, we identified GRPR, NPFF and TRPA1 genes as potential biomarkers for irritating abdominal pain of IBS patients.
Conclusions: Overexpression of certain pain-related genes (GRPR, NPFF and TRPA1) may contribute to chronic visceral hypersensitivity, therefore be partly responsible for recurrent abdominal pain or discomfort in IBS patients. Several synapses modification and biological process of psychological distress may be risk factors of IBS.
... Besides, certain pathways directly involved in pain transmission were enriched, including Morphine addiction and Retrograde endocannabinoid signaling. Endocannabinoids are involved in controlling motility, secretion and intestinal inflammation [36]. The endocannabinoid system in DRG neurons mediate stress-induced visceral hypersensitivity in a mouse model of IBS [37]. ...
Background: Irritable bowel syndrome (IBS) is the most common functional gastrointestinal disease characterized by chronic abdominal discomfort and pain. The mechanisms of abdominal pain, as a relevant symptom, in IBS are still unclear. We aimed to explore the key genes and neurobiological changes specially involved in abdominal pain in IBS.
Methods: Gene expression data (GSE36701) was downloaded from Gene Expression Omnibus (GEO) database. Fifty-three rectal mucosa samples from 27 Irritable Bowel Syndrome with diarrhea (IBS-D) patients and 40 samples from 21 healthy volunteers (HV) as controls were included. Differentially expressed genes (DEGs) between two groups were identified using the GEO2R online tool. Functional enrichment analysis of DEGs was performed on the DAVID database. Then a protein-protein interaction (PPI) network was constructed and visualized using STRING database and Cytoscape.
Results: The microarray analysis demonstrated a subset of genes (CCKBR, CCL13
ACPP, BDKRB2, GRPR, SLC1A2, NPFF, P2RX4, TRPA1, CCKBR, TLX2, MRGPRX3, PAX2, CXCR1) specially involved in pain transmission. Among these genes, we identified GRPR, NPFF and TRPA1 genes as potential biomarkers for irritating abdominal pain of IBS patients.
Conclusions: Overexpression of certain pain-related genes (GRPR, NPFF and TRPA1) may contribute to chronic visceral hypersensitivity, therefore be partly responsible for recurrent abdominal pain or discomfort in IBS patients. Several synapses modification and biological process of psychological distress may be risk factors of IBS.
... CB1 receptors are found throughout the gastrointestinal tract, mainly in the enteric nervous system where receptor activity inhibits neurotransmission to reduce motility and gastric acid secretion 18 , and produces relations of the lower esophageal sphincter (LES). CB2 receptors are mainly located in immunocytes, myenteric plexus neurons, and epithelial cells and may have an important role under pathophysiological conditions. ...
... Furthermore, the growth of Akkermansia muciniphila could be promoted by the administration of prebiotics and it was followed by improved plasma lipid and glucose profile, characterized by reduced weight gain, metabolic endotoxemia, adipose tissue inflammation, and insulin resistance [111]. Furthermore, Akkermansia muciniphila administration upregulated the intestinal levels of endocannabinoids which are involved in the regulation of metabolic homeostasis and gut barrier function through the microbiota-gut-brain axis [112]. In addition, it was reported that declined populations of phylum Verrucomicrobiaceae and genera Akkermansia muciniphila in the gastrointestinal tract could be linked to the metabolic profiles of patients with prediabetes [27]. ...
Chitosan and its derivatives can alleviate metabolic syndrome by different regulation mechanisms, phosphorylation of AMPK (AMP-activated kinase) and Akt (also known as protein kinase B), suppression of PPAR-γ (peroxisome proliferator-activated receptor-γ) and SREBP-1c (sterol regulatory element–binding proteins), and translocation of GLUT4 (glucose transporter-4), and also the downregulation of fatty-acid-transport proteins, fatty-acid-binding proteins, fatty acid synthetase (FAS), acetyl-CoA carboxylase (acetyl coenzyme A carboxylase), and HMG-CoA reductase (hydroxy methylglutaryl coenzyme A reductase). The improved microbial profiles in the gastrointestinal tract were positively correlated with the improved glucose and lipid profiles in hosts with metabolic syndrome. Hence, this review will summarize the current literature illustrating positive correlations between the alleviated conditions in metabolic syndrome hosts and the normalized gut microbiota in hosts with metabolic syndrome after treatment with chitosan and its derivatives, implying that the possibility of chitosan and its derivatives to serve as therapeutic application will be consolidated. Chitosan has been shown to modulate cardiometabolic symptoms (e.g., lipid and glycemic levels, blood pressure) as well as gut microbiota. However, the literature that summarizes the relationship between such metabolic modulation of chitosan and prebiotic-like effects is limited. This review will discuss the connection among their structures, biological properties, and prebiotic effects for the treatment of metabolic syndrome. Our hope is that future researchers will consider the prebiotic effects as significant contributors to the mitigation of metabolic syndrome.
... Besides, certain pathways directly involved in pain transmission were enriched, including Morphine addiction and Retrograde endocannabinoid signaling. Endocannabinoids are involved in controlling motility, secretion and intestinal inflammation [36]. The endocannabinoid system in DRG neurons mediate stress-induced visceral hypersensitivity in a mouse model of IBS [37]. ...
Background: Irritable bowel syndrome (IBS) is the most common functional gastrointestinal disease characterized by chronic abdominal discomfort and pain. The mechanisms of abdominal pain, as a relevant symptom, in IBS are still unclear. We aimed to explore the key genes and neurobiological changes specially involved in abdominal pain in IBS.
Methods: Gene expression data (GSE36701) was downloaded from Gene Expression Omnibus (GEO) database. Fifty-three rectal mucosa samples from Irritable Bowel Syndrome with diarrhea (IBS-D) patients and 40 samples from healthy volunteers (HV) as controls were included. Differentially expressed genes (DEGs) between two groups were identified using the GEO2R online tool. Functional enrichment analysis of DEGs was performed on the DAVID database. Then a protein-protein interaction (PPI) network was constructed and visualized using STRING database and Cytoscape.
Results: The microarray analysis demonstrated a subset of genes (CCKBR, CCL13
ACPP, BDKRB2, GRPR, SLC1A2, NPFF, P2RX4, TRPA1, CCKBR, TLX2, MRGPRX3, PAX2, CXCR1) specially involved in pain transmission. Among these genes, we identified GRPR, NPFF and TRPA1 genes as potential biomarkers for irritating abdominal pain of IBS patients.
Conclusions: Overexpression of certain pain-related genes (GRPR, NPFF and TRPA1) may contribute to chronic visceral hypersensitivity, therefore be partly responsible for recurrent abdominal pain or discomfort in IBS patients. Several synapses modification and biological process of psychological distress may be risk factors of IBS.
... The 2-AG and AEA enter the cells and are inactivated by a different set of enzymes. AEA is inactivated by FAAH to arachidonate and ethanolamine [35,36]. FAAH is present throughout the gut in the myenteric plexus. ...
Cannabis use has been increasing in the United States and throughout the world. It is derived from one of the earliest plants cultivated by humans - Cannabis sativa. Cannabis (also called marijuana) is the most commonly used psychoactive substance worldwide. The cannabis plant has more than 400 chemicals, of which more than 100 cannabinoids (such as cannabigerol, cannabidiol, and cannabinol) have been identified. The endocannabinoid system (ECS) plays an essential role in the effects of cannabis on end organs. Although cannabis use has been reported for many decades, some of its unique adverse effects of nausea, vomiting, and abdominal pain, termed as cannabis hyperemesis syndrome (CHS), were noted recently. The legal status of cannabis in the United States has been rapidly changing from state to state. The incidence of CHS is expected to rise with rising access to cannabis in the United States. Furthermore, CHS is frequently underdiagnosed due to a lack of uniform criteria, subjective nature of symptoms, and overlap with cyclical vomiting syndrome (CVS). Understanding the ECS and its role in biphasic response (proemetic and antiemetic) of CHS is critical to explain its pathophysiology. As the use of cannabis increases globally, awareness of CHS is warranted for early recognition and prompt treatment to avoid complications. We describe the putative mechanism of CHS with an overview of the clinical features in these patients. Furthermore, we highlight the differences between CHS and CVS with important differentials to consider. We provide a narrative update on the current evidence on CHS pathophysiology, diagnosis, treatment, and identifying research gaps.
... Besides, certain pathways directly involved in pain transmission were enriched, including Morphine addiction and Retrograde endocannabinoid signaling. Endocannabinoids are involved in controlling motility, secretion and intestinal in ammation [34]. The endocannabinoid system in DRG neurons mediate stress-induced visceral hypersensitivity in a mouse model of IBS [35]. ...
Background: Irritable bowel syndrome (IBS) is the most common functional gastrointestinal disease characterized by chronic abdominal discomfort and pain. The mechanisms of abdominal pain, as a relevant symptom, in IBS are still unclear. We aimed to explore the key genes and neurobiological changes specially involved in abdominal pain in IBS.
Methods: Gene expression data (GSE36701) was downloaded from Gene Expression Omnibus (GEO) database. Fifty-three rectal mucosa samples from Irritable Bowel Syndrome with diarrhea (IBS-D) patients and 40 samples from healthy volunteers (HV) as controls were included. Differentially expressed genes (DEGs) between two groups were identified using the GEO2R online tool. Functional enrichment analysis of DEGs was performed on the DAVID database. Then a protein-protein interaction (PPI) network was constructed and visualized using STRING database and Cytoscape.
Results: The microarray analysis demonstrated a subset of genes (CCKBR, CCL13
ACPP, BDKRB2, GRPR, SLC1A2, NPFF, P2RX4, TRPA1, CCKBR, TLX2, MRGPRX3, PAX2, CXCR1) specially involved in pain transmission. Among these genes, we identified GRPR, NPFF and TRPA1 genes as potential biomarkers for irritating abdominal pain of IBS patients.
Conclusions: Overexpression of certain pain-related genes (GRPR, NPFF and TRPA1) may contribute to chronic visceral hypersensitivity, therefore be partly responsible for recurrent abdominal pain or discomfort in IBS patients. Several synapses modification and biological process of psychological distress may be risk factors of IBS.
... In recent decades, cannabinoid research has been widely performed with the identification of an endocannabinoid system including two G protein-coupled receptors [cannabinoid receptor type 1 (CB1) and type 2 (CB2)], endogenous ligands (anandamide, 2-arachidonoyl glycerol, nolandin ether) and enzymes that degrade endocannabinoids [115,116]. It has been accepted that the endogenous cannabinoid system is a ubiquitous lipid-signaling system involved in the regulation of numerous behaviors and physiological functions and dietary fatty acids can affect energy homeostasis via changes to the endocannabinoid system [117,118]. ...
A typical feature of marine foods is that they are rich in docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), which have formed a large-scale global industry. DHA/EPA phospholipids (PLs) are ubiquitous in marine foods and are the main DHA/EPA molecular forms in fish roe, shrimp and shellfish. Much attention has been focused on the bioavailability and health benefits that are influenced by the type and esterified form of dietary fatty acids. Recently, numerous findings have suggested that dietary DHA/EPA-PLs are superior to the triacylglycerol (TAG) or ethyl ester forms in exerting their functional properties through specific mechanisms of action. However, there is no comprehensive review covering the health benefits of dietary marine DHA/EPA-enriched PLs. In this paper, we review publications on the nutritional functions of DHA/EPA-enriched glycerophospholipids, including the effects on brain function, antitumor activity, lipid metabolism, and glucose metabolism. The current research status regarding the active ingredients, sources, models, treatment, duration, and mechanisms are presented. In addition, the way in which the structure-activity relationship of DHA/EPA-PLs is affected by ester-bond structure at the sn-1 position, fatty acid at the sn-2 position and polar head group at the sn-3 position is also reviewed. DHA/EPA-PLs are one of the major n-3 long-chain polyunsaturated fatty acid dietary forms in our diet, and we should maximize the ability to fully exploit the nutritional properties of DHA/EPA.
... First, we showed detailed localization of these receptors in the bowel wall, confirming that CB 1 is largely present in enteric neurons (Duncan et al. 2005) and only moderately in the epithelial lining. CB 1 mRNA was also detectable in the longitudinal muscle layer (but hardly in the circular layer) ...
Surveys suggest that Cannabis provides benefit for people with inflammatory bowel disease. However, mechanisms underlying beneficial effects are not clear. We performed in situ hybridization RNAscope® combined with immunohistochemistry to show cell-specific distribution and regulation of cannabinoid receptor 1 and 2 (CB1, CB2), G protein-coupled receptor 55 (GPR55), and monoacylglycerol lipase (MGL) mRNA in immune cells using murine models of intestinal and systemic inflammation. In healthy animals, the presence in enteric ganglia is high for CB1 mRNA, but low for CB2 and GPR55 mRNAs. MGL mRNA is predominant throughout the intestinal wall including myenteric neurons, epithelium, circular and longitudinal muscular layers, and the lamina propria. Within the immune system, B220⁺ cells exhibit high gene expression for CB2 while the expression of CB2 in F4/80⁺ and CD3⁺ cells is less prominent. In contrast, GPR55 mRNA is highly present in F4/80⁺ and CD3⁺ cells. qRT-PCR of total colonic segments shows that the expression of GPR55 and MGL genes drops during intestinal inflammation. Also at cellular levels, GPR55 and MGL gene expression is reduced in F4/80⁺, but not CD3⁺ cells. As to systemic inflammation, reduced gene expression of MGL is observed in ileum by qRT-PCR, while at cellular levels, altered gene expression is also seen for CB1 and GPR55 in CD3⁺ but not F4/80⁺ cells. In summary, our study reveals changes in gene expression of members of the endocannabinoid system in situ attesting particularly GPR55 and MGL a distinct cellular role in the regulation of the immune response to intestinal and systemic inflammation.
Electronic supplementary material
The online version of this article (10.1007/s00418-018-1719-0) contains supplementary material, which is available to authorized users.
... Further, endocannabinoid (EC)-producing enzymes, such as Nacyl phosphatidylethanolamine-specific phospholipase D and diacylglycerol lipase, and EC-degrading enzymes, such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL), are found in the gut. CB 1 and CB 2 localize mainly to enteric nerves, the intestinal epithelium, and immune cells with variable expression [5][6][7]. While CB 1 is expressed at high levels on cholinergic enteric neurons [8], CB 2 is largely expressed on immune cells [9]. ...
In the past few years, we have witnessed a surge of new reports dealing with the role of cannabinoids, synthetic as well as herbal, in the mechanisms of inflammation and carcinogenesis. However, despite the wealth of in vitro data and anecdotal reports, evidence that cannabinoids could act as beneficial drugs in inflammatory bowel disease (IBD) or in neoplastic development of the human gastrointestinal tract is lacking. Some insight into the effects of medical Cannabis (usually meaning dried flowers) and cannabinoids in IBD has been gained through questionnaires and small pilot studies. As to colorectal cancer, only preclinical data are available. Currently, Δ9-tetrahydrocannabinol (THC) and its synthetic forms, dronabinol and nabilone, are used as an add-on treatment to alleviate chronic pain and spasticity in multiple sclerosis patients as well as chemotherapy-induced nausea. The use of medical Cannabis is authorized only in a limited number of countries. None of the mentioned substances are currently indicated for IBD. This review is an update of our knowledge on the role of cannabinoids in intestinal inflammation and carcinogenesis and a discussion on their potential therapeutic use.
... CB2 receptors are expressed in most enteric neurons and peripheral immune cells (Duncan et al., 2008;Storr et al., 2008b). The endogenous agonists of these receptors, endocannabinoids, are involved in controlling motility, secretion and intestinal inflammation (Duncan et al., 2005;Massa et al., 2005). DRG neurons from rats with stress-induced visceral hypersensitivity levels have increased levels of the endocannabinoid anandamide, and decreased levels of endocannabinoid degradation enzymes COX2 and FAAH, decreased CB1 receptor expression, but reciprocal increases in TRPV1 expression (Hong et al., 2009). ...
Irritable bowel syndrome and inflammatory bowel disease are major forms of chronic visceral pain, which affect over 15% of the global population. In order to identify new therapies, it is important to understand the underlying causes of chronic visceral pain. This review provides recent evidence demonstrating that inflammation or infection of the gastrointestinal tract triggers specific changes in the neuronal excitability of sensory pathways responsible for the transmission of nociceptive information from the periphery to the central nervous system. Specific changes in the expression and function of a variety of ion channels and receptors have been documented in inflammatory and chronic visceral pain conditions relevant to Irritable bowel syndrome and inflammatory bowel disease. An increase in pro-nociceptive mechanisms enhances peripheral drive from the viscera and provides an underlying basis for enhanced nociceptive signalling during chronic visceral pain states. Recent evidence also highlights increases in anti-nociceptive mechanisms in models of chronic visceral pain, which present novel targets for pharmacological treatment of this condition.
... Interestingly, also the inhibition of the 2-AG synthesizer DAGL using orlistat was found to normalize stool frequency in a mouse model of chronic constipation, without affecting basal motility [98]. In addition, several lines of evidence suggested that the increase in CB1 activity might lead to a reduction in visceral sensitivity [66,[99][100][101]. Esfandyari et al. have tested the efficacy of dronabinol in visceral sensitivity in a randomized, double-blind, placebo-controlled trial showing its ability to increase colonic compliance and relaxation in vivo [90]. ...
The endocannabinoid system (ECS) is an endogenous signalling pathway involved in the control of several gastrointestinal (GI) functions at both peripheral and central levels. In recent years, it has become apparent that the ECS is pivotal in the regulation of GI motility, secretion and sensitivity, but endocannabinoids (ECs) are also involved in the regulation of intestinal inflammation and mucosal barrier permeability, suggesting their role in the pathophysiology of both functional and organic GI disorders. Genetic studies in patients with irritable bowel syndrome (IBS) or inflammatory bowel disease have indeed shown significant associations with polymorphisms or mutation in genes encoding for cannabinoid receptor or enzyme responsible for their catabolism, respectively. Furthermore, ongoing clinical trials are testing EC agonists/antagonists in the achievement of symptomatic relief from a number of GI symptoms. Despite this evidence, there is a lack of supportive RCTs and relevant data in human beings, and hence, the possible therapeutic application of these compounds is raising ethical, political and economic concerns. More recently, the identification of several EC-like compounds able to modulate ECS function without the typical central side effects of cannabino-mimetics has paved the way for emerging peripherally acting drugs. This review summarizes the possible mechanisms linking the ECS to GI disorders and describes the most recent advances in the manipulation of the ECS in the treatment of GI diseases.
Cannabidiol (CBD) is a non-intoxicating cannabinoid extracted from the cannabis plant that is used for medicinal purposes. Ingestion of CBD is claimed to address several pathologies, including gastrointestinal disorders, although limited evidence has been generated thus far to substantiate many of its health claims. Nevertheless, CBD usage as an over-the-counter treatment for gastrointestinal disorders is likely to expand in response to increasing commercial availability, permissive legal status, and acceptance by consumers. This systematic review critically evaluates the knowledge boundaries of the published research on CBD, intestinal motility, and intestinal motility disorders. Research on CBD and intestinal motility is currently limited but does support the safety and efficacy of CBD for several therapeutic applications, including seizure disorders, inflammatory responses, and upper gastrointestinal dysfunction (i.e., nausea and vomiting). CBD, therefore, may have therapeutic potential for addressing functional gastrointestinal disorders. The results of this review show promising in vitro and preclinical data supporting a role of CBD in intestinal motility. This includes improved gastrointestinal-related outcomes in murine models of colitis. These studies, however, vary by dose, delivery method, and CBD-extract composition. Clinical trials have yet to find a conclusive benefit of CBD on intestinal motility disorders, but these trials have been limited in scope. In addition, critical factors such as CBD dosing parameters have not yet been established. Further research will establish the efficacy of CBD in applications to address intestinal motility.
Kanser,kannabidiol
Neuropathic pain is experienced due to injury to the nerves, underlying disease conditions or toxicity induced by chemotherapeutics. Multiple factors can contribute to neuropathic pain such as central nervous system (CNS)-related autoimmune and metabolic disorders, nerve injury, multiple sclerosis and diabetes. Hence, development of pharmacological interventions to reduce the drawbacks of existing chemotherapeutics and counter neuropathic pain is an urgent unmet clinical need. Cannabinoid treatment has been reported to be beneficial for several disease conditions including neuropathic pain. Cannabinoids act by inhibiting the release of neurotransmitters from presynaptic nerve endings, modulating the excitation of postsynaptic neurons, activating descending inhibitory pain pathways, reducing neural inflammation and oxidative stress and also correcting autophagy defects. This review provides insights on the various preclinical and clinical therapeutic applications of cannabidiol (CBD), cannabigerol (CBG), and cannabinol (CBN) in various diseases and the ongoing clinical trials for the treatment of chronic and acute pain with cannabinoids. Pharmacological and genetic experimental strategies have well demonstrated the potential neuroprotective effects of cannabinoids and also elaborated their mechanism of action for the therapy of neuropathic pain.
Increased interest in cannabis as a potential treatment and/or adjuvant therapy for inflammatory bowel disease (IBD) has been driven by patients with refractory disease seeking relief as well those who desire alternatives to conventional therapies. Available data have shown a potential role of cannabis as a supportive medication, particularly in pain reduction; however, it remains unknown whether cannabis has any impact on the underlying inflammatory process of IBD. The purpose of this review article is to summarize the available literature concerning the use of cannabis for the treatment of IBD and highlight potential areas for future study.
Colic is a common digestive disorder in horses and one of the most urgent problems in equine medicine. A growing body of literature has indicated that the activation of cannabinoid receptors could exert beneficial effects on gastrointestinal inflammation and visceral hypersensitivity. The localisation of cannabinoid and cannabinoid-related receptors in the intestine of the horse has not yet been investigated. The purpose of this study was to immunohistochemically localise the cellular distribution of canonical and putative cannabinoid receptors in the ileum of healthy horses. Distal ileum specimens were collected from six horses at the slaughterhouse. The tissues were fixed and processed to obtain cryosections which were used to investigate the immunoreactivity of canonical cannabinoid receptors 1 (CB1R) and 2 (CB2R), and three putative cannabinoid-related receptors: nuclear peroxisome proliferator-activated receptor-alpha (PPARα), transient receptor potential ankyrin 1 (TRPA1) and serotonin 5-HT1a receptor (5-HT1aR). Cannabinoid and cannabinoid-related receptors showed a wide distribution in the ileum of the horse. The epithelial cells showed immunoreactivity for CB1R, CB2R and 5-HT1aR. Lamina propria inflammatory cells showed immunoreactivity for CB2R and 5-HT1aR. The enteric neurons showed immunoreactivity for CB1R, TRPA1 and PPARα. The enteric glial cells showed immunoreactivity for CB1R and PPARα. The smooth muscle cells of the tunica muscularis and the blood vessels showed immunoreactivity for PPARα. The present study represents a histological basis which could support additional studies regarding the distribution of cannabinoid receptors during gastrointestinal inflammatory diseases as well as studies assessing the effects of non-psychotic cannabis-derived molecules in horses for the management of intestinal diseases.
Chronic diabetes leads to complex biochemical and cellular changes resulting in gastric dysfunction that is often underappreciated by care providers. While gastric symptoms of nausea, vomit, bloating, abdominal pain and early satiety are generally attributed to delay in gastric emptying, the latter poorly correlates with the timing or severity of these symptoms. Other physiological changes including rapid emptying, particularly of liquids, decreased accommodation, poor antropyloral coordination, gastric dysrhythmias, decreased or delayed onset of antral contractions, and hyperalgesia are generally not assessed clinically. A broader term of diabetic gastropathy appears more appropriate to represent the heterogeneous mixture of the various physiological disorders. Moreover, potentially underlying muscular, neuronal, hormonal and inflammatory changes in deeper submucosal structures may explain some of the complex aberrations in chronic diabetes, but remain poorly understood and has largely limited current therapies as empiric and palliative. Also newer understanding of driving forces in the progression of the metabolic syndrome has brought greater understanding for the role of hormonal and surgical therapies. Meanwhile, a better mechanistic understanding of gastric motility and of the various potential pharmacological agents, of which many are undergoing clinical studies as reviewed here, ushers hopes not only for more treatment options, but for optimal individualized therapy.
It is accepted that the ability to vomit developed as a protective mechanism to rid the body of ingested toxins Unfortunately vomiting also frequently occurs unrelated to the ingestion of noxious agents, a circumstance that produces several clinical challenges. First, vomiting can be a sign of many diseases that affect different organ systems. Therefore, determining the cause of a vomiting episode can be difficult. On the other hand, vomiting can be present in a patient without any evidence of an underlying inflammatory, anatomic, neoplastic, or metabolic process. Second, vomiting can produce several complications (e.g., electrolyte derangement, prolapse gastropathy, and blood loss) that demand diagnosis and treatment. Third, vomiting is a frequent complication of medical therapy (surgical procedures, cancer chemotherapy). Fourth, selection of appropriate therapy for this distressing problem is essential to improve patient comfort and avoid the additional medical complications associated with the vomiting.
Although cannabinoid hyperemesis syndrome (CHS) was first reported more than 15 years ago, it still remains an unfamiliar clinical entity among physicians worldwide. CHS is categorized by Rome IV classification as a functional gastroduodenal disorder. It is characterized by stereotypical episodic vomiting in the setting of chronic, daily cannabis use, with cycles decreasing by the cessation of cannabis. CHS is also associated with abdominal pain reduced by hot baths and showers with comparative well-being between attacks. Thus, its clinical presentation resembles ‘classic’ cyclic vomiting syndrome, but eliciting a cannabis history is crucial in diagnosing this entity. In acute attacks, parenteral benzodiazepines are very effective. For prevention and long-term management, tricyclic antidepressants such as amitriptyline are the mainstay of therapy requiring doses in the range of 50–200 mg/d to achieve symptom control. In addition, counseling to achieve marijuana cessation, accompanied by antianxiety medications, is necessary for sustaining clinical outcomes. Once the patient is in remission and off marijuana for a period of 6–12 months, then tapering the dose of amitriptyline can be implemented, with the goal of no therapy being achieved in the majority of patients over time. With the legalization of marijuana in many states, CHS will become an increasingly prevalent clinical entity, so educating about CHS is an important goal, particularly for emergency department physicians who generally first encounter these patients.
Cannabis hyperemesis syndrome (CHS) is a form of functional gut-brain axis disorder characterized by bouts of episodic nausea and vomiting worsened by cannabis intake. It is considered as a variant of cyclical vomiting syndrome seen in cannabis users especially characterized by compulsive hot bathing/showers to relieve the symptoms. CHS was reported for the first time in 2004, and since then, an increasing number of cases have been reported. With cannabis use increasing throughout the world as the threshold for legalization becomes lower, its user numbers are expected to rise over time. Despite this trend, a strict criterion for the diagnosis of CHS is lacking. Early recognition of CHS is essential to prevent complications related to severe volume depletion. The recent body of research recognizes that patients with CHS impose a burden on the healthcare systems. Understanding the pathophysiology of the endocannabinoid system (ECS) remains central in explaining the clinical features and potential drug targets for the treatment of CHS. The frequency and prevalence of CHS change in accordance with the doses of tetrahydrocannabinol and other cannabinoids in various formulations of cannabis. CHS is unique in presentation, because of the cannabis's biphasic effect as anti-emetic at low doses and pro-emetic at higher doses, and the association with pathological hot water bathing. In this narrative review, we elaborate on the role of the ECS, its management, and the identification of gaps in our current knowledge of CHS to further enhance its understanding in the future.
Cannabis and cannabinoids (such as tetrahydrocannabinol and cannabidiol) are frequently used to relieve gastrointestinal symptoms. Cannabinoids have effects on the immune system and inflammatory responses, as well as neuromuscular and sensory functions of digestive organs, including pancreas and liver. Cannabinoids can cause hyperemesis and cyclic vomiting syndrome, but might also be used to reduce gastrointestinal, pancreatic, or hepatic inflammation, as well as to treat motility, pain, and functional disorders. Cannabinoids activate cannabinoid receptors, which inhibit release of transmitters from pre-synaptic neurons, and also inhibit diacylglycerol lipase alpha, to prevent synthesis of the endocannabinoid 2- arachidonoyl glycerol. However, randomized trials are needed to clarify their effects in patients; these compounds can have adverse effects on the central nervous system (such as somnolence and psychosis) or the developing fetus, when used for nausea and vomiting during pregnancy. Cannabinoid-based therapies can also hide symptoms and disease processes, such as in patients with inflammatory bowel diseases. It is important for gastroenterologists and hepatologists to understand cannabinoid mechanisms, effects, and risks.
Over the last decade, interest in the therapeutic potential of cannabis and its constituents (e.g. cannabidiol) in the management of inflammatory bowel diseases (IBD) has escalated. Cannabis has been increasingly approved for a variety of medical conditions in several jurisdictions around the world. In animal models, cannabinoids have been shown to improve intestinal inflammation in experimental models of IBD through their interaction with the endocannabinoid system. However, the few randomized controlled trials of cannabis or cannabidiol in patients with IBD have not demonstrated efficacy in modulating inflammatory disease activity. Cannabis may be effective in the symptomatic management of IBD. Given the increasing utilization and cultural acceptance of cannabis, physicians need to be aware of its safety and efficacy in order to better counsel patients. The aim of this review is to provide an overview of the role of cannabis in the management of patients with IBD.
Background and purpose:
Though still controversial, there is increasing agreement that postnatal neurogenesis occurs in the enteric nervous system in response to injury. Following acute colitis, there is significant cell death of enteric neurons and evidence suggests that subsequent neural regeneration follows. An enteric neural stem/progenitor cell population with neurogenic potential has been identified in culture; in vivo, compensatory neurogenesis is driven by enteric glia and may also include de-differentiated Schwann cells. Recent evidence suggests that changes in the enteric microenvironment due to injury-associated increases in glial cell-derived neurotrophic factor (GDNF), serotonin (5-HT), products from the gut microbiome and possibly endocannabinoids may lead to the transdifferentiation of mature enteric glia and may reprogram recruited Schwann cells. Targeting neurogenic pathways presents a promising avenue toward the development of new and innovative treatments for acquired damage to the enteric nervous system. In this review we discuss potential sources of newly generated adult enteric neurons, the involvement of GDNF, 5-HT, endocannabinoids, and Lipopolysaccharide, as well therapeutic applications of this evolving work.
Significance statement:
This review offers a concise and wide-ranging survey on the current state of progress in research related to adult enteric neurogenesis, specifically regarding GDNF, 5-HT, endocannabinoids, and Lipopolysaccharide signaling. Our paper describes the current understanding of this process, the systems known to be involved, and highlights promising avenues for potential clinical development. Treatments that promote enteric neurogenesis would give clinicians new and powerful tools to treat gastrointestinal injury. © AlphaMed Press 2019.
The current study aimed to evaluate the role of cannabinoid receptors in the regulation of gastric acid secretion and oxidative stress in gastric mucosa. To fulfill this aim, gastric acid secretion stimulated with histamine (5 mg/kg, subcutaneous [SC]), 2‐deoxy‐ d‐glucose (D‐G) (200 mg/kg, intravenous) or ‐carbachol (4 μg/kg, SC) in the 4‐hour pylorus‐ligated rats. The CB1R agonist ( N‐arachidonoyl dopamine, 1 mg/kg, SC) inhibited gastric acid secretion stimulated by D‐G and carbachol but not in histamine, reduced pepsin content, and increased mucin secretion. Furthermore, it decreased malondialdehyde (MDA) and nitric oxide (NO) contents with an increase in glutathione (GSH) and paraoxonase 1 (PON‐1). Meanwhile, CB2R antagonist (AM630, 1 mg/kg, SC) inhibited gastric acid secretion stimulated by D‐G and reduced MDA and NO contents with an increase in GSH and PON‐1. Meanwhile, CB1R antagonist rimonabant or CB2R agonist GW 405833 had no effect on stimulated gastric acid secretion. Therefore, both CB1R agonist and CB2R antagonist may exert antisecretory and antioxidant potential in the stomach.
Background
Cannabinoid agents and cannabis are frequently used for relief of diverse gastrointestinal symptoms.
Purpose
The objective of this article is to increase the awareness of gastroenterologists to the effects of cannabinoids on gastrointestinal motility, as gastroenterologists are likely to encounter patients who are taking cannabinoids, or those with dysmotility that may be associated with cannabinoid mechanisms. The non‐selective cannabinoid agonist, dronabinol, retards gastric emptying and inhibits colonic tone and phasic pressure activity. In addition to the well‐recognized manifestations of cannabinoid hyperemesis, cannabinoid mechanisms result in human and animal models of gastrointestinal and colonic dysmotility. Decreased enteric FAAH activity is associated with colonic inertia in slow transit constipation and, conversely, the orphan G protein‐coupled receptor, GPR55, is overexpressed in streptozotocin‐induced gastroparesis, suggesting it is involved in inhibition of antral motility. Experimental therapies in gastrointestinal motility and functional disorders are focused predominantly on pain relief mediated through cannabinoid 2 receptors or inhibition of DAGLα to normalize colonic transit. In summary, cannabinoid mechanisms and pharmacology are relevant to the current and future practice of clinical gastroenterology.
The increasing prevalence of cannabis use in the United States requires awareness of cannabis-related disorders and familiarity with treatment options. We present a case of cannabinoid hyperemesis syndrome that required psychiatric consultation for diagnostic clarification and effective treatment with intravenous haloperidol. Literature from emergency medicine, toxicology, and gastroenterology is reviewed, including proposed diagnostic criteria for cannabinoid hyperemesis syndrome and reported off-label treatment options, with a specific focus on clinical questions facing the practicing psychiatrist regarding this emerging disorder.
With increasing use of cannabis, we will increasingly face a so-called cannabis hyperemesis syndrome, which is so far hardly known in Germany. It is characterized by chronic cannabis use, persistent or cyclic nausea and vomiting, unclear abdominal pain and high consumption of warm water, or frequent showering/bathing with warm water. Cannabis is attributed with antiemetic properties. In chronic consumption, this effect can be reversed and paradoxical. The pathogenesis of these different effects is still unclear. The syndrome is presented in this article on the basis of two cases presented in an emergency room with the above-mentioned symptoms, and the pathophysiological relationships are elucidated more closely. In case of missing pathological findings and appropriate anamnesis, it must be considered as an important differential diagnosis in chronic or cyclic vomiting and unclear abdominal complaints in chronic cannabis use.
Two types of endogenous cannabinoid-receptor agonists have been identified thus far. They are the ethanolamides of polyunsaturated fatty acids--arachidonoyl ethanolamide (anandamide) is the best known compound in the amide series--and 2-arachidonoyl glycerol, the only known endocannabinoid in the ester series. We report now an example of a third, ether-type endocannabinoid, 2-arachidonyl glyceryl ether (noladin ether), isolated from porcine brain. The structure of noladin ether was determined by mass spectrometry and nuclear magnetic resonance spectroscopy and was confirmed by comparison with a synthetic sample. It binds to the CB(1) cannabinoid receptor (K(i) = 21.2 +/- 0.5 nM) and causes sedation, hypothermia, intestinal immobility, and mild antinociception in mice. It binds weakly to the CB(2) receptor (K(i) > 3 microM).
We examined the effect of 2-arachidonoylglycerol, an endogenous cannabinoid receptor ligand, on the intracellular free Ca(2+) concentrations in HL-60 cells that express the cannabinoid CB2 receptor. We found that 2-arachidonoylglycerol induces a rapid transient increase in intracellular free Ca(2+) concentrations in HL-60 cells. The response was affected by neither cyclooxygenase inhibitors nor lipoxygenase inhibitors, suggesting that arachidonic acid metabolites are not involved. Consistent with this notion, free arachidonic acid was devoid of any agonistic activity. Importantly, the Ca(2+) transient induced by 2-arachidonoylglycerol was blocked by pretreatment of the cells with SR144528, a CB2 receptor-specific antagonist, but not with SR141716A, a CB1 receptor-specific antagonist, indicating the involvement of the CB2 receptor but not the CB1 receptor in this cellular response. G(i) or G(o) is also assumed to be involved, because pertussis toxin treatment of the cells abolished the response. We further examined the structure-activity relationship. We found that 2-arachidonoylglycerol is the most potent compound among a number of naturally occurring cannabimimetic molecules. Interestingly, anandamide and N-palmitoylethanolamine, other putative endogenous ligands, were found to be a weak partial agonist and an inactive ligand, respectively. These results strongly suggest that the CB2 receptor is originally a 2-arachidonoylglycerol receptor, and 2-arachidonoylglycerol is the intrinsic natural ligand for the CB2 receptor that is abundant in the immune system.
The cannabinoid receptor type 1 (CB1) and its endogenous ligands, the endocannabinoids, are involved in the regulation of food intake. Here we show that the lack of CB1 in mice with a disrupted CB1 gene causes hypophagia and leanness. As compared with WT (CB1(+/+)) littermates, mice lacking CB 1 (CB1(-/-)) exhibited reduced spontaneous caloric intake and, as a consequence of reduced total fat mass, decreased body weight. In young CB1(-/-) mice, the lean phenotype is predominantly caused by decreased caloric intake, whereas in adult CB1(-/-) mice, metabolic factors appear to contribute to the lean phenotype. No significant differences between genotypes were detected regarding locomotor activity body temperature, or energy expenditure. Hypothalamic CB 1 mRNA was found to be coexpressed with neuropeptides known to modulate food intake, such as corticotropin-releasing hormone (CRH), cocaine-amphetamine-regulated transcript (CART), melanin-concentrating hormone (MCH), and prepro-orexin, indicating a possible role for endocannabinoid receptors within central networks governing appetite. CB1(-/-) mice showed significantly increased CRH mRNA levels in the paraventricular nucleus and reduced CART mRNA levels in the dorsomedial and lateral hypothalamic areas. CB1 was also detected in epidydimal mouse adipocytes, and CB1-specific activation enhanced hpogenesis in primary adipocyte cultures. Our results indicate that the cannabinoid system is an essential endogenous regulator of energy homeostasis via central orexigenic as well as peripheral lipogenic mechanisms and might therefore represent a promising target to treat diseases characterized by impaired energy balance.
Arachidonylethanolamide, an arachidonic acid derivative in porcine brain, was identified in a screen for endogenous ligands
for the cannabinoid receptor. The structure of this compound, which has been named "anandamide," was determined by mass spectrometry
and nuclear magnetic resonance spectroscopy and was confirmed by synthesis. Anandamide inhibited the specific binding of a
radiolabeled cannabinoid probe to synaptosomal membranes in a manner typical of competitive ligands and produced a concentration-dependent
inhibition of the electrically evoked twitch response to the mouse vas deferens, a characteristic effect of psychotropic cannabinoids.
These properties suggest that anandamide may function as a natural ligand for the cannabinoid receptor.
Marijuana and many of its constituent cannabinoids influence the central nervous system (CNS) in a complex and dose-dependent manner. Although CNS depression and analgesia are well documented effects of the cannabinoids, the mechanisms responsible for these and other cannabinoid-induced effects are not so far known. The hydrophobic nature of these substances has suggested that cannabinoids resemble anaesthetic agents in their action, that is, they nonspecifically disrupt cellular membranes. Recent evidence, however, has supported a mechanism involving a G protein-coupled receptor found in brain and neural cell lines, and which inhibits adenylate cyclase activity in a dose-dependent, stereoselective and pertussis toxin-sensitive manner. Also, the receptor is more responsive to psychoactive cannabinoids than to non-psychoactive cannabinoids. Here we report the cloning and expression of a complementary DNA that encodes a G protein-coupled receptor with all of these properties. Its messenger RNA is found in cell lines and regions of the brain that have cannabinoid receptors. These findings suggest that this protein is involved in cannabinoid-induced CNS effects (including alterations in mood and cognition) experienced by users of marijuana.
The recently cloned CB2 cannabinoid receptor subtype was stably transfected into AtT-20 and Chinese hamster ovary cells to compare the binding and signal transduction properties of this receptor with those of the CB1 receptor subtype. The binding of [3H]CP 55,940 to both CB1 and CB2 was of similar high affinity (2.6 and 3.7 nM, respectively) and saturable. In competitive binding experiments, (-)-delta 9-tetrahydrocannabinol and CP 55,940 were equipotent at the CB1 and CB2 receptors, but WIN 55212-2 and cannabinol bound with higher affinity to the CB2 than the CB1 receptor. HU 210 had a higher affinity for the CB1 receptor. Anandamide, a recently identified endogenous cannabinoid agonist, was essentially equipotent at both receptor subtypes. The structurally related fatty acid ethanolamides dihomo-gamma-linolenylethanolamide and mead ethanolamide also bound with relatively equal affinity to both receptors, but adrenylethanolamide had a higher affinity for the CB1 receptor. The rank order of potency and efficacy for binding of the selected agonists to the CB1 and CB2 receptors was mimicked in functional inhibition of cAMP accumulation experiments for all compounds tested. Both CB1 and CB2 receptors couple to the inhibition of cAMP accumulation that was pertussis toxin sensitive. SR141716A, a CB1 receptor antagonist, was a poor antagonist at the CB2 receptor in both binding and functional inhibition of cAMP accumulation experiments. When expressed in AtT-20 cells, the CB1 receptor mediated an inhibition of Q-type calcium channels and an activation of inward rectifying potassium channels. In contrast, the CB2 receptor did not modulate the activity of either channel under identical assay conditions. Similar to results obtained for CB1 receptor, the CB2 receptor did not couple to the activation of phospholipases A2, C, or D or to the mobilization of intracellular Ca2+. Except for its inability to couple to the modulation of Q-type calcium channels or inwardly rectifying potassium channels, the CB1 and CB2 receptors display similar pharmacological and biochemical properties.
In this study, we report the isolation from canine intestines of 2-arachidonyl glycerol (2-Ara-Gl). Its structure was determined by mass spectrometry and by direct comparison with a synthetic sample. 2-Ara-Gl bound to membranes from cells transiently transfected with expression plasmids carrying DNA of either CB1 or CB2--the two cannabinoid receptors identified thus far--with Ki values of 472 +/- 55 and 1400 +/- 172 nM, respectively. In the presence of forskolin, 2-Ara-Gl inhibited adenylate cyclase in isolated mouse spleen cells, at the potency level of delta 9-tetrahydrocannabinol (delta 9-THC). Upon intravenous administration to mice, 2-Ara-Gl caused the typical tetrad of effects produced by THC: antinociception, immobility, reduction of spontaneous activity, and lowering of the rectal temperature. 2-Ara-Gl also shares the ability of delta 9-THC to inhibit electrically evoked contractions of mouse isolated vasa deferentia; however, it was less potent than delta 9-THC.
The major active ingredient of marijuana, delta 9-tetrahydrocannabinol (delta 9-THC), has been used as a psychoactive agent for thousands of years. Marijuana, and delta 9-THC, also exert a wide range of other effects including analgesia, anti-inflammation, immunosuppression, anticonvulsion, alleviation of intraocular pressure in glaucoma, and attenuation of vomiting. The clinical application of cannabinoids has, however, been limited by their psychoactive effects, and this has led to interest in the biochemical bases of their action. Progress stemmed initially from the synthesis of potent derivatives of delta 9-THC, and more recently from the cloning of a gene encoding a G-protein-coupled receptor for cannabinoids. This receptor is expressed in the brain but not in the periphery, except for a low level in testes. It has been proposed that the nonpsychoactive effects of cannabinoids are either mediated centrally or through direct interaction with other, non-receptor proteins. Here we report the cloning of a receptor for cannabinoids that is not expressed in the brain but rather in macrophages in the marginal zone of spleen.
The cDNA sequences encoding the central cannabinoid receptor, CB1, are known for two species, rat and human. However, little information concerning the flanking, noncoding regions is presently available. We have isolated two overlapping clones from a human lung cDNA library with CB1 cDNA inserts. One of these, cann7, contains a short stretch of the CB1 coding region and 4 kilobase pairs (kb) of the 3′-untranslated region (UTR), including two polyadenylation signals. The other, cann6, is identical to cann7 upstream from the first polyadenylation signal, and in addition, it contains the whole coding region and extends for 1.8 kb into the 5′-UTR. Comparison of cann6 with the published sequence (Gérard, C. M., Mollereau, C., Vassart, G., and Parmentier, M.(1991) Biochem. J. 279, 129-134) shows the coding regions to be identical, but reveals important differences in the flanking regions. Notably, the cann6 sequence appears to be that of an immature transcript, containing 1.8 kb of an intronic sequence in the 5′-UTR.
In addition, polymerase chain reaction amplification of the CB1 coding region in the IM-9 cell line cDNA resulted in two fragments, one containing the whole CB1 coding region and the second lacking a 167-base pair intron within the sequence encoding the amino-terminal tail of the receptor. This alternatively spliced form would translate to an NH2-terminal modified isoform (CB1A) of the receptor, shorter than CB1 by 61 amino acids. In addition, the first 28 amino acids of the putative truncated receptor are completely different from those of CB1, containing more hydrophobic residues. Rat CB1 mRNA is similarly alternatively spliced. A study of the distribution of the human CB1 and CB1A mRNAs by reverse transcription-polymerase chain reaction analysis showed the presence of both CB1 and CB1A throughout the brain and in all the peripheral tissues examined, with CB1A being present in amounts of up to 20% of CB1.
The amino acid L-glutamate is a neurotransmitter that mediates fast neuronal excitation in a majority of synapses in the central nervous system. Glutamate stimulates both N-methyl-D-aspartate (NMDA) and non-NMDA receptors. While activation of NMDA receptors has been implicated in a variety of neurophysiologic processes, excessive NMDA receptor stimulation (excitotoxicity) is thought to be primarily responsible for neuronal injury in a wide variety of acute neurological disorders including hypoxia-ischemia, seizures, and trauma. Very little is known about endogenous molecules and mechanisms capable of modulating excitotoxic neuronal death. Saturated N-acylethanolamides like palmitoylethanolamide accumulate in ischemic tissues and are synthesized by neurons upon excitatory amino acid receptor activation. Here we report that palmitoylethanolamide, but not the cognate N-acylamide anandamide (the ethanolamide of arachidonic acid), protects cultured mouse cerebellar granule cells against glutamate toxicity in a delayed postagonist paradigm. Palmitoylethanolamide reduced this injury in a concentration-dependent manner and was maximally effective when added 15-min postglutamate. Cannabinoids, which like palmitoylethanolamide are functionally active at the peripheral cannabinoid receptor CB2 on mast cells, also prevented neuron loss in this delayed postglutamate model. Furthermore, the neuroprotective effects of palmitoylethanolamide, as well as that of the active cannabinoids, were efficiently antagonized by the candidate central cannabinoid receptor (CB1) agonist anandamide. Analogous pharmacological behaviors have been observed for palmitoylethanolamide (ALI-Amides) in downmodulating mast cell activation. Cerebellar granule cells expressed mRNA for CB1 and CB2 by in situ hybridization, while two cannabinoid binding sites were detected in cerebellar membranes. The results suggest that (i) non-CB1 cannabinoid receptors control, upon agonist binding, the downstream consequences of an excitotoxic stimulus; (ii) palmitoylethanolamide, unlike anandamide, behaves as an endogenous agonist for CB2-like receptors on granule cells; and (iii) activation of such receptors may serve to downmodulate deleterious cellular processes following pathological events or noxious stimuli in both the nervous and immune systems.
The endogenous cannabinoid receptor agonist anandamide is present in central and peripheral tissues. As the kidney contains both the amidase that degrades anandamide and transcripts for anandamide receptors, we characterized the molecular components of the anandamide signaling system and the vascular effects of exogenous anandamide in the kidney. We show that anandamide is present in kidney homogenates, cultured renal endothelial cells (EC), and mesangial cells; these cells also contain anandamide amidase. Reverse-transcriptase PCR shows that EC contain transcripts for cannabinoid type 1 (CB1) receptors, while mesangial cells have mRNA for both CB1 and CB2 receptors. EC exhibit specific, high-affinity binding of anandamide (Kd = 27.4 nM). Anandamide (1 microM) vasodilates juxtamedullary afferent arterioles perfused in vitro; the vasodilation can be blocked by nitric oxide (NO) synthase inhibition with L-NAME (0.1 mM) or CB1 receptor antagonism with SR 141716A (1 microM), but not by indomethacin (10 microM). Anandamide (10 nM) stimulates CB1-receptor-mediated NO release from perfused renal arterial segments; a similar effect was seen in EC. Finally, anandamide (1 microM) produces a NO-mediated inhibition of KCl-stimulated [3H]norepinephrine release from sympathetic nerves on isolated renal arterial segments. Hence, an anandamide signaling system is present in the kidney, where it exerts significant vasorelaxant and neuromodulatory effects.
The effect of cannabinoid receptor agonists was studied in guinea‐pig myenteric neurones in vitro by use of conventional intracellular recording techniques.
Exposure of myenteric neurones of the S‐cell type to the cannabinoid receptor agonists WIN 55,212‐2 (100 n M ) and CP 55,940 (100 n M ) reversibly and significantly depressed the amplitude of fast excitatory synaptic potentials (fast e.p.s.ps) by 46% and 37%, respectively.
The depressant effect of WIN 55,212‐2 and CP 55,940 on fast e.p.s.p. amplitude (expressed as the area above the amplitude‐time curve (mVs)) was significantly greater than that of the vehicle, Tween 80, which had no detectable effect.
The inhibitory effect of WIN 55,212‐2 appeared to be concentration‐dependent over the range 1–100 n M . WIN 55,212‐3, its (−)‐enantiomer (100 n M ), was inactive.
The cannabinoid CB 1 receptor antagonist, SR141716A (1 μ M ), reversed the inhibitory effects of WIN 55,212‐2 on fast e.p.s.ps in 38% of neurones tested (3/8) and acetylcholine (ACh)‐induced depolarizations in 42% of neurones tested (5/12).
When tested on its own, SR141716A (1 μ M ) caused a 40–50% reduction in the amplitude of fast e.p.s.ps ( n =9).
WIN 55,212‐2 reversibly depressed the amplitude of the slow e.p.s.p. and, in 2 out of 7 neurones, this effect was reversed by SR141716A (1 μ M ).
It is concluded that cannabinoid‐induced inhibition of fast cholinergic synaptic transmission occurred by reversible activation of both presynaptic and postsynaptic CB 1 receptors and that slow excitatory synaptic transmission can also be reversibly depressed by cannabinoids. Furthermore, it would seem that subpopulations of myenteric S‐neurones and their synapsing cholinergic and non‐cholinergic, non‐adrenergic terminals are not endowed with cannabinoid receptors.
British Journal of Pharmacology (1997) 122 , 330–334; doi: 10.1038/sj.bjp.0701393
Based on both binding and functional data, this study introduces SR 144528 as the first, highly potent, selective and orally active antagonist for the CB2 receptor. This compound which displays subnanomolar affinity (Ki = 0.6 nM) for both the rat spleen and cloned human CB2 receptors has a 700-fold lower affinity (Ki = 400 nM) for both the rat brain and cloned human CB1 receptors. Furthermore it shows no affinity for any of the more than 70 receptors, ion channels or enzymes investigated (IC50 > 10 microM). In vitro, SR 144528 antagonizes the inhibitory effects of the cannabinoid receptor agonist CP 55,940 on forskolin-stimulated adenylyl cyclase activity in cell lines permanently expressing the h CB2 receptor (EC50 = 10 nM) but not in cells expressing the h CB1 (no effect at 10 microM). Furthermore, SR 144528 is able to selectively block the mitogen-activated protein kinase activity induced by CP 55,940 in cell lines expressing h CB2 (IC50 = 39 nM) whereas in cells expressing h CB1 an IC50 value of more than 1 microM is found. In addition, SR 144528 is shown to antagonize the stimulating effects of CP 55,940 on human tonsillar B-cell activation evoked by cross-linking of surface Igs (IC50 = 20 nM). In vivo, after oral administration SR 144528 totally displaced the ex vivo [3H]-CP 55,940 binding to mouse spleen membranes (ED50 = 0.35 mg/kg) with a long duration of action. In contrast, after the oral route it does not interact with the cannabinoid receptor expressed in the mouse brain (CB1). It is expected that SR 144528 will provide a powerful tool to investigate the in vivo functions of the cannabinoid system in the immune response.
Macrophages are the primary cellular targets of bacterial lipopolysaccharide (LPS), but the role of macrophage-derived cytokines in LPS-induced septic shock is uncertain. Recent evidence indicates that activation of peripheral CB1 cannabinoid receptors contributes to hemorrhagic hypotension and that macrophage-derived anandamide as well as unidentified platelet-derived substances may be contributing factors. Here we demonstrate that rat platelets contain the endogenous cannabinoid 2-arachidonyl glyceride (2-AG), as identified by reverse phase high-performance liquid chromatography, gas chromatography, and mass spectrometry, and that in vitro exposure of platelets to LPS (200 microg/ml) markedly increases 2-AG levels. LPS-stimulated, but not control, macrophages contain anandamide, which is undetectable in either control or LPS-stimulated platelets. Prolonged hypotension and tachycardia are elicited in urethane-anesthetized rats treated 1) with LPS (15 mg/kg i.v.); 2) with macrophages plus platelets isolated from 3 ml of blood from an LPS-treated donor rat; or 3) with rat macrophages or 4) platelets preincubated in vitro with LPS (200 microg/ml). In all four cases, the hypotension but not the tachycardia is prevented by pretreatment of the recipient rat with the CB1 receptor antagonist SR141716A (3 mg/kg i.v.), which also inhibits the hypotensive response to anandamide or 2-AG. The hypotension elicited by LPS-treated macrophages or platelets remains unchanged in the absence of sympathetic tone or after blockade of nitric oxide synthase. These findings indicate that platelets and macrophages generate different endogenous cannabinoids, and that both 2-AG and anandamide may be paracrine mediators of endotoxin-induced hypotension via activation of vascular CB1 receptors.
CB1-type cannabinoid receptors in the brain mediate effects of the drug cannabis. Anandamide and sn-2 arachidonylglycerol (2-AG) are putative endogenous ligands for CB1 receptors, but it is not known which cells in the brain produce these molecules. Recently, an enzyme which catalyses hydrolysis of anandamide and 2-AG, known as fatty acid amide hydrolase (FAAH), was identified in mammals. Here we have analysed the distribution of FAAH in rat brain and compared its cellular localization with CB1-type cannabinoid receptors using immunocytochemistry. High concentrations of FAAH activity were detected in the cerebellum, hippocampus and neocortex, regions of the rat brain which are enriched with cannabinoid receptors. Immunocytochemical analysis of these brain regions revealed a complementary pattern of FAAH and CB1 expression with CB1 immunoreactivity occurring in fibres surrounding FAAH-immunoreactive cell bodies and/or dendrites. In the cerebellum, FAAH was expressed in the cell bodies of Purkinje cells and CB1 was expressed in the axons of granule cells and basket cells, neurons which are presynaptic to Purkinje cells. The close correspondence in the distribution of FAAH and CB1 in rat brain and the complementary pattern of FAAH and CB1 expression at the cellular level provides important new evidence that FAAH may participate in cannabinoid signalling mechanisms of the brain.
Fatty acid amides (FAAs) represent a class of neuromodulatory lipids that includes the endocannabinoid anandamide and the sleep-inducing substance oleamide. Both anandamide and oleamide produce behavioral effects indicative of cannabinoid activity, but only anandamide binds the cannabinoid (CB1) receptor in vitro. Accordingly, oleamide has been proposed to induce its behavioral effects by serving as a competitive substrate for the brain enzyme fatty acid amide hydrolase (FAAH) and inhibiting the degradation of endogenous anandamide. To test the role that FAAH plays as a mediator of oleamide activity in vivo, we have compared the behavioral effects of this FAA in FAAH(+/+) and (−/−) mice. In both genotypes, oleamide produced hypomotility, hypothermia, and ptosis, all of which were enhanced in FAAH(−/−) mice, were unaffected by the CB1 antagonist N -(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-di-chlorophenyl)-4-methyl-1 H -pyrazole-3-carboxamide hydrochloride (SR141716A) and occurred in CB1(−/−) mice. Additionally, oleamide displayed negligible binding to the CB1 receptor in brain extracts from either FAAH(+/+) or (−/−) mice. In contrast, anandamide exhibited a 15-fold increase in apparent affinity for the CB1 receptor in brains from FAAH(−/−) mice, consistent with its pronounced CB1-dependent behavioral effects in these animals. Contrary to both oleamide and anandamide, monoacylglycerol lipids exhibited equivalent hydrolytic stability and pharmacological activity in FAAH(+/+) and (−/−) mice. Collectively, these results indicate that FAAH is a key regulator, but not mediator of FAA activity in vivo. More generally, these findings suggest that FAAs represent a family of signaling lipids that, despite sharing similar chemical structures and a common pathway for catabolism, produce their behavioral effects through distinct receptor systems in vivo.
The enteric nervous system (ENS) is a quasi autonomous part of the nervous system and includes a number of neural circuits that control motor functions, local blood flow, mucosal transport and secretions, and modulates immune and endocrine functions. Although these functions operate in concert and are functionally interlinked, it is useful to consider the neural circuits involved in each separately.1 This short summary will concentrate mainly on the neural circuits involved in motor control.2 The enteric neural circuits are composed of enteric neurones arranged in networks of enteric ganglia connected by interganglionic strands. Most enteric neurones involved in motor functions are located in the myenteric plexus with some primary afferent neurones located in the submucous plexus. As in all nervous systems involved in sensory-motor control, the ENS comprises primary afferent neurones, sensitive to chemical and mechanical stimuli, interneurones and motorneurones that act on the different effector cells including smooth muscle, pacemaker cells, blood vessels, mucosal glands, and epithelia, and the distributed system of intestinal cells involved in immune responses and endocrine and paracrine functions.
The digestive tract is unique among internal organs because it is exposed to a large variety of physicochemical stimuli from the external world in the form of ingested food. As a consequence, the intestine has developed a rich repertoire of coordinated movements of its muscular apparatus to ensure the appropriate mixing and propulsion of contents during digestion, absorption, and excretion. The oro-aboral transit of the intestinal contents can be regarded as a form of adaptive locomotion that occurs over a wide range of spatial and temporal domains.3 The movements of the intestine are the result of interaction of the neural apparatus and the muscular apparatus.4
The muscular apparatus is organised in muscle layers made up of large collections of smooth muscle cells …
Δ9-Tetrahydrocannabinol (Δ9-THC), the primary psychoactive constituent of marijuana (Cannabis sativa), is known to bind to two cannabinoid receptors: CB1 receptors, located primarily in the brain, and CB2 receptors, located primarily in the periphery. Recent research has suggested that other cannabinoids, including anandamide and WIN 55,212-2, may also act at novel non-CB1, non-CB2 cannabinoid receptor(s). Anandamide produces a number of in vivo pharmacological effects in CB1 knockout mice that are not produced by Δ9-THC and cannot be explained by anandamide's rapid metabolism. In addition, in vitro anandamide and WIN 55,212-2 stimulate [35S]GTPS binding in both CB1 knockout and wildtype mice while Δ9-THC stimulates this binding only in wildtype mice. Although anandamide and vanilloid agonists share pharmacological effects, anandamide's actions in CB1 knockout mice do not appear to be mediated by vanilloid VR1 receptors. While not yet conclusive, these results suggest the possibility of additional cannabinoid receptors in the brain and periphery.
Anandamide (arachidonylethanolamide), an endogenous ligand for cannabinoid receptors, is hydrolyzed by an amidohydrolase and its biological activity is lost. Previously, we partially purified the enzyme from porcine brain and anandamide synthesis by its reverse reaction was proposed (Ueda et al., (1995) J. Biol. Chem. 270, 23823–23827). The anandamide hydrolase and synthase activities were examined with various rat tissues. Rat liver showed the highest specific activities (4.4±0.3 and 4.5±0.5 nmol/min/mg protein) for the hydrolase and synthase, respectively. In most other tissues such as brain, testis and parotid gland, the ratio of synthase/hydrolase activity was 0.7–1.6. However, small intestine showed a relatively high synthase/hydrolase ratio of about 5.0 (1.0±0.1 and 0.2±0.1 nmol/min/mg protein). When a homogenate of small intestine was subjected to acetone extraction to remove lipids, a higher hydrolase activity was found (2.0±0.2 nmol/min/mg protein). Furthermore, Northern blotting detected an intense mRNA band of anandamide hydrolase in small intestine as well as liver and brain. These results demonstrated for the first time a high content of anandamide hydrolase in small intestine.
Δ9-Tetrahydrocannabinol from Cannabis sativa is mimicked by cannabimimetic analogs such as CP55940 and WIN55212-2, and antagonized by rimonabant and SR144528, through G-protein-coupled receptors, CB1 in the brain, and CB2 in the immune system. Eicosanoids anandamide and 2-arachidonoylglycerol are the “endocannabinoid” agonists for these receptors. CB1 receptors are abundant in basal ganglia, hippocampus and cerebellum, and their functional activity can be mapped during behaviors using cerebral metabolism as the neuroimaging tool. CB1 receptors couple to Gi/o to inhibit cAMP production, decrease Ca2+ conductance, increase K+ conductance, and increase mitogen-activated protein kinase activity. Functional activation of G-proteins can be imaged by [35S]GTPγS autoradiography. Post-synaptically generated endocannabinoids form the basis of a retrograde signaling mechanism referred to as depolarization-induced suppression of inhibition (DSI) or excitation (DSE). Under circumstances of sufficient intracellular Ca2+ (e.g., burst activity in seizures), synthesis of endocannabinoids releases a diffusible retrograde messenger to stimulate presynaptic CB1 receptors. This results in suppression of γ-aminobutyric acid (GABA) release, thereby relieving the post-synaptic inhibition. Tolerance develops as neurons adjust both receptor number and cellular signal transduction to the chronic administration of cannabinoid drugs. Future therapeutic drug design can progress based upon our current understanding of the physiology and pharmacology of CB1, CB2 and related receptors. One very important role for CB1 antagonists will be in the treatment of craving in the disease of substance abuse.
The effect of the cannabinoid (CB) receptor agonist WIN 55,212-2 on gastric acid secretion was studied in the anaesthetized rat after stimulation with pentagastrin. WIN 55,212-2 (0.5-2 mg/kg, i.v.) was inactive on basal secretion but caused a marked inhibition (80%) of the acid secretion stimulated by pentagastrin (10 microg/kg, i.v.). The enantiomer WIN 55,212-3 (1-3 mg/kg, i.v.) did not significantly modify basal or pentagastrin-induced acid secretion. The inhibitory effect of WIN 55,212-2 against pentagastrin was prevented by the administration of the selective cannabinoid CB1 receptor antagonists SR141716A (1 mg/kg, i.v.) and LY320135 (1 mg/kg, i.v.); by contrast, the CB2 receptor antagonist SR144528 (0.3-1 mg/kg, i.v.) was without effect. The selective CB2 receptor agonist JWH-015 (0.1-10 mg/kg, i.v.) was inactive on the increase of acid output stimulated by pentagastrin. These results suggest that the inhibitory effect of WIN 55,212-2 on pentagastrin-stimulated acid secretion in the anaesthetized rat is mediated by specific cannabinoid receptors. Moreover, the antagonism of WIN 55,212-2-induced effects by the selective CB1 receptor antagonists SR141716A and LY320135 together with the ineffectiveness of both the CB2 receptor agonist JWH-015 and the CB2 receptor antagonist SR144528 indicate that CB1 receptor subtypes are predominantly involved in the antisecretory effect of WIN 55,212-2.
This study was directed at exploring the structure-activity relationship for anandamide and certain of its analogues at the rat VR1 receptor in transfected cells and at investigating the relative extent to which anandamide interacts with CB1 and vanilloid receptors in the mouse vas deferens.
pKi values for displacement of [3H]-resiniferatoxin from membranes of rVR1 transfected CHO cells were significantly less for anandamide (5.78) than for its structural analogues N-(4-hydroxyphenyl)-arachidonylamide (AM404; 6.18) and N-(3-methoxy-4-hydroxy)benzyl-arachidonylamide (arvanil; 6.77).
pEC50 values for stimulating 45Ca2+ uptake into rVR1 transfected CHO cells were significantly less for anandamide (5.80) than for AM404 (6.32) or arvanil (9.29). Arvanil was also significantly more potent than capsaicin (pEC50=7.37), a compound with the same substituted benzyl polar head group as arvanil.
In the mouse vas deferens, resiniferatoxin was 218 times more potent than capsaicin as an inhibitor of electrically-evoked contractions. Both drugs were antagonized to a similar extent by capsazepine (pKB=6.93 and 7.18 respectively) but were not antagonized by SR141716A (1 μM). Anandamide was less susceptible than capsaicin to antagonism by capsazepine (pKB=6.02) and less susceptible to antagonism by SR141716A (pKB=8.66) than methanandamide (pKB=9.56). WIN55212 was antagonized by SR141716A (pKB=9.02) but not by capsazepine (10 μM).
In conclusion, anandamide and certain of its analogues have affinity and efficacy at the rat VR1 receptor. In the mouse vas deferens, which seems to express vanilloid and CB1 receptors, both receptor types appear to contribute to anandamide-induced inhibition of evoked contractions.
British Journal of Pharmacology (2001) 132, 631–640; doi:10.1038/sj.bjp.0703850
(−)-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
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
We have studied the effect of capsaicin, piperine and anandamide, drugs which activate vanilloid receptors and capsazepine, a vanilloid receptor antagonist, on upper gastrointestinal motility in mice.
Piperine (0.5 – 20 mg kg−1 i.p.) and anandamide (0.5 – 20 mg kg−1 i.p.), dose-dependently delayed gastrointestinal motility, while capsaicin (up to 3 mg kg−1 i.p.) was without effect. Capsazepine (15 mg kg−1 i.p.) neither per se affected gastrointestinal motility nor did it counteract the inhibitory effect of both piperine (10 mg kg−1) and anandamide (10 mg kg−1).
A per se non effective dose of SR141716A (0.3 mg kg−1 i.p.), a cannabinoid CB1 receptor antagonist, counteracted the inhibitory effect of anandamide (10 mg kg−1) but not of piperine (10 mg kg−1). By contrast, the inhibitory effect of piperine (10 mg kg−1) but not of anandamide (10 mg kg−1) was strongly attenuated in capsaicin (75 mg kg−1 in total, s.c.)-treated mice.
Pretreatment of mice with NG-nitro-L-arginine methyl ester (25 mg kg−1 i.p.), yohimbine (1 mg kg−1, i.p.), naloxone (2 mg kg−1 i.p.), or hexamethonium (1 mg kg−1 i.p.) did not modify the inhibitory effect of both piperine (10 mg kg−1) and anandamide (10 mg kg−1).
The present study indicates that the vanilloid ligands anandamide and piperine, but not capsaicin, can reduce upper gastrointestinal motility. The effect of piperine involves capsaicin-sensitive neurones, but not vanilloid receptors, while the effect of anandamide involves cannabinoid CB1, but not vanilloid receptors.
British Journal of Pharmacology (2001) 132, 1411–1416; doi:10.1038/sj.bjp.0703975
Cannabis has been used for centuries in the medicinal treatment of gastrointestinal disorders. Endogenous cannabinimimetic substances such as 2-arachidonylglycerol have been isolated from gut homogenates and CB1-cannabinoid binding sites have been identified in small intestine. In this study, CB1-cannabinoid receptors (CB1-R) were immunohistochemically localized within the enteric nervous system of the pig, an omnivorous species whose digestive tract is functionally similar to humans. Two anti-CB1-R antisera, raised against N-terminal epitopes in the human CB1-R, were employed to localize receptor immunoreactivity by secondary immunofluorescence. CB1-R immunoreactivity was observed in the myenteric and submucosal ganglionated plexuses of porcine ileum and colon. In the ileum, all CB1-R-immunoreactive neurons coexpressed immunoreactivity to the cholinergic marker, choline acetyltransferase (ChAT). CB1-R/ChAT-immunoreactive neurons appeared to be in close apposition to ileal Peyer's patches, submucosal blood vessels, and intestinal crypts. In the distal colon, CB1-R-immunoreactive neurons also expressed immunoreactivity to ChAT, albeit less frequently than in ileum. Immunoreactivity to vasoactive intestinal peptide or nitric oxide synthase was not colocalized in ileal or colonic CB1-R-immunoreactive neurons. These studies indicate that CB1-R are present in cholinergic neurons in the porcine enteric nervous system. The potential roles of these receptors in intestinal motility and epithelial transport, host defense and visceral pain transmission are discussed.