No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Cannabinoids and the gut: New developments and emerging concepts
Abstract
Cannabis has been used to treat gastrointestinal (GI) conditions that range from enteric infections and inflammatory conditions to disorders of motility, emesis and abdominal pain. The mechanistic basis of these treatments emerged after the discovery of Delta(9)-tetrahydrocannabinol as the major constituent of Cannabis. Further progress was made when the receptors for Delta(9)-tetrahydrocannabinol were identified as part of an endocannabinoid system, that consists of specific cannabinoid receptors, endogenous ligands and their biosynthetic and degradative enzymes. Anatomical, physiological and pharmacological studies have shown that the endocannabinoid system is widely distributed throughout the gut, with regional variation and organ-specific actions. It is involved in the regulation of food intake, nausea and emesis, gastric secretion and gastroprotection, GI motility, ion transport, visceral sensation, intestinal inflammation and cell proliferation in the gut. Cellular targets have been defined that include the enteric nervous system, epithelial and immune cells. Molecular targets of the endocannabinoid system include, in addition to the cannabinoid receptors, transient receptor potential vanilloid 1 receptors, peroxisome proliferator-activated receptor alpha receptors and the orphan G-protein coupled receptors, GPR55 and GPR119. Pharmacological agents that act on these targets have been shown in preclinical models to have therapeutic potential. Here, we discuss cannabinoid receptors and their localization in the gut, the proteins involved in endocannabinoid synthesis and degradation and the presence of endocannabinoids in the gut in health and disease. We focus on the pharmacological actions of cannabinoids in relation to GI disorders, highlighting recent data on genetic mutations in the endocannabinoid system in GI disease.
... Interactions with type 1 cannabinoid receptors are mainly associated with the regulation of appetite, motivation to eat, and pain perception. CB1 receptors have been described to be present throughout the enteric nervous system, where they act to inhibit both motility and secretion [14]. Interaction with type 2 cannabinoid receptors is primarily associated with the regulation of immune response processes [7]. ...
... It has been shown that disruption of homeostasis in the endocannabinoid system can cause the progression of many pathological conditions, including those affecting the cardiovascular system, central nervous system, kidneys (progression of nephropathy), adipose tissue (development of insulin resistance, obesity), liver, pancreas, bones, eyes, reproductive system, respiratory tract, and skin [8,9]. The cannabinoid system acts centrally through its effects on hypothalamic and mesolimbic appetite-regulating neurons and peripherally by influencing the function of adipocytes, hepatocytes, and the endocrine part of the pancreas [14]. See Table S1 in Supplementary Materials. ...
... Recently, the endocannabinoid system has been linked to metabolism, gut motility, and eating behaviors as well as chronic diseases such as obesity [37]. Research to date has provided information on the influence of the gut microbiome and diet on the endocannabinoid system [14,19,44]. Polyunsaturated fatty acids act on CB1 and CB2 receptors. ...
The endocannabinoid system is a complex communication system involved in maintaining homeostasis in various physiological processes, including metabolism, immune response, pain modulation, and neuroprotection. Endocannabinoids, mainly anandamide and 2-arachidonoylglycerol, are natural ligands of the cannabinoid receptors CB1 and CB2, which are widely distributed throughout the central nervous system and peripheral tissues. Their biosynthesis, degradation, and interaction with other signaling pathways play crucial roles in both health and disease. This article provides a comprehensive overview of the physiological and pathological roles of endocannabinoids, discusses their potential as therapeutic targets, and highlights recent advances in endocannabinoid-based treatments.
... 1,2 The eCB system is distributed in both the central and peripheral nervous systems and also expressed in the gastrointestinal tract, namely in the enteric nervous system, smooth muscle, epithelial, glial, and immune cells. [3][4][5][6] Cannabinoid ligands have been implicated in a broad range of gut function (secretion, motility, ion transport, intestinal barrier integrity, and gastroprotection) as well as in the modulation of pathophysiological processes such as intestinal inflammation and pain signaling (see reviews). 4,5,[7][8][9][10] Endocannabinoids are rapidly degraded mainly by two enzymes, the fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase. ...
... [3][4][5][6] Cannabinoid ligands have been implicated in a broad range of gut function (secretion, motility, ion transport, intestinal barrier integrity, and gastroprotection) as well as in the modulation of pathophysiological processes such as intestinal inflammation and pain signaling (see reviews). 4,5,[7][8][9][10] Endocannabinoids are rapidly degraded mainly by two enzymes, the fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase. [11][12][13] FAAH is the major enzyme responsible for the catabolism of anandamide (AEA) and several other acylethanolamides (fatty acid amides, "FAAs"), including palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) which do not activate cannabinoid receptors, while monoacylglycerol lipase degrades 2-arachidonoylglycerol (2-AG). ...
... 83 By contrast, the model of cortagine-induced visceral hypersensitivity did not show signs of colonic inflammation histologically 48 and we found that cortagine alone did not modify brain and intestinal levels of anandamide levels contrary to what is observed in intestinal inflamed tissues. 4,84 We further found that URB597 suppressed cortagine-induced visceral hypersensitivity to CRD without modifying the basal VMR. ...
Background and Aims
The endocannabinoid (eCB) system includes ligands (anandamide and 2‐arachidonoyl glycerol, 2‐AG), receptors and catabolizing enzymes (fatty acid amide hydrolase, FAAH and monoacylglycerol lipase) expressed in both the brain and gut. We investigated whether the FAAH inhibitor, URB597, influenced visceral pain to colorectal distension (CRD) in an acute stress‐related model of visceral hypersensitivity induced by the selective corticotropin‐releasing factor receptor subtype 1 (CRF1) agonist, cortagine.
Methods
Male Sprague–Dawley rats were injected subcutaneously (SC) with URB597 (3 mg/kg) or vehicle and 2 h later, intraperitoneally with cortagine (10 μg/kg) or vehicle. The visceromotor responses (VMR) were assessed to a first CRD (baseline) before injections, and to a second CRD 15 min after the last treatment. Brain, jejunum, and proximal colon were collected from treated and naïve rats for levels quantification of three fatty acid amides (FAAs) [anandamide (arachidonyl‐ethanolamide, AEA), oleoyl‐ethanolamide (OEA) and palmitoyl‐ethanolamide (PEA)], and 2‐AG. In separate animals, defecation/diarrhea were monitored after URB597 and cortagine.
Key Results
URB597 inhibited cortagine‐induced increased VMR at 40 mmHg (89.0 ± 14.8% vs. 132.5 ± 15.6% for vehicle SC, p < 0.05) and 60 mmHg (107.5 ± 16.1% vs. 176.9 ± 24.4% for vehicle SC, p < 0.001) while not influencing basal VMR. In URB597 plus cortagine group, FAAs levels increased in the brain and intestinal tissue while 2‐AG did not change. URB597 did not modify cortagine‐induced defecation/diarrhea versus vehicle.
Conclusions and Inferences
URB597 shows efficacy to elevate brain and intestinal FAAs and to counteract the colonic hypersensitivity induced by peripheral activation of CRF1 signaling supporting a potential strategy of FAAH inhibitors to alleviate stress‐related visceral hypersensitivity.
... Consistent with laboratory in vivo reports, the ECS regulates numerous physiological functions in the intestines, including gut motility secretion and visceral sensation. In the intestines, the activation of CB 1 receptors in the enteric nervous system can be inhibitory for neurotransmitter release, negatively affecting gastrointestinal motility [34] and intestinal secretions [35]. CB 2 receptor activation in immune cells within the intestinal mucosa can influence inflammatory responses and contribute to intestinal immune equilibrium [36]. ...
... Diagrammatic representation of ECS receptors CB R 1 and CB R 2 that have been identified on neuronal cells[95] and immune system cells (i.e., B lymphocytes)[96] and can bind CBD and THC and their effects on the gut and intestinal microbiota (adapted and modified from Izzo and Sharkey; Storr et al.; Al-Khazaleh et al.)[35,36,71]. ECS = endocannabinoid system; CBD = cannabidiol; CB R 1 = Cannabinoid Receptor 1; CB R 2 = Cannabinoid Receptor 2. ...
Historically, the multiple uses of cannabis as a medicine, food, and for recreational purposes as a psychoactive drug span several centuries. The various components of the plant (i.e., seeds, roots, leaves and flowers) have been utilized to alleviate symptoms of inflammation and pain (e.g., osteoarthritis, rheumatoid arthritis), mood disorders such as anxiety, and intestinal problems such as nausea, vomiting, abdominal pain and diarrhea. It has been established that the intestinal microbiota progresses neurological, endocrine, and immunological network effects through the gut–microbiota–brain axis, serving as a bilateral communication pathway between the central and enteric nervous systems. An expanding body of clinical evidence emphasizes that the endocannabinoid system has a fundamental connection in regulating immune responses. This is exemplified by its pivotal role in intestinal metabolic and immunity equilibrium and intestinal barrier integrity. This neuromodulator system responds to internal and external environmental signals while also serving as a homeostatic effector system, participating in a reciprocal association with the intestinal microbiota. We advance an exogenous cannabinoid–intestinal microbiota–endocannabinoid system axis potentiated by the intestinal microbiome and medicinal cannabinoids supporting the mechanism of action of the endocannabinoid system. An integrative medicine model of patient care is advanced that may provide patients with beneficial health outcomes when prescribed medicinal cannabis.
... On the other hand, pain, inflammation, secretion, motility, and gut microbiota are potentially regulated by endocannabinoids and may modulate the expression of CB 2 receptors [110]. What is crucial is that all these factors are part of the pathophysiology of IBS. ...
... What is crucial is that all these factors are part of the pathophysiology of IBS. As cannabinoids have an analgesic effect, it can be presumed that there is a deficiency of the endocannabinoid system in conditions with symptoms like pain or discomfort, in this case, in IBS [110,111]. Here, it is important to emphasize that there are different study results on the connection between the endocannabinoid system and subtypes of IBS. In one small study, it was shown that in IBS patients with diarrhea, higher levels of 2-arachidonoyl-glycerol were recorded and lower levels of OEA and PEA were recorded, but increased levels of OEA were recorded in IBS patients with constipation [34]. ...
Palmitoylethanolamide (PEA) is an endocannabinoid-like bioactive lipid mediator belonging to the family of N-acylethanolamines, most abundantly found in peanuts and egg yolk. When the gastrointestinal (GI) effects of PEA are discussed, it must be pointed out that it affects intestinal motility but also modulates gut microbiota. This is due to anti-inflammatory, antioxidant, analgesic, antimicrobial, and immunomodulatory features. Additionally, PEA has shown beneficial effects in several GI diseases, particularly irritable bowel syndrome and inflammatory bowel diseases, as various studies have shown, and it is important to emphasize its relative lack of toxicity, even at high dosages. Unfortunately, there is not enough endogenous PEA to treat disturbed gut homeostasis, even though it is produced in the GI tract in response to inflammatory stimuli, so exogenous intake is mandatory to achieve homeostasis. Intake of PEA could be through animal and/or vegetable food, but bearing in mind that a high dosage is needed to achieve a therapeutic effect, it must be compensated through dietary supplements. There are still open questions pending to be answered, so further studies investigating PEA’s effects and mechanisms of action, especially in humans, are crucial to implementing PEA in everyday clinical practice.
... The ECS regulates various physiological functions in the gastrointestinal tract, such as gut motility, secretion, and visceral sensation. Activation of CB1 receptors in the enteric nervous system can inhibit neurotransmitter release, resulting in reduced gastrointestinal motility and intestinal secretion ( Figure 2) [75,76]. On the other hand, CB2 receptor activation in immune cells within the gut mucosa can influence the inflammatory response and contribute to gut immune homeostasis [77]. ...
... Cannabinoids have well-known effects on gut motility, influencing gastrointestinal transit and smooth muscle contractions [76]. The gut microbiota can modulate these effects by interacting with the ECS and affecting the production of certain neurotransmitters and neuromodulators involved in gut motility regulation. ...
Emerging research has revealed a complex bidirectional interaction between the gut microbiome and cannabis. Preclinical studies have demonstrated that the gut microbiota can significantly influence the pharmacological effects of cannabinoids. One notable finding is the ability of the gut microbiota to metabolise cannabinoids, including Δ⁹-tetrahydrocannabinol (THC). This metabolic transformation can alter the potency and duration of cannabinoid effects, potentially impacting their efficacy in cancer treatment. Additionally, the capacity of gut microbiota to activate cannabinoid receptors through the production of secondary bile acids underscores its role in directly influencing the pharmacological activity of cannabinoids. While the literature reveals promising avenues for leveraging the gut microbiome–cannabis axis in cancer therapy, several critical considerations must be accounted for. Firstly, the variability in gut microbiota composition among individuals presents a challenge in developing universal treatment strategies. The diversity in gut microbiota may lead to variations in cannabinoid metabolism and treatment responses, emphasising the need for personalised medicine approaches. The growing interest in understanding how the gut microbiome and cannabis may impact cancer has created a demand for up-to-date, comprehensive reviews to inform researchers and healthcare practitioners. This review provides a timely and invaluable resource by synthesizing the most recent research findings and spotlighting emerging trends. A thorough examination of the literature on the interplay between the gut microbiome and cannabis, specifically focusing on their potential implications for cancer, is presented in this review to devise innovative and effective therapeutic strategies for managing cancer.
... The ECS regulates various physiological functions in the gastrointestinal tract, such as gut motility, secretion, and visceral sensation. Activation of CB1 receptors in the enteric nervous system can inhibit neurotransmitter release, resulting in reduced gastrointestinal motility and intestinal secretion (Figure 3) (Izzo et al., 2012;Izzo & Sharkey, 2010). On the other hand, CB2 receptor activation in immune cells within the gut mucosa can influence the inflammatory response and contribute to gut immune homeostasis (Storr, 2008). ...
... Cannabinoids have well-known effects on gut motility, influencing gastrointestinal transit and smooth muscle contractions (Izzo & Sharkey, 2010). The gut microbiota can modulate these effects by interacting with the ECS and affecting the production of certain neurotransmitters and neuromodulators involved in gut motility regulation. ...
Emerging research has revealed a complex bidirectional interaction between the gut microbiome and cannabis. Preclinical studies have demonstrated that the gut microbiota can significantly influence the pharmacological effects of cannabinoids. One notable finding is the ability of the gut microbiota to metabolise cannabinoids, including Δ^9-tetrahydrocannabinol (THC). This metabolic transformation can alter the potency and duration of cannabinoid effects, potentially impacting their efficacy in cancer treatment. Additionally, the capacity of gut microbiota to activate cannabinoid receptors through the production of secondary bile acids underscores its role in directly influencing the pharmacological activity of cannabinoids. While the literature reveals promising avenues for leveraging the gut microbiome-cannabis axis in cancer therapy, several critical considerations must be accounted for. Firstly, the variability in gut microbiota composition among individuals presents a challenge in developing universal treatment strategies. The diversity in gut microbiota may lead to variations in cannabinoid metabolism and treatment responses, emphasising the need for personalised medicine approaches. The growing interest in understanding how the gut microbiome and cannabis may impact cancer has created a demand for up-to-date, comprehensive reviews to inform researchers and healthcare practitioners. This review provides a timely and invaluable resource by synthesizing the most recent research findings and spotlighting emerging trends. A thorough examination of the literature on the interplay between the gut microbiome and cannabis, specifically focusing on their potential implications for cancer, is presented in this review to devise innovative and effective therapeutic strategies for managing cancer.
... These components are widely spread throughout the human body 3 . Regarding the breadth of its distribution, ECS performs its functions in all areas of the body, such as: its role in the regulation of neuronal energy metabolism through the presence of CB1 receptor on neuronal mitochondria membrane 4 , its action in the gastrointestinal system with specific actions, involved with regulation of food intake, gastric secretion and gastroprotection, cell proliferation in the intestine 5 , and immune response regulation with the expression of CB2 receptors in hematopoietic system cells 6 , in addition to its action in tissue homeostasis of the entire skin, since it is also present in keratinocytes and dermal nerve cells 7 . Thus, imbalances that occur on the ECS disturb the body homeostasis and can lead to numerous pathologies. ...
... Thus, imbalances that occur on the ECS disturb the body homeostasis and can lead to numerous pathologies. Therefore, the study of the system itself and the effects that PHYTs can have is primordial to health, and especially to the quality of life of individuals affected by diseases that are difficult to control, with chronic pain, and poor prognosis, as in the case of neurodegenerative diseases 5 . The PHYTs extracted from Cannabis sativa L. interact with ECS through CB1 and CB2 receptors 8 , and their applications can be the most diverse, depending on the pathological condition in question, which reflects on the type of PHYT to be administered, its dosage and frequency of use. ...
... These components are widely spread throughout the human body 3 . Regarding the breadth of its distribution, ECS performs its functions in all areas of the body, such as: its role in the regulation of neuronal energy metabolism through the presence of CB1 receptor on neuronal mitochondria membrane 4 , its action in the gastrointestinal system with specific actions, involved with regulation of food intake, gastric secretion and gastroprotection, cell proliferation in the intestine 5 , and immune response regulation with the expression of CB2 receptors in hematopoietic system cells 6 , in addition to its action in tissue homeostasis of the entire skin, since it is also present in keratinocytes and dermal nerve cells 7 . Thus, imbalances that occur on the ECS disturb the body homeostasis and can lead to numerous pathologies. ...
... Thus, imbalances that occur on the ECS disturb the body homeostasis and can lead to numerous pathologies. Therefore, the study of the system itself and the effects that PHYTs can have is primordial to health, and especially to the quality of life of individuals affected by diseases that are difficult to control, with chronic pain, and poor prognosis, as in the case of neurodegenerative diseases 5 . The PHYTs extracted from Cannabis sativa L. interact with ECS through CB1 and CB2 receptors 8 , and their applications can be the most diverse, depending on the pathological condition in question, which reflects on the type of PHYT to be administered, its dosage and frequency of use. ...
BACKGROUND AND OBJECTIVES
Since the relatively recent discovery of the endocannabinoid system (ECS) and its fundamental role in regulating other systems, the subject has aroused interest in all areas of health, including Dentistry. Among the possible uses and benefits of cannabinoids are their performance in pain and its predisposing or perpetuating factors, such as bruxism and sleep disorders. Although the literature is still scarce, the mechanisms of action and satisfactory results of cannabinoids and other cannabis derivatives in these situations already allow their safe prescription. The objective of this study was to verify the current evidence on the use of cannabis derivatives in orofacial pain (OFP), reviewing what is known, to date, about the ECS and the prospects for its use with support and criteria.
CONTENTS
This research carried out a brief review of the cannabis plant history, addressing issues such as prejudice, prohibitions and interests, as well as its therapeutic use. Then, a review on ECS and its mechanisms of interest in OFP was presented. Next, the products derived from the plant and their effects, indications, contraindications, adverse effects, drug interactions, peculiarities and perspectives were discussed.
CONCLUSION
The more knowledge is gained about the ECS and the therapeutic benefits of cannabis components and derivatives, the greater the conviction that a new therapeutic frontier has indeed emerged. The growing number of good outcomes, including cases of OFP, obtained through well-conducted studies, brings a mixture of satisfaction and excitement. No therapy will achieve good results if it does not start from an accurate diagnosis. Thus, it is of the utmost importance to know the ECS, the products and derivatives of the plant, the synthetic cannabinoids, their indications and effects. New studies are necessary and, at this moment, it can be said that the perspectives are very good and a new and challenging horizon is emerging.
Keywords:
Cannabidiol; Cannabis; Orofacial pain; Endocannabinoids; Dentistry
... The medicinal and recreational use of Cannabis plant dates from centuries. The plant contains over 100 cannabinoids, alongside with other biological active compounds (Devinsky et al., 2024;Dubrow et al., 2021;Izzo and Sharkey, 2010). The major psychoactive constituent of Cannabis is delta-9 tetrahydrocannabinol (THC), while cannabidiol (CBD) is the most prevalent non-intoxicating cannabinoid of the plant (Mead, 2019). ...
... On DRG neurons that innervate the colon, bladder, pancreas, stomach, and duodenum, TRPV1 is abundantly expressed. Afferents expressing TRPV1 are involved in the control of mucosal homeostasis, motility, nociception, secretion, and GI circulation (Izzo and Sharkey 2010) (Table 3). ...
Chronic painful autoimmune disorders such as multiple sclerosis (MS), inflammatory bowel disease (IBD), and rheumatoid arthritis (RA) induce significant discomfort. They are defined by persistent inflammation and immune-mediated tissue injury. The activation and sensitisation of nociceptors, mutated in various disorders, are fundamental components contributing to the pain experienced in these conditions. Recent discoveries indicate that immunological mediators and nociceptive receptors interact functionally within peripheral and central sensitisation pathways, amplifying chronic pain. This research examines the involvement of nociceptors in rheumatoid arthritis, multiple sclerosis, and inflammatory bowel disease. It explores how immune cells and pro-inflammatory cytokines induce, sensitise and regulate various nociceptive receptors (P2X, TRPA1 and TRPV1). Finally, we address possible future directions with respect to the treatment of long-lasting effects on immunity, and what new drug targets could be pursued as well, in order to counteract such either neuro-immune interactions in conditions involving the immunological system. By studying nociceptive mechanisms across autoimmune illnesses, we want to identify shared pathways and activation of nociceptors specific to individual diseases. This will shed insight on potential therapies for managing pain associated with autoimmune diseases.
Graphical Abstract
... 38 Palmitoylethanolamide acts as an endogenous fatty acid amide; it belongs to the class of nuclear factor agonists. 10,39 It specifically binds to PPAR-α, which plays a crucial role in inhibiting the expression of proinflammatory genes and thus reduces inflammation and nociception. 5,6 This interaction not only contributes to the anti-inflammatory properties of PEA but also moderates neuropathic pain through neuroinflammatory pathways. ...
Context
Chronic pain is a debilitating condition that affects a significant proportion of the population. Palmitoylethanolamide (PEA), a naturally occurring fatty acid amide derived from omega-7 fatty acids, has emerged as a safe and effective alternative for pain management and exerts its effects by interacting with the endocannabinoid system, modulating inflammation, and regulating immune responses.
Objective
A comprehensive meta-analysis was conducted to evaluate the efficacy of PEA in alleviating pain across various pathologies, considering the nociceptive, neuropathic, or nociplastic nature of pain.
Data Sources
A systematic search was conducted of 4 databases: PubMed, Embase, Scopus, and Cochrane Collaboration Library.
Data Extraction
Randomized clinical trials were selected for analysis. This meta-analysis included 18 studies involving 1196 patients.
Data Analysis
Continuous variables were assessed using a standard mean difference (SMD). Heterogeneity was evaluated using the χ2 test and I2 statistics. Pain was significantly reduced in the PEA group at 6 weeks (SMD, –0.9; 95% CI, –1.60 to –0.31), 8 weeks (SMD, –0.98; 95% CI, –1.61 to –0.36), and 24-26 weeks (SMD, –1.16; 95% CI, –2.15 to –0.17). Quality of life, including pain-related items, was significantly higher in the PEA group (SMD, –0.61; 95% CI, –0.93 to –0.30). Significant differences in favor of PEA were observed at 4 (SMD, –0.36; 95% CI, –0.65 to –0.07) and 8 weeks (SMD, –0.66; 95% CI, –1.15 to –0.17). Palmitoylethanolamide was effective for all pain types: nociceptive (SMD, –0.74; 95% CI, –1.42 to –0.06), neuropathic (SMD, –0.97; 95% CI, –1.54 to –0.39), and nociplastic (SMD, –0.59; 95% CI, –1.15 to –0.03).
Conclusions
This meta-analysis confirmed that PEA effectively reduces pain and enhances quality of life, with significant benefits observed within 4-6 weeks of treatment. Palmitoylethanolamide is a promising alternative to chronic opioid analgesics, potentially reducing the risk of opioid abuse and dependency.
Systematic Review Registration
PROSPERO registration no. CRD42024550546.
... We hypothesized that the CRBP II-induction in bowel-resected rats had broader effects on the metabolism of not only vitamin A but also other nutritional components such as lipids and cholesterol. Specifically, upregulation of Rbp2 mRNA in SB rats may sequester MAGs from functioning as a signaling molecule to modulate expression of genes concerning lipids and cholesterol metabolism in the intestine (Izzo and Sharkey 2010). To examine this hypothesis, we re-evaluated the expression levels of genes related to lipid and cholesterol metabolism in the livers and intestines of bowel-resected rats, as done previously (Hebiguchi et al., 2015). ...
We have previously shown that vitamin A-absorptive function was enhanced in bowel-resected rats via increased expression of cellular retinol-binding protein II (CRBP II). Recently, CRBP II was shown to bind not only to retinol but also to monoacylglycerols to modulate gut endocrine signaling. We hypothesized that the increased CRBP II in bowel-resected rats had broader effects than vitamin A metabolism. Acetyl-CoA carboxylase 1 (fatty-acid biosynthesis) and sterol O-acyltransferase 1 (cholesterol esterification) expressions were down-regulated in the bowel-resected rats. Adjustment of nutritional absorption may take place in a limited area of the small intestine by the modulation of gene expression.
... Within the CNS, it acts at the level of inhibitory and excitatory synapses in brain regions involved in emotional or nonemotional processes, and mediates the effects of THC, the main psychoactive constituent of Cannabis [47]. Increasing evidence suggest that altered EC signalling could play a role in the pathophysiology of several diseases such as pain and inflammation [48]; immunological disorders [49,50]; neurodegenerative [9] and stress-related conditions [51]; obesity, metabolic [52,53] and cardiovascular [54] diseases; cancer [55], gastrointestinal [53,56] and hepatic [57] disorders. However, the exact pathophysiological mechanisms through which the ECS plays are not clearly understood at present. ...
Increasing evidence suggests a close relationship between the endocannabinoid system and schizophrenia. The endocannabinoid system comprises of two G protein-coupled receptors (the cannabinoid receptors 1 and 2 [CB1 and CB2] for marijuana's psychoactive principle 9-tetrahydrocannabinol), their endogenous small lipid ligands (namely anan-damide [AEA] and 2-arachidonoylglycerol [2-AG], also known as endocannabinoids), and proteins for endocannabinoid biosynthesis and degradation. It has been suggested to be a pro-homeostatic and pleiotropic signalling system activated in a time-and tissue-specific manner during pathophysiological conditions. In the brain, activation of this system impacts the release of numerous neurotransmitters in various systems and cytokines from glial cells. Hence, the endocannabinoid system is strongly involved in neuropsychiatric disorders, such as schizophrenia. Therefore, adolescence use of Cannabis may alter the endocannabinoid signalling and pose a potential environmental risk to develop psychosis. Consistently, preclinical and clinical studies have found a dysregulation in the endocannabinoid system such as changed expression of CB1 and CB2 receptors or altered levels of AEA and 2-AG. Thus, due to the partial efficacy of actual antipsychotics, compounds which modulate this system may provide a novel therapeutic target for the treatment of schizophrenia. The present article reviews current available knowledge on herbal, synthetic and endogenous cannabinoids with respect to the modulation of schizophrenic symptomatology. Furthermore, this review will be highlighting the therapeutic potential of cannabinoid-related compounds and presenting some promising patents targeting potential treatment options for schizo-phrenia.
... Besides modulating immune response and inflammation, CB2R governs bone metabolism, neuroprotection, and pain perception. It has also been linked to several conditions, including inflammatory bowel disease, neurological disorders, and cancer [11,12]. Moreover, targeted CB2R stimulation has been proven to exert an anti-inflammatory effect [13]. ...
Postoperative cognitive dysfunction (POCD) is a major concern, particularly among older adults. This study used social isolation (ISO) and multiomics analyses in aged mice to investigate potential mechanisms underlying POCD development. Aged mice were divided into two groups: ISO and paired housing (PH). Oleamide and the cannabinoid receptor type 2 (CB2R) antagonist AM630 were administered intraperitoneally, while Foxq1 adeno‐associated viral (AAV) vector was injected directly into the hippocampus. Intramedullary tibial surgeries were subsequently performed to establish the POCD models. Behavioral tests comprising the Y‐maze, open field test, and novel object recognition were conducted 2 days after surgery. Hippocampal and serum inflammatory cytokines were assessed. Following surgery, ISO mice demonstrated intensified cognitive impairments and escalated inflammatory markers. Integrative transcriptomic and metabolomic analysis revealed elevated oleamide concentrations in the hippocampus and serum of PH mice, with associative investigations indicating a close relationship between the Foxq1 gene and oleamide levels. While oleamide administration and Foxq1 gene overexpression substantially ameliorated postoperative cognitive performance and systemic inflammation in mice, CB2R antagonist AM630 impeded these enhancements. The Foxq1 gene and oleamide may be crucial in alleviating POCD. While potentially acting through CB2R‐mediated pathways, these factors may modulate neuroinflammation and attenuate proinflammatory cytokine levels within the hippocampus, substantially improving cognitive performance postsurgery. This study lays the groundwork for future research into therapeutic approaches targeting the Foxq1‐oleamide‐CB2R axis, with the ultimate goal of preventing or mitigating POCD.
... To support this idea, previous findings from our laboratory and work with collaborators have determined that naloxoneprecipitated and spontaneous withdrawal from chronic opioids disturbs gut microbiota, and OlAla pretreatment by injection attenuates some of these disturbances [14]. Additionally, a high level of PPARα and CB 1 receptor expression is found in gut tissue [25], and OlAla exerts its effects on opioid withdrawal responses via these receptors. The possibility that OlAla may regulate somatic withdrawal behaviors at the level of the gut would also explain the tendency for i.p. ...
(1) Background: Intraperitoneal injections of the endogenous N-acyl amino acid N-Oleoyl alanine (OlAla) effectively reduces both the affective and somatic responses produced by opioid withdrawal in preclinical models. To increase the translational appeal of OlAla in clinical drug applications, the current experiments tested whether oral OlAla pretreatment also attenuates opioid withdrawal in rats. (2) Methods: In Experiment 1, to assess its impact on affective withdrawal behavior, OlAla (0, 5, 20 mg/kg) was orally administered during the conditioning phase of an acute naloxone-precipitated morphine withdrawal conditioned place avoidance task. In Experiment 2, to assess its impact on somatic withdrawal behavior, OlAla (5–80 mg/kg) was orally administered prior to naloxone-precipitated withdrawal from chronic heroin exposure. (3) Results: Pretreatment with oral OlAla at the higher (20 mg/kg), but not lower (5 mg/kg) dose, reduced the establishment of an acute morphine withdrawal-induced conditioned place aversion. Instead, the lower dose of oral OlAla (5 mg/kg) reduced heroin withdrawal-induced abdominal contractions and diarrhea, whereas higher doses were without effect. (4) Conclusions: The results suggest a dose-dependent reduction of opioid withdrawal responses by orally administered OlAla, and further highlight the potential utility of this compound for opioid withdrawal in clinical populations.
... In a mouse model of terminal ileitis, CB1 receptors are overexpressed, thereby decreasing motility. It is hypothesized that this upregulation of CB1 receptors is a protective mechanism regulated by the endocannabinoid system to counteract the pathophysiologic hypermotile state, which defines inflammatory bowel disease and possibly other functional disorders of the gut such as irritable bowel syndrome (12). Relaxation of the lower esophageal sphincter is also inhibited by tetrahydrocannabinol, preventing gastroesophageal reflux (13). ...
The use of medicinal cannabis has a long history dating back thousands of years. Recent discoveries have shed light on its mechanism of action with the identification of cannabinoid receptors and endocannabinoids, which make up the body's endocannabinoid system. Cannabinoid receptors, particularly the cannabinoid 1 and 2 receptors, play a crucial role in modulating the gut-brain axis and serve as potential therapeutic targets for gastrointestinal motility and inflammatory disorders. With increasing legalization of cannabis and a rising number of users, understanding the effects of cannabis on gut motility is essential for nuclear medicine providers. Although tetrahydrocannabinol, the principal psychoactive constituent of cannabis, may decrease gut motility in experimental settings, it appears to paradoxically improve symptoms in gastroparesis. Treatment effects are difficult to measure given the large number of variables that could significantly alter outcomes, such as cannabinoid type, potency, and route of intake. Another consideration is the highly personalized gut microbiome, which directly interacts with the endocannabinoid system. Further research is required to delineate these multifaceted, complex cannabinoid interactions. The goal of this article is to explore the knowns and unknowns of the impact of cannabis on the alimentary system.
... The orexigenic hormone ghrelin, which is released when the gastric CB1R is activated, raises the perception of fat and encourages consumption of fat (135). Furthermore, in both rodents and humans, the ECS in the gut may change cholinergic transmission to the colon, lowering intestinal motility (136). Additionally, the CB1Rs' anti-inflammatory properties make the ECS a possible enhancer of food absorption in the GI tract (136). ...
Cannabinoids are a group of bioactive compounds abundantly present in Cannabis sativa plant. The active components of cannabis with therapeutic potential are known as cannabinoids. Cannabinoids are divided into three groups: plant-derived cannabinoids (phytocannabinoids), endogenous cannabinoids (endocannabinoids), and synthetic cannabinoids. These compounds play a crucial role in the regulation various physiological processes including the immune modulation by interacting with the endocannabinoid system (A complex cell-signaling system). Cannabinoid receptor type 1 (CB1) stimulates the binding of orexigenic peptides and inhibits the attachment of anorexigenic proteins to hypothalamic neurons in mammals, increasing food intake. Digestibility is unaffected by the presence of any cannabinoids in hemp stubble. Endogenous cannabinoids are also important for the peripheral control of lipid processing in adipose tissue, in addition to their role in the hypothalamus regulation of food intake. Regardless of the kind of synaptic connection or the length of the transmission, endocannabinoids play a crucial role in inhibiting synaptic transmission through a number of mechanisms. Cannabidiol (CBD) mainly influences redox equilibrium through intrinsic mechanisms. Useful effects of cannabinoids in animals have been mentioned e.g., for disorders of the cardiovascular system, pain treatment, disorders of the respiratory system or metabolic disorders. Dietary supplementation of cannabinoids has shown positive effects on health, growth and production performance of small and large animals. Animal fed diet supplemented with hemp seeds (180 g/day) or hemp seed cake (143 g/kg DM) had achieved batter performance without any detrimental effects. But the higher level of hemp or cannabinoid supplementation suppress immune functions and reduce productive performance. With an emphasis on the poultry and ruminants, this review aims to highlight the properties of cannabinoids and their derivatives as well as their significance as a potential feed additive in their diets to improve the immune status and health performance of animals.
... CB1 and, to a lesser extent, CB2 are located in nerve fibers throughout the gut, but their concentration is highest in the myenteric and submucosal plexi [37]. Importantly, CB receptors are believed to be localized only to excitatory nerves in the gut [38]. The endocannabinoids function as retrograde neurotransmitters since they are synthetized in the postsynaptic cell, then cross the synapse and activate CB receptors presynaptically [39]. ...
The maintenance of homeostasis in the gastrointestinal (GI) tract is ensured by the presence of the endocannabinoid system (ECS), which regulates important physiological activities, such as motility, permeability, fluid secretion, immunity, and visceral pain sensation. Beside its direct effects on the GI system, the ECS in the central nervous system indirectly regulates GI functions, such as food intake and energy balance. Mounting evidence suggests that the ECS may play an important role in modulating central neurotransmission which affects GI functioning. It has also been found that the interaction between the ECS and microbiota affects brain and gut activity in a bidirectional manner, and a number of studies demonstrate that there is a strong relationship between GI dysfunctions and mood disorders. Thus, microbiota can regulate the tone of the ECS. Conversely, changes in intestinal ECS tone may influence microbiota composition. In this mini-review, we propose the concept of neuro-gastro-cannabinology as a novel and alternative paradigm for studying and treating GI disorders that affect mood, as well as mood disorders that imbalance GI physiology. This concept suggests the use of prebiotics or probiotics for improving the tone of the ECS, as well as the use of phytocannabinoids or endocannabinoid-like molecules, such as palmitoylethanolamide, to restore the normal intestinal microbiota. This approach may be effective in ameliorating the negative effects of GI dysfunctions on mood and/or the effects of mood disorders on digestive health.
... Furthermore, this effect is paradoxical, given the wellestablished antiemetic properties of cannabis and its derivatives [70]. Cannabis has been shown to slow gastric emptying, potentially promoting nausea and vomiting [71,72]. The impact of prolonged cannabis use on the hypothalamic-pituitary-adrenal axis is a potential contributor to this syndrome [73]. ...
Cannabis, a plant known for its recreational use, has gained global attention due to its widespread use and addiction potential. Derived from the Cannabis sativa plant, it contains a rich array of phytochemicals concentrated in resin-rich trichomes. The main cannabinoids, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), interact with CB1 and CB2 receptors, influencing various physiological processes. Particularly concerning is its prevalence among adolescents, often driven by the need for social connection and anxiety alleviation. This paper provides a comprehensive overview of cannabis use, its effects, and potential health risks, especially in adolescent consumption. It covers short-term and long-term effects on different body systems and mental health and highlights the need for informed decision making and public health initiatives, particularly regarding adolescent cannabis use.
... Também é sabido que a neuromodulação dos movimentos finos é decorrente da interação DA e acetilcolina (ACh)(Rizzi & Tan, 2017). Além disso, receptores CB1 também se localizam na junção neuromuscular em músculos estriados periféricos e músculo intestinal liso pré juncional(Izzo et al., 1998;Izzo & Sharkey, 2010), sendo de real interesse verificar o impacto do efeito do CBD sobre o sistema neuromotor como consequência do uso crônico, ainda não relatado. Os resultados aqui obtidos de desempenho neuromotor avaliados em preparações nervo frênico-diafragma de ratos, resultantes de estudo crônico, não mostraram diferença entre os grupos experimental e controle, pelo parâmetro da técnica miográfica.Pelo parâmetro da eletrofisiologia, entretanto, os resultados do CBD diretamente adicionado em preparações isoladas ainda é controverso, pois foi constatado o aumento da amplitude de potenciais de placa terminal em um estudo(Morsch et al., 2018) e sua diminuição em outro(Sanchez-Pastor et al., 2007), sem uma real compreensão desses resultados, que necessitam ser esclarecidos. ...
O canabidiol (CBD) tem sido utilizado para tratar inúmeras condições patológicas principalmente doenças que afetam o sistema nervoso central como epilepsia, esquizofrenia e doenças neurodegenerativas crônicas como Alzheimer e Parkinson. A liberação das formulações com CBD, no Brasil, limita em 0,2% a presença de D9-tetrahidrocanabinol, a substância psicoativa da Cannabis sativa. O neurotransmissor dopamina está relacionado com o sistema de recompensa cerebral e com a doença de Parkinson, entre outras funções. O objetivo deste estudo foi administrar cronicamente CBD, em ratos, via gavage, para avaliar o impacto sobre os níveis de dopamina e no desempenho neuromotor. O estudo foi aprovado pela Comissão de Ética em Uso de Animais institucional (protocolo 173/2020). Ratos Wistar, machos (n=8), receberam via gavage 50 μL completado até 1 mL água/dia de CBD (200 mg/mL). Grupo controle recebeu pela mesma via, 1 mL de água/dia (n=8). Os animais foram pesados mensalmente. Findo o período de 90 dias, os animais foram eutanasiados em câmara de CO2 para a coleta de tecido cerebral e isolamento da preparação neuromuscular. A dosagem neuroquímica foi realizada via HPLC/MS-MS após realização de curva de calibração com 1 mg/mL de dopamina e seus metabólitos 3,4-di-hidroxifenilacetico (DOPAC) e ácido homovanílico (HVA), utilizando como padrão interno, 3,4-di-hidroxibenzilamina. O desempenho neuromotor foi avaliado por técnica miográfica convencional e análise histológica dos músculos por procedimentos de rotina. Os resultados foram expressos em média ± EPM ou ± DP, analisados por Anova One way seguido de Tukey, com p<0,05 indicando significância. Não houve diferença significativa na concentração de dopamina e seus metabólitos entre os grupos experimental e controle, CBD não afetou o desempenho neuromotor e as células musculares esqueléticas. Conclui-se que o CBD administrado cronicamente na concentração eleita mostrou-se seguro, sem causar alterações em nível neuroquímico, nem no desempenho neuromotor, além de preservar a célula muscular esquelética.
... The ECS also modulates neuroinflammatory responses and microglial activation states through CB2 receptor signaling [36]. Peripherally, the ECS regulates gastrointestinal motility, sensation of pain and appetite [37]. The psychoactive effects of cannabis are mediated through CB1 activation in the CNS. ...
Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. The primary injury results in neuronal damage and initiates secondary injuries like neuroinflammation, excitotoxicity, oxidative stress and blood-brain barrier disruption. This results in long-term cognitive, behavioral and motor deficits. Existing therapeutic options for TBI focus on symptomatic management rather than directly addressing the cellular processes that drive secondary damage. Novel neuroprotective therapies are urgently needed. The endocannabinoid system (ECS) is a promising therapeutic target for TBI. The ECS comprises the endocannabinoids anandamide and 2-AG, cannabinoid receptors CB1 and CB2, and metabolic enzymes like fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). It is involved in synaptic function, neuroinflammation, excitotoxicity, blood-brain barrier disruption, oxidative stress and neuronal loss. Modulation the ECS through receptor agonists/antagonists, inhibitors of endocannabinoid catabolism, or combination approaches represents a novel neuroprotective strategy in TBI.
... Dessa forma, desequilíbrios que incorrem sobre o SEC perturbam a homeostase corporal e podem acarretar inúmeras patologias. Frente a isso, o estudo do próprio sistema em questão e dos efeitos que os FIT podem desempenhar é primordial para a saúde, e principalmente para a qualidade de vida de indivíduos acometidos por doenças de difícil controle, com dor crônica e prognóstico ruim, como no caso de doenças neurodegenerativas 5 . Os FIT extraídos da Cannabis sativa L. interagem com o SEC por meio dos receptores CB1 e CB2 8 e suas aplicações podem ser as mais diversas, a depender do quadro patológico em questão, o que reflete no tipo de FIT a ser administrado, sua dosagem e frequência de uso. ...
... There are many cannabinoid compounds; however, cannabis has two main receptors, Cannabinoid receptors 1 and 2 (CB1, CB2). 50 These receptors are found within the gut wall and enteric nervous system. Experimental studies in animals have found alterations in the endocannabinoid system to affect development of colitis. ...
Inflammatory bowel disease (IBD) is a chronic disease of the intestines. The pathophysiology of IBD, namely Crohn’s disease and ulcerative colitis, is a complex interplay between environmental, genetic, and immune factors. Physicians and patients often seek complementary and alternative medicines (CAMs) as primary and supplementary treatment modalities. CAMs in IBD span a wide range of plants, herbs, pre/probiotics, and include formulations, such as cannabis, curcumin, fish oil, and De Simone Formulation. Dietary measures are also used to improve symptoms by attempting to target trigger foods and reducing inflammation. Examples include the specific carbohydrate diet, the Mediterranean diet, and a diet low in fermentable oligo-, di- and monosaccharides as well as polyols (FODMAP). We examine and review the most common complementary supplements and diets used by patients with IBD.
... Thus, a more complete characterization of this receptor, with respect to its tissue distribution, subcellular localization, temporal pattern of expression, and the intracellular signaling pathways, is needed to lead to a greater comprehension of the ECs. Another orphan receptor that has also been listed as a possible cannabinoid receptor in the gastrointestinal tract is GPR119 64 . Robust evidence has been accumulated on the interaction between cannabinoids and transient receptor potential ion channels 33,60,65 . ...
... Thus, a more complete characterization of this receptor, with respect to its tissue distribution, subcellular localization, temporal pattern of expression, and the intracellular signaling pathways, is needed to lead to a greater comprehension of the ECs. Another orphan receptor that has also been listed as a possible cannabinoid receptor in the gastrointestinal tract is GPR119 64 . Robust evidence has been accumulated on the interaction between cannabinoids and transient receptor potential ion channels 33,60,65 . ...
BACKGROUND AND OBJECTIVES
Pharmaceutical preparations of cannabis have been used by mankind since long time ago, and recently they have been the pharmaceutical industry’s focus. However, for proper therapeutic application, in-depth knowledge of the endocannabinoid system, which is made mainly by lipid signaling, is needed. The purpose of this study was to explore the current understanding of the players in this system, paying special attention to the molecular machinery required to process it.
CONTENTS
This is a narrative review of the current literature regarding major components of the endocannabinoid system, in particular: the receptors, main endogenous ligands, and the enzymes responsible for its components processing. The pharmacological and preclinical aspects were emphasized.
CONCLUSION
The better comprehension of the molecular structure of receptors and enzymes will be crucial to developing new pharmacological strategies. A detailed description of the machinery responsible for endocannabinoid lipid metabolization will pave the way for the discovery of new drugs that act on the endogenous system and that can be applied effectively in clinical practice.
Keywords
Cannabinoids; Membrane lipids; Pharmacology
... Recent literature has begun to uncover the role the EC system plays in this line of defense. CB 1 Rs and CB 2 Rs have been found via mRNA and proteins (Galiègue et al., 1995) detection in vagal afferents , nerve fibers that innervate bronchioles (Calignano et al., 2000), and bronchiolar smooth muscle cells (Pertwee, 1997;Ständer et al., 2005;Izzo and Sharkey, 2010;Szymaszkiewicz et al., 2018), as well as the peripheral termini of lung tissue (Rice et al., 1997;Calignano et al., 2000;Niederhoffer et al., 2003;Schmid et al., 2003) and are believed to play a homeostatic role in bronchial contractility (Calignano et al., 2000). This is important given that current literature has not reported CB 1 Rs and CB 2 Rs expression in the epithelial cells of the primary airway despite the presence of their mRNA being found in the human bronchial epithelial cell line, 16HBE14o (Turcotte et al., 2016). ...
Recent changes in cannabis accessibility have provided adjunct therapies for patients across numerous disease states and highlights the urgency in understanding how cannabinoids and the endocannabinoid (EC) system interact with other physiological structures. The EC system plays a critical and modulatory role in respiratory homeostasis and pulmonary functionality. Respiratory control begins in the brainstem without peripheral input, and coordinates the preBötzinger complex, a component of the ventral respiratory group that interacts with the dorsal respiratory group to synchronize burstlet activity and drive inspiration. An additional rhythm generator: the retrotrapezoid nucleus/parafacial respiratory group drives active expiration during conditions of exercise or high CO2. Combined with the feedback information from the periphery: through chemo- and baroreceptors including the carotid bodies, the cranial nerves, stretch of the diaphragm and intercostal muscles, lung tissue, and immune cells, and the cranial nerves, our respiratory system can fine tune motor outputs that ensure we have the oxygen necessary to survive and can expel the CO2 waste we produce, and every aspect of this process can be influenced by the EC system. The expansion in cannabis access and potential therapeutic benefits, it is essential that investigations continue to uncover the underpinnings and mechanistic workings of the EC system. It is imperative to understand the impact cannabis, and exogenous cannabinoids have on these physiological systems, and how some of these compounds can mitigate respiratory depression when combined with opioids or other medicinal therapies. This review highlights the respiratory system from the perspective of central versus peripheral respiratory functionality and how these behaviors can be influenced by the EC system. This review will summarize the literature available on organic and synthetic cannabinoids in breathing and how that has shaped our understanding of the role of the EC system in respiratory homeostasis. Finally, we look at some potential future therapeutic applications the EC system has to offer for the treatment of respiratory diseases and a possible role in expanding the safety profile of opioid therapies while preventing future opioid overdose fatalities that result from respiratory arrest or persistent apnea.
... Because of the high expression of CB1 in neurons of the CNS, this receptor is also implicated in the regulation of peripheral organs that play an important part in metabolic homeostasis and also control feeding, reward, and energy expenditure. When inflammation is present in the GI tract, the activation of both receptors takes place, resulting in the synthesis of anti-inflammatory cytokines with a role in reducing inflammation and its secondary damages [87][88][89][90][91][92]. ...
The endocannabinoid system (ECS) is involved in various processes, including brain plasticity, learning and memory, neuronal development, nociception, inflammation, appetite regulation, digestion, metabolism, energy balance, motility, and regulation of stress and emotions. Physical exercise (PE) is considered a valuable non-pharmacological therapy that is an immediately available and cost-effective method with a lot of health benefits, one of them being the activation of the endogenous cannabinoids. Endocannabinoids (eCBs) are generated as a response to high-intensity activities and can act as short-term circuit breakers, generating antinociceptive responses for a short and variable period of time. A runner’s high is an ephemeral feeling some sport practitioners experience during endurance activities, such as running. The release of eCBs during sustained physical exercise appears to be involved in triggering this phenomenon. The last decades have been characterized by an increased interest in this emotional state induced by exercise, as it is believed to alleviate pain, induce mild sedation, increase euphoric levels, and have anxiolytic effects. This review provides information about the current state of knowledge about endocannabinoids and physical effort and also an overview of the studies published in the specialized literature about this subject.
Cannabis sativa has been used therapeutically since early civilizations, with key cannabinoids Δ9-tetrahydrocannabinol (THC) 3.1 and cannabidiol characterized in the 1960s, leading to the discovery of cannabinoid receptors type 1 (CB1R) and type 2 (CB2R) and the endocannabinoid system (ECS) in the 1990s. The ECS, involving endogenous ligands like 2-arachidonoylglycerol (2-AG) 1.1, anandamide (N-arachidonoylethanolamine (AEA)) 1.2, and various proteins, regulates vital processes such as sleep, appetite, and memory, and holds significant therapeutic potential, especially for neurological disorders. Small molecule-derived pharmacological tools, or chemical probes, target key components of the ECS and are crucial for target validation, mechanistic studies, pathway elucidation, phenotypic screening, and drug discovery. These probes selectively interact with specific proteins or pathways, enabling researchers to modulate target activity and observe biological effects. When they carry an additional reporter group, they are referred to as labeled chemical probes. Developed through medicinal chemistry, structural biology, and high-throughput screening, effective chemical probes must be selective, potent, and depending on their purpose meet additional criteria such as cell permeability and metabolic stability.
This chapter describes high-quality labeled and unlabeled chemical probes targeting ECS constituents that have been successfully applied for various research purposes. CB1R and CB2R, class A G protein-coupled receptors, are activated by 2-AG 1.1, AEA 1.2, and THC 3.1, with numerous ligands developed for these receptors. Imaging techniques like single-photon emission computed tomography, positron emission tomography, and fluorescently labeled CB1R and CB2R probes have enhanced CB receptor studies. CB2R activation generally results in immunosuppressive effects, limiting tissue injury. AEA 1.2 is mainly degraded by fatty acid amide hydrolase (FAAH) or N-acylethanolamine acid amidase (NAAA) into ethanolamine and arachidonic acid (AA) 1.3. FAAH inhibitors increase endogenous fatty acid amides, providing analgesic effects without adverse effects. NAAA inhibitors reduce inflammation and pain in animal models. Diacylglycerol lipase (DAGL) is essential for 2-AG 1.1 biosynthesis, while monoacylglycerol lipase (MAGL) degrades 2-AG 1.1 into AA 1.3, thus regulating cannabinoid signaling. Multiple inhibitors targeting FAAH and MAGL have been generated, though NAAA and DAGL probe development lags behind. Similarly, advancements in inhibitors targeting endocannabinoid (eCB) cellular uptake or trafficking proteins like fatty acid-binding proteins have been slower. The endocannabinoidome (eCBome) includes the ECS and related molecules and receptors, offering therapeutic opportunities from non-THC cannabinoids and eCBome mediators. Ongoing research aims to refine chemical tools for ECS and eCBome study, addressing unmet medical needs in central nervous system disorders and beyond.
Background:
Ulcerative colitis (UC) is a frequent inflammatory bowel disease (IBD) that causes long-lasting inflammation in the innermost lining of the rectum and colon.
Objective:
The aim of this study was to evaluate the therapeutic effect of Cannabis sativa (C. sativa) on the amelioration of acetic acid-induced colitis in rats.
Materials and methods:
Group 1: normal control group was intrarectally administered saline solution (0.9%); group 2: acetic acid (AA) group was given AA intra-rectally (2 mL of 4% (v/v) in 0.9% NaCl) once.; group 3&4: This group represented the ulcerative colitis-induced rats that were injected with acetic acid intra-rectally, then s.c. injection with C. sativa (20 and 40 mg/kg daily for 8 days).
Results:
Colonic architectural abnormality significantly improved after pretreatment with C. sativa. Additionally, it significantly reduced the MDA level and prevented the depletion of GSH content. Moreover, C. sativa administration showed suppressive activities on pro-inflammatory cytokines, including NF-κB, MAPK, ERK, PI3K, AKT, HIF-1α, and TLR4. Moreover, it significantly upregulated the level of SIRT and CB1 in the colon tissue.
Conclusion:
This study provided a novel impact for CB1 receptor activation produced by C. sativa against AA-induced UC in rats through inhibiting the TLR-4 MAPK/ERK, PI3K, and NFκB signaling pathways.
Background: O sistema endocanabinoidoma (eCBoma) é um complexo de interações entre substâncias endocanabinoides, enzimas e diversos receptores presentes em todo o organismo. Dessa forma, a terapia canábica, com seus fitocanabinoides, entra como um potencial terapêutico muito pesquisado em outras áreas, mas ainda escasso na veterinária. Destaca-se a potencial utilização dessa terapia em cães com dermatite atópica, a segunda dermatopatia alérgica mais presente na rotina clínica e que representa um desafio terapêutico quando se trata de controle dos sinais clínicos. O objetivo deste trabalho é relatar um caso de associação do óleo de cannabis com a ciclosporina em um cão. Case: Foi atendido no Hospital Veterinário Universitário de uma Instituição de Ensino Superior, um canino, fêmea, castrada, oito anos de idade, sem raça definida com diagnóstico anterior de dermatite atópica e histórico de terapias com resultados ineficientes. No atendimento foram solicitados para avaliação o perfil de estresse oxidativo e histopatologia de pele, com contagem de mastócitos, para avaliação da eficácia da associação, além de mensuração de glicemia, aferição de pressão arterial sistólica e coleta de sangue para hemograma e perfil bioquímico para avaliar a eficácia do tratamento utilizado. Outra forma de avaliação utilizada foi a percepção do tutor frente à adaptação ao novo tratamento com relação ao prurido, lesões de pele e efeitos adversos, por meio de um questionário. Como tratamento foi instituído a utilização da ciclosporina (Cyclavance®), na dose de 1,25mg/kg, SID em associação com oléo cannabis full spectrum high canabidiol (CBD) 4%, sendo este utilizado 8 gotas uma vez ao dia durante 60 dias. Os banhos com shampoo cloresten® foram mantidos. Segundo a percepção do tutor o animal apresentou uma boa aceitação ao tratamento, relatando como efeitos adversos sonolência, hiperexia, ganho de peso e comportamento mais calmo, os quais não foram prejudiciais ao animal, não necessitando interromper o tratamento. Foram verificados diminuição dos níveis de glicemia, aumento de substâncias antioxidantes e diminuição do prurido. Discussion: A dermatite atópica canina é caracterizada como uma doença cutânea alérgica mais frequentemente diagnosticada em cães, com uma patogenia multifatorial e de controle desafiador, necessitando do uso de tratamento contínuo ao logo da vida do paciente. A opção mais utilizada comercialmente é a ciclosporina. A ciclosporina é uma medicação inibidora de cálcio que se liga ao citoplasma de linfócitos e inibe a translocação do fator nuclear de células T ativadas para o núcleo, regulando negativamente a síntese de diversas citocinas como IL-2 e IFNγ. O sistema endocanabinóide tem seus receptores CB1 e CB2 localizados em diversas partes do organismo, inclusive na pele, com funções de manutenção da barreira cutânea, de crescimento e diferenciação celular, processos imunológicos e inflamatórios. A particularidade do eCBoma na pele é um alvo terapêutico em ascensão. Pelos seus receptores, presentes em células específicas da pele, tornam-se alvos de diferentes terapias em diversas doenças que acomete o maior órgão do corpo, principalmente devido às propriedade anti-inflamatórias, antioxidantes e analgésicas. Não apenas presente na pele, esse sistema possui influência entre diferentes mecanismos como a regulação da glicemia, pressão sistêmica e aumento de substâncias antioxidantes no organismo. Sabe-se da importância dos efeitos do excesso de radicais livres na homeostase do organismo e sua relação direta com o aparecimento de doenças, sendo desta forma não importante o conhecimento a cerca do estudo de moléculas antioxidades como o CBD, promovendo um aumento desses antioxidantes no organismo, mantendo o equilíbrio do sistema endocanabinóide. Conclui-se que o óleo de Cannabis é promissor quando em associação com ciclosporina a fim de controle dos sinais clínicos da dermatite atópica canina, melhorando desta forma a qualidade de vida do paciente.
The present research aimed to evaluate the effects of the continuative dietary administration of a hemp oil extract containing cannabinoids (cannabidiol, CBD) on the macroscopic morphology, morphometry, and enzymatic activity of different intestinal tracts as well as on the production of short-chain fatty acids (SCFAs) in the cecum of growing rabbits. The research was performed on 16 rabbits randomly selected from 2 experimental groups (8 per group). In detail, 42 sixty-day-old New Zealand White × California rabbits (sex ratio 1:1, average weight 1621.3 ± 46.2 g) were homogeneously divided into 2 groups (21 animals/group), namely control and CBD. Both groups were fed the same commercial diet, but the CBD one was supplemented with 0.1 mL of hemp extract in coconut-based oil corresponding to 10 mg of CBD/animal/d. Up to 92 d of age (for 27 d), individual live weight and feed intake were measured weekly. At 92 d of age, 8 rabbits/group (sex ratio 1:1) were moved to a specialized slaughterhouse, and the gastrointestinal tract was separated from the carcass. Samples from 8 rabbits per dietary treatment were used for the histomorphological analysis of small and large intestines. In addition, duodenum, jejunum, ileum, and cecum were processed for enzymatic analysis. The caecal contents were used for the SCFAs determination. The administration of CBD did not affect feed intake and the final rabbits’ whole body weight (P > 0.05), but some changes were detected in the gastrointestinal tract of the animals. CBD seemed to interfere with protein digestion, with a significantly lower activity of the enzymes related to peptides in the small intestine and a consequent increase of the fermentative activity of caecal microbiota. This effect, in combination with a general decrease of fermentative activity in the caecal content of rabbits submitted to CBD treatment, was responsible for a change in the SCFA proportion mainly regarding the reduction of butyrate production (P < 0.01) that resulted significant higher in CTR group compared to CBD. This last result is very important for intestinal health. Such fermentation activity modification was coupled with changes in the relative abundance of goblet cells in the colon. Overall, our findings suggest that a relatively long-term administration of CBD may affect digestion in rabbits, in particular at enzymatic and fermentative levels.
The demand for biotics as alternatives to antibiotics that promote growth and lessen the use of antimicrobials in poultry farms is fueled by recent worldwide regulations and consumer expectations. Phytogenic substances are becoming increasingly valuable options because many of these natural compounds possess anti-inflammatory and antioxidant properties that are only less commercialized. The usage of phytogenic substances can also help maintain a balance of healthy microorganisms in the gut, which is beneficial for the digestive system to withstand various chronic stressors, both infectious and non-infectious. Although some phytogenic substances are commercially available, these are typically hampered by inconsistencies in their effectiveness, low bioavailability, and low stability. This chapter discusses the current and potential phytogenic compounds that can exert antioxidant and anti-inflammatory properties to improve poultry production and restore intestinal microbiota. Additionally, the main challenges still related to phytogenic products will be discussed.
Cannabidiol (CBD) is a major non-psychotropic phytocannabinoid that exists in the Cannabis sativa plant. CBD has been found to act on various receptors, including both cannabinoid and non-cannabinoid receptors. In addition, CBD has antioxidant effects that are independent of receptors. CBD has demonstrated modulatory effects at different organ systems, such as the central nervous system, immune system, and the gastrointestinal system. Due to its broad effects within the body and its safety profile, CBD has become a topic of therapeutic interest. This literature review summarizes previous research findings with regard to the effect of CBD on the gastrointestinal (GI) system, including its effects at the molecular, cellular, organ, and whole-body levels. Both pre-clinical animal studies and human clinical trials are reviewed. The results of the studies included in this literature review suggest that CBD has significant impact on intestinal permeability, the microbiome, immune cells and cytokines. As a result, CBD has been shown to have therapeutic potential for GI disorders such as inflammatory bowel disease (IBD). Furthermore, through interactions with the gut, CBD may also be helpful in the treatment of disorders outside the GI system, such as non-alcoholic liver disease, postmenopausal disorders, epilepsy, and multiple sclerosis. In the future, more mechanistic studies are warranted to elucidate the detailed mechanisms of action of CBD in the gut. In addition, more well-designed clinical trials are needed to explore the full therapeutic potential of CBD on and through the gut.
The endocannabinoid system (ECS) is a critical regulatory network composed of endogenous cannabinoids (eCBs), their synthesizing and degrading enzymes, and associated receptors. It is integral to maintaining homeostasis and orchestrating key functions within the central nervous and immune systems. Given its therapeutic significance, we have launched a series of drug discovery endeavors aimed at ECS targets, including peroxisome proliferator-activated receptors (PPARs), cannabinoid receptors types 1 (CB1R) and 2 (CB2R), and monoacylglycerol lipase (MAGL), addressing a wide array of medical needs. The pursuit of new therapeutic agents has been enhanced by the creation of specialized labeled chemical probes, which aid in target localization, mechanistic studies, assay development, and the establishment of biomarkers for target engagement. By fusing medicinal chemistry with chemical biology in a comprehensive, translational end-to-end drug discovery strategy, we have expedited the development of novel therapeutics. Additionally, this strategy promises to foster highly productive partnerships between industry and academia, as will be illustrated through various examples.
Introduction:
Cannabinoid receptor type 2 (CB2R), predominantly expressed in immune tissues, is believed to play a crucial role within the body's protective mechanisms. Its modulation holds immense therapeutic promise for addressing a wide spectrum of dysbiotic conditions, including cardiovascular, gastrointestinal, liver, kidney, neurodegenerative, psychiatric, bone, skin, and autoimmune diseases, as well as lung disorders, cancer, and pain management.
Areas covered:
This review is an account of patents from 2016 up to 2023 which describes novel CB2R ligands, therapeutic applications, synthesis, as well as formulations of CB2R modulators.
Expert opinion:
The patents cover a vast, structurally diverse chemical space. The focus of CB2R ligand development has shifted from unselective dual-cannabinoid receptor type 1 (CB1R) and 2 agonists toward agonists with high selectivity over CB1R, particularly for indications associated with inflammation and tissue injury. Currently, there are at least eight CB2R agonists and one antagonist in active clinical development. A better understanding of the endocannabinoid system (ECS) and in particular of CB2R pharmacology is required to unlock the receptor's full therapeutic potential.
The present study aimed to evaluate the effect of a Cannabis sativa extract rich in cannabidiol in the diet of chickens under induced stress conditions. This was achieved through the administration of subclinical doses of inflammation-inducing Clostridium perfringens bacteria and lipopolysaccharide, which are commonly found in poultry production. A total of 204 male Ross (line 308) chicks were divided into 6 groups, with variations in Cannabis sativa extract addition (30 g/1000 g of feed on top) and stress induction methods. At 21 and 22 days of age the birds from the CH1 group were infected ( per os ) with 1 mL of inoculum (brain-heart infusion medium) containing approximately 10 ⁸ CFU/mL of C. perfringens . At the same times birds of group CH2 were per os administered lipopolysaccharide in a dose of 1 mL containing 250 μg/kg body weight of. The results indicate that incorporating a 30 g/1000 g Cannabis sativa extract (CBD) additive in chicken diets leads to an increase in ultimate body weight and maintains weight under stressed conditions (P<0.05), without adverse effects on slaughter analysis. Moreover, CBD supplementation does not significantly affect (P>0.05) the physical and chemical parameters or primary composition of breast muscle and liver. However, it may alter the n-6/n-3 acid ratio. Additionally, CBD supplementation helps maintain blood biochemical and antioxidant parameters, supporting overall chicken body homeostasis stressed. Incorporating Cannabis sativa extracts at 30 g/1000 g of feed presents a potential protective measure to enhance poultry farming in challenging intensive production conditions.
In recent years, the legalization and social acceptability of cannabis use have increased in the United States. Concurrently, the prevalence of cannabis use has continued to rise, and cannabis products have diversified. There are growing concerns regarding the health effects of regular and high‐potency cannabis use, and new research has shed light on its potentially negative effects. Here, we review evidence of the gastrointestinal (GI) effects of cannabis and cannabinoids. Dysregulation of the endocannabinoid system might contribute to various GI disorders, including irritable bowel syndrome and cyclic vomiting syndrome, and endocannabinoids have been found to regulate visceral sensation, nausea, vomiting, and the gut microbiome. Cannabis has been shown to have antiemetic properties, and the US Food and Drug Administration has approved cannabis‐based medications for treating chemotherapy‐induced nausea and vomiting. Yet, chronic heavy cannabis use has been linked to recurrent episodes of severe nausea and intractable vomiting (cannabinoid hyperemesis syndrome). Given the considerable heterogeneity in the scientific literature, it is unclear if cannabinoid hyperemesis syndrome is truly a distinct entity or a subtype of cyclic vomiting that is unmasked by heavy cannabis use and the associated dysregulation of the endocannabinoid system. The changes in cannabis legalization, availability, and public risk perceptions have outpaced research in this area and there is a need for robust, prospective, large‐scale studies to understand the effects of cannabis use on GI health.
Background
Adolescents and young adults may use cannabidiol (CBD) products in an attempt to reduce depression and anxiety symptoms, despite little research examining this use. This systematic review evaluated preclinical and clinical research on the effects of CBD on depressive and anxiety disorders in adolescence and young adulthood. To provide context, we discuss CBD’s mechanism of action and neurodevelopmental effects.
Methods
PubMed was searched for articles published through June 2022. Preclinical or clinical CBD administration studies with N > 1 that examined depressive and/or anxiety disorders were eligible.
Results
Initially, 224 publications were identified. After excluding duplicates and applying eligibility criteria, 6 preclinical (depression: n≈133; anxiety: n≈161) and 4 clinical (anxiety: n=113) articles remained. Due to the low number of studies, results were synthesized qualitatively. The Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence were used to rate each study’s evidence. The preclinical effects of CBD on depression-like behavior appear to differ by sex, early life stress, and duration of use. Despite no evidence that CBD exerts anxiolytic effects in preclinical adolescent models, CBD may reduce anxiety symptoms in human adolescents and young adults with anxiety disorders.
Conclusion
The existing evidence suggests that CBD may reduce symptoms of anxiety in adolescents and young adults. However, the evidence is sparse and limited by variations in samples and CBD dosing duration. Further research is needed to understand the potential benefits and/or harms of CBD for depression and anxiety disorders in this population. Implications for clinical practice and research are discussed.
Practical guide about endocannabinoid medicine and its clinical applications.
Guia prático sobre medicina endocanabinoide e suas aplicações clínicas.
#medicalcannabis #endocannabinology
Multiple studies confirm use of Integrative Health (IH) therapies is common among children with IBD. Pediatric prevalence rates are compatible with or exceed IH use in adult IBD. Surveys indicate that biologically-based therapies are the most frequently utilized modality among the pediatric IBD population. Concurrent use of herbal remedies and dietary supplements (which we will define as biologically based IH therapies for the purpose of this chapter) and prescription medication is common and may cause untoward drug interactions. In this chapter, we review the available evidence for the safety and efficacy of the most commonly used biologically-based therapies and mind-body therapies in IBD. Clinicians need to know the prevalence of IH therapy utilization in the pediatric IBD population, parents’ receptivity towards these modalities as adjuvant therapies, and the reticence to disclose utilization. We suggest that maintenance of a cursory level of understanding and awareness of IH modalities, including knowledge of efficacy, interactions and contraindications, is essential to ensure patient safety.
Objective: To quantify the antiemetic efficacy and adverse effects of cannabis used for sickness induced by chemotherapy.
Design: Systematic review.
Data sources: Systematic search (Medline, Embase, Cochrane library, bibliographies), any language, to August 2000.
Studies: 30 randomised comparisons of cannabis with placebo or antiemetics from which dichotomous data on efficacy and harm were available (1366 patients). Oral nabilone, oral dronabinol (tetrahydrocannabinol), and intramuscular levonantradol were tested. No cannabis was smoked. Follow up lasted 24 hours.
Results: Cannabinoids were more effective antiemetics than prochlorperazine, metoclopramide, chlorpromazine, thiethylperazine, haloperidol, domperidone, or alizapride: relative risk 1.38 (95% confidence interval 1.18 to 1.62), number needed to treat 6 for complete control of nausea; 1.28 (1.08 to 1.51), NNT 8 for complete control of vomiting. Cannabinoids were not more effective in patients receiving very low or very high emetogenic chemotherapy. In crossover trials, patients preferred cannabinoids for future chemotherapy cycles: 2.39 (2.05 to 2.78), NNT 3. Some potentially beneficial side effects occurred more often with cannabinoids: “high” 10.6 (6.86 to 16.5), NNT 3; sedation or drowsiness 1.66 (1.46 to 1.89), NNT 5; euphoria 12.5 (3.00 to 52.1), NNT 7. Harmful side effects also occurred more often with cannabinoids: dizziness 2.97 (2.31 to 3.83), NNT 3; dysphoria or depression 8.06 (3.38 to 19.2), NNT 8; hallucinations 6.10 (2.41 to 15.4), NNT 17; paranoia 8.58 (6.38 to 11.5), NNT 20; and arterial hypotension 2.23 (1.75 to 2.83), NNT 7. Patients given cannabinoids were more likely to withdraw due to side effects 4.67 (3.07 to 7.09), NNT 11.
Conclusions: In selected patients, the cannabinoids tested in these trials may be useful as mood enhancing adjuvants for controlling chemotherapy related sickness. Potentially serious adverse effects, even when taken short term orally or intramuscularly, are likely to limit their widespread use.
What is already known on this topic
What is already known on this topic Requests have been made for legalisation of cannabis (marijuana) for medical use
Long term smoking of cannabis can have physical and neuropsychiatric adverse effects Cannabis may be useful in the control of chemotherapy related sickness
The endocannabinoid (EC) system mediates protection against intestinal inflammation. In this study, we investigated the effects
of blocking EC degradation or cellular reuptake in experimental colitis in mice. Mice were treated with trinitrobenzene-sulfonic
acid in presence and absence of the fatty acid amide hydrolase (FAAH) blocker URB597, the EC membrane transport inhibitor
VDM11, and combinations of both. Inflammation was significantly reduced in the presence of URB597, VDM11, or both as evaluated
by macroscopic damage score, myeloperoxidase levels, and colon length. These effects were abolished in CB1- and CB2-receptor-gene-deficient mice. Quantitative reverse transcription polymerase chain reaction after induction of experimental
colitis by different pathways showed that expression of FAAH messenger RNA (mRNA) is significantly reduced in different models
of inflammation early in the expression of colitis, and these return to control levels as the disease progresses. Genomic
DNA from 202 patients with Crohn’s disease (CD) and 206 healthy controls was analyzed for the C385A polymorphism in the FAAH
gene to address a possible role in humans. In our groups, the C385A polymorphism was equally distributed in patients with
CD and healthy controls. In conclusion, drugs targeting EC degradation offer therapeutic potential in the treatment of inflammatory
bowel diseases. Furthermore, reduction of FAAH mRNA expression is involved in the pathophysiological response to colitis.
The endocannabinoid system is upregulated in both human inflammatory bowel diseases and experimental models of colitis. In this study, we investigated whether this upregulation is a marker also of celiac disease-induced atrophy. The levels of the cannabinoid CB(1) receptor, of the endocannabinoids, anandamide, and 2-arachidonoyl-glycerol (2-AG), and of the anti-inflammatory mediator palmitoylethanolamide (PEA) were analyzed in bioptic samples from the duodenal mucosa of celiac patients at first diagnosis assessed by the determination of antiendomysial antibodies and histological examination. Samples were analyzed during the active phase of atrophy and after remission and compared to control samples from non-celiac patients. The levels of anandamide and PEA were significantly elevated (approx. 2- and 1.8-fold, respectively) in active celiac patients and so were those of CB(1) receptors. Anandamide levels returned to normal after remission with a gluten-free diet. We also analyzed endocannabinoid and PEA levels in the jejunum of rats 2, 3, and 7 days after treatment with methotrexate, which causes inflammatory features (assessed by histopathological analyses and myeloperoxidase activity) similar to those of celiac patients. In both muscle/serosa and mucosa layers, the levels of anandamide, 2-AG, and PEA peaked 3 days after treatment and returned to basal levels at remission, 7 days after treatment. Thus, intestinal endocannabinoid levels peak with atrophy and regress with remission in both celiac patients and methotrexate-treated rats. The latter might be used as a model to study the role of the endocannabinoid system in celiac disease.
Recent studies suggest potential roles of the endocannabinoid system in gastrointestinal inflammation. Although cannabinoid CB(2) receptor expression is increased in inflammatory disorders, the presence and function of the remaining proteins of the endocannabinoid system in the colonic tissue is not well characterized.
Cannabinoid CB(1) and CB(2) receptors, the enzymes for endocannabinoid biosynthesis DAGLalpha, DAGLbeta and NAPE-PLD, and the endocannabinoid-degradating enzymes FAAH and MAGL were analysed in both acute untreated active ulcerative pancolitis and treated quiescent patients in comparison with healthy human colonic tissue by immunocytochemistry. Analyses were carried out according to clinical criteria, taking into account the severity at onset and treatment received.
Western blot and immunocytochemistry indicated that the endocannabinoid system is present in the colonic tissue, but it shows a differential distribution in epithelium, lamina propria, smooth muscle and enteric plexi. Quantification of epithelial immunoreactivity showed an increase of CB(2) receptor, DAGLalpha and MAGL expression, mainly in mild and moderate pancolitis patients. In contrast, NAPE-PLD expression decreased in moderate and severe pancolitis patients. During quiescent pancolitis, CB(1), CB(2) and DAGLalpha expression dropped, while NAPE-PLD expression rose, mainly in patients treated with 5-ASA or 5-ASA+corticosteroids. The number of immune cells containing MAGL and FAAH in the lamina propria increased in acute pancolitis patients, but dropped after treatment.
Endocannabinoids signaling pathway, through CB(2) receptor, may reduce colitis-associated inflammation suggesting a potential drugable target for the treatment of inflammatory bowel diseases.
Inflammatory bowel disease affects millions of individuals; nevertheless, pharmacological treatment is disappointingly unsatisfactory. Cannabidiol, a safe and non-psychotropic ingredient of marijuana, exerts pharmacological effects (e.g., antioxidant) and mechanisms (e.g., inhibition of endocannabinoids enzymatic degradation) potentially beneficial for the inflamed gut. Thus, we investigated the effect of cannabidiol in a murine model of colitis. Colitis was induced in mice by intracolonic administration of dinitrobenzene sulfonic acid. Inflammation was assessed both macroscopically and histologically. In the inflamed colon, cyclooxygenase-2 and inducible nitric oxide synthase (iNOS) were evaluated by Western blot, interleukin-1beta and interleukin-10 by ELISA, and endocannabinoids by isotope dilution liquid chromatography-mass spectrometry. Human colon adenocarcinoma (Caco-2) cells were used to evaluate the effect of cannabidiol on oxidative stress. Cannabidiol reduced colon injury, inducible iNOS (but not cyclooxygenase-2) expression, and interleukin-1beta, interleukin-10, and endocannabinoid changes associated with 2,4,6-dinitrobenzene sulfonic acid administration. In Caco-2 cells, cannabidiol reduced reactive oxygen species production and lipid peroxidation. In conclusion, cannabidiol, a likely safe compound, prevents experimental colitis in mice.
Cannabinoids have long been known to be potent inhibitors of intestinal and colonic propulsion. This effect has generally been attributed to their ability to prejunctionally inhibit release of acetylcholine from excitatory motor neurons that mediate, in part, the ascending contraction phase of the peristaltic reflex. In the present study we examined the effect of cannabinoids on the other transmitters known to participate in the peristaltic reflex using a three-compartment preparation of rat colon that allows separation of ascending contraction, descending relaxation, and the sensory components of the reflex. On addition to the orad motor compartment, anandamide decreased and AM-251, a CB-1 antagonist, increased ascending contraction and the concomitant substance P (SP) release. Similarly, on addition to the caudad motor compartment, anandamide decreased and AM-251 increased descending relaxation and the concomitant vasoactive intestinal peptide (VIP) release. On addition to the central sensory compartment, anandamide decreased and AM-251 increased both ascending contraction and SP release orad, and descending relaxation and VIP release caudad. This suggested a role for CB-1 receptors in modulation of sensory transmission that was confirmed by the demonstration that central addition of anandamide decreased and AM-251 increased release of the sensory transmitter, calcitonin gene-related peptide (CGRP). We conclude that the potent antipropulsive effect of cannabinoids is the result of inhibition of both excitatory cholinergic/tachykininergic and inhibitory VIPergic motor neurons that mediate ascending contraction and descending relaxation, respectively, as well as inhibition of the intrinsic sensory CGRP-containing neurons that initiate the peristaltic reflex underlying propulsive motility.
Emerging evidence suggests that cannabinoids may exert beneficial effects in intestinal inflammation and cancer. Adaptive changes of the endocannabinoid system have been observed in intestinal biopsies from patients with inflammatory bowel disease and colon cancer. Studies on epithelial cells have shown that cannabinoids exert antiproliferative, antimetastatic and apoptotic effects as well as reducing cytokine release and promoting wound healing. In vivo, cannabinoids - via direct or indirect activation of CB(1) and/or CB(2) receptors - exert protective effects in well-established models of intestinal inflammation and colon cancer. Pharmacological elevation of endocannabinoid levels may be a promising strategy to counteract intestinal inflammation and colon cancer.
Cannabinoids are broadly immunosuppressive, and anti-inflammatory properties have been reported for certain marijuana constituents and endogenously produced cannabinoids. The CB2 cannabinoid receptor is an established constituent of immune system cells, and we have recently established that the CB1 cannabinoid receptor is expressed in mast cells. In the present study, we sought to define a role for CB1 in mast cells and to identify the signalling pathways that may mediate the suppressive effects of CB1 ligation on mast cell activation. Our results show that CB1 and CB2 mediate diametrically opposed effects on cAMP levels in mast cells. The observed long-term stimulation of cAMP levels by the G alpha(i/o)- coupled CB1 is paradoxical, and our results indicate that it may be attributed to CB1-mediated transcriptional regulation of specific adenylate cyclase isoenzymes that exhibit superactivatable kinetics. Taken together, these results reveal the complexity in signalling of natively co-expressed cannabinoid receptors and suggest that some anti-inflammatory effects of CB1 ligands may be attributable to sustained cAMP elevation that, in turn, causes suppression of mast cell degranulation.
Delta(9)-tetrahydrocannabinol binds cannabinoid (CB(1) and CB(2)) receptors, which are activated by endogenous compounds (endocannabinoids) and are involved in a wide range of physiopathological processes (e.g. modulation of neurotransmitter release, regulation of pain perception, and of cardiovascular, gastrointestinal and liver functions). The well-known psychotropic effects of Delta(9)-tetra hydrocannabinol, which are mediated by activation of brain CB(1) receptors, have greatly limited its clinical use. However, the plant Cannabis contains many cannabinoids with weak or no psychoactivity that, therapeutically, might be more promising than Delta(9)-tetra hydrocannabinol. Here, we provide an overview of the recent pharmacological advances, novel mechanisms of action, and potential therapeutic applications of such non-psychotropic plant-derived cannabinoids. Special emphasis is given to cannabidiol, the possible applications of which have recently emerged in inflammation, diabetes, cancer, affective and neurodegenerative diseases, and to Delta(9)-tetrahydrocannabivarin, a novel CB(1) antagonist which exerts potentially useful actions in the treatment of epilepsy and obesity.
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.
The onset and duration of tolerance to three effects of δ
9-tetrahydrocannabinol (δ
9-THC) given orally to mice were compared. The effects of δ
9-THC studied were: hypothermia, the depression of intestinal motility and the effect on spontaneous locomotor activity. When mice were dosed and tested at 24 hrs intervals it was apparent that tolerance was complete to its hypothermic and locomotor depressant effects after the first doses and to depression of intestinal motility after the fourth dose. Duration of tolerance also differed so that the normal hypothermic response had returned after 12 dose-free days, but not after 5 drug-free days; the effect on locomotor activity had returned within 4 days; and, apparent partial tolerance to the depressant effect of an acute challenging dose of δ
9-THC on intestinal motility still existed after 19 dose-free days.
It is apparent that the time of onset and the duration of tolerance to δ
9-THC in mice showed a different pattern in the three parameters studied. It seems unlikely therefore that any one mechanism, such as metabolic tolerance, explains all the results observed and that several mechanisms should be explored to explain the phenomenon of tolerance to δ
9-THC.
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
N-oleoylethanolamine (OEA) and N-palmitoylethanolamine (PEA) are endogenous lipids that activate peroxisome proliferator–activated receptor-α with high and intermediate potency, and exert anorectic and anti-inflammatory actions in rats, respectively. We investigated OEA and PEA tissue level regulation by the nutritional status in lean and obese rats. OEA and PEA levels in the brainstem, duodenum, liver, pancreas, and visceral (VAT) or subcutaneous (SAT) adipose tissues of 7-week-old wild-type (WT) and Zucker rats, fed ad libitum or following overnight food deprivation, with and without refeeding, were measured by liquid chromatography–mass spectrometry. In WT rats, duodenal OEA, but not PEA, levels were reduced by food deprivation and restored by refeeding, whereas the opposite was observed for OEA in the pancreas, and for both mediators in the liver and SAT. In ad lib fed Zucker rats, PEA and OEA levels were up to tenfold higher in the duodenum, slightly higher in the brainstem, and lower in the other tissues. Fasting/refeeding-induced changes in OEA levels were maintained in the duodenum, liver, and SAT, and lost in the pancreas, whereas fasting upregulated this compound also in the VAT. The observed changes in OEA levels in WT rats are relevant to the actions of this mediator on satiety, hepatic and adipocyte metabolism, and insulin release. OEA dysregulation in Zucker rats might counteract hyperphagia in the duodenum, but contribute to hyperinsulinemia in the pancreas, and to fat accumulation in adipose tissues and liver. Changes in PEA levels might be relevant to the inflammatory state of Zucker rats.
Wild growing Cannabis from different altitudes and locations was collected in northern India. Plant material from each collection was analyzed quantitatively for ten cannabinoids by GC. The average total cannabinoid content of plants growing above 2,000 m was 1.33 %, whereas below 2,000 m the average total cannabinoid content was 2.74 %. Morphological characteristics were recorded. Data obtained from wild growing Indian Cannabis (twenty variants) are compared with data obtained from the same variants grown in Mississippi, USA.
ANANDAMIDE (N-arachidonoyl-ethanolamine) was recently identified as a brain arachidonate derivative that binds to and activates cannabinoid receptors14, yet the mechanisms underlying formation, release and inactivation of this putative messenger molecule are still unclear. Here we report that anandamide is produced in and released from cultured brain neurons in a calcium ion-dependent manner when the neurons are stimulated with membrane-depolarizing agents. Anandamide formation occurs through phos-phodiesterase-mediated cleavage of a novel phospholipid precursor, N-arachidonoyl-phosphatidylethanolamine. A similar mechanism also governs the formation of a family of anandamide congeners, whose possible roles in neuronal signalling remain unknown. Our results and those of others5,6indicate therefore that multiple biochemical pathways may participate in anandamide formation in brain tissue. The life span of extracellular anandamide is limited by a rapid and selective process of cellular uptake, which is accompanied by hydrolytic degradation to ethanolamine and arachidonate. Our results thus strongly support the proposed role of anandamide as an endogenous neuronal messenger.
British Journal of Pharmacology (2007) 150, 249. doi:10.1038/sj.bjp.0707128
Dietary fatty acid (FA) absorption across the gastrointestinal (GI) tract is of critical importance for sustenance, however, excessive FA absorption has also been linked to metabolic syndrome and associated disorders. The expression of isoforms that regulate the dietary FA absorption are not as well characterized in the GI tract as they are elsewhere. Peroxisome proliferator-activated receptors (PPAR, β, and ) and 9-cis-retinoic acid receptors (RXR, β, and ) are nuclear hormone transcription factors that control FA homeostasis, in part through the regulation of expression of membrane-bound FA transporting proteins. The present study was designed to elucidate the expression of PPAR and RXR isoforms and FA transporting proteins (FABPpm and FAT/CD36) in the rat and human GI tracts using reverse transcriptase-polymerase chain reaction (RT-PCR), immunoblotting, and immunohistochemical staining. The results revealed rat GI expression of all the PPAR and RXR isoforms, FABPpm and FAT/CD36. PPAR, PPARβ, PPAR, RXR, FABPpm, and FAT/CD36 isoforms exhibited ubiquitous expression in human GI tract, whereas RXRβ was not detected. RXR was observed in a majority of the human GI samples. These results provide a physiological foundation for rational drug design and drug delivery for the mitigation of metabolic syndrome and associated disorders to normalize intestinal FA absorption. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 94:363–372, 2005
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.
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 Δ9-tetrahydrocannabinol (Δ9-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 Δ9-THC to inhibit electrically evoked contractions of mouse isolated vasa deferentia; however, it was less potent than Δ9-THC.
Cannabinoids (CBs) have been found to exert antiproliferative effects upon a variety of cancer cells, including colorectal carcinoma cells. However, little is known about the signalling mechanisms behind the antitumoural effect in these cells, whether the effects are shared by endogenous lipids related to endocannabinoids, or whether such effects are synergistic with treatment paradigms currently used in the clinic. The aim of this preclinical study was to investigate the effect of synthetic and endogenous CBs and their related fatty acids on the viability of human colorectal carcinoma Caco-2 cells, and to determine whether CB effects are synergistic with those seen with the pyrimidine antagonist 5-fluorouracil (5-FU). The synthetic CB HU 210, the endogenous CB anandamide, the endogenous structural analogue of anandamide, N-arachidonoyl glycine (NAGly), as well as the related polyunsaturated fatty acids arachidonic acid and eicosapentaenoic acid showed antiproliferative and cytotoxic effects in the Caco-2 cells, as measured by using [(3)H]-thymidine incorporation assay, the CyQUANT proliferation assay and calcein-AM fluorescence. HU 210 was the most potent compound examined, followed by anandamide, whereas NAGly showed equal potency and efficacy as the polyunsaturated fatty acids. Furthermore, HU 210 and 5-FU produced synergistic effects in the Caco-2 cells, but not in the human colorectal carcinoma cell lines HCT116 or HT29. The compounds examined produced cytotoxic, rather than antiproliferative effects, by a mechanism not involving CB receptors, since the CB receptor antagonists AM251 and AM630 did not attenuate the effects, nor did pertussis toxin. However, alpha-tocopherol and the nitric oxide synthase inhibitor L-NAME attenuated the CB toxicity, suggesting involvement of oxidative stress. It is concluded that the CB system may provide new targets for the development of drugs to treat colorectal cancer.
Cannabinoid receptors (CBR) are located on cholinergic neurons in the brain stem, stomach, and colon. CBR stimulation inhibits motility in rodents. Effects in humans are unclear. Dronabinol (DRO), a nonselective CBR agonist, inhibits colonic motility and sensation. The aim of this study was to compare effects of DRO and placebo (PLA) on colonic motility and sensation in healthy volunteers. Fifty-two volunteers were randomly assigned (double-blind) to a single dose of 7.5 mg DRO or PLA postoperative with concealed allocation. A balloon-manometric assembly placed into the descending colon allowed assessment of colonic compliance, motility, tone, and sensation before and 1 h after oral ingestion of medication, and during fasting, and for 1 h after 1,000-kcal meal. There was an overall significant increase in colonic compliance (P = 0.045), a borderline effect of relaxation in fasting colonic tone (P = 0.096), inhibition of postprandial colonic tone (P = 0.048), and inhibition of fasting and postprandial phasic pressure (P = 0.008 and 0.030, respectively). While DRO did not significantly alter thresholds for first gas or pain sensation, there was an increase in sensory rating for pain during random phasic distensions at all pressures tested and in both genders (P = 0.024). In conclusion, in humans the nonselective CBR agonist, DRO, relaxes the colon and reduces postprandial colonic motility and tone. Increase in sensation ratings to distension in the presence of relaxation of the colon suggests central modulation of perception. The potential for CBR to modulate colonic motor function in diarrheal disease such as irritable bowel syndrome deserves further study.
We have studied the effects of the cannabinoid receptor agonists (R)-(+)[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2, 3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone (WIN 55,212-2, 0. 3-5 mg/kg, i.p.) and (-)-cis-3-[2-hydroxy-4-(1, 1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol) (CP 55,940, 0.03-1 mg/kg, i.p.), the cannabinoid CB(1) receptor antagonist (N-piperidin-1-yl)-5-(4-chlorophenyl)-1-2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A, 0. 3-5 mg/kg, i.p.) and the cannabinoid CB(2) receptor antagonist N-[-(1S)-endo-1,3,3-trimethyl bicyclo [2.2.1] heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazo le- 3-carboxamide (SR144528, 1 mg/kg, i.p.) on intestinal motility, defaecation and castor-oil (1 ml/100 g rat, orally)-induced diarrhoea in the rat. SR141716A, but not SR144528, increased defaecation and upper gastrointestinal transit, while WIN 55,212-2 and CP 55,940 decreased upper gastrointestinal transit but not defaecation. WIN 55,212-3 (5 mg/kg), the less active enantiomer of WIN 55,212-2, was without effect. A per se non-effective dose of SR141716A (0.3 mg/kg), but not of SR144528 (1 mg/kg) or the opioid receptor antagonist, naloxone (2 mg/kg i.p.), counteracted the inhibitory effect of both WIN 55,212-2 (1 mg/kg) and CP 55,940 (0.1 mg/kg) on gastrointestinal motility. WIN 55,212-2 did not modify castor-oil-induced diarrhoea, while CP 55,940 produced a transient delay in castor-oil-induced diarrhoea at the highest dose tested (1 mg/kg), an effect counteracted by SR141715A (5 mg/kg). These results suggest that (i) intestinal motility and defaecation could be tonically inhibited by the endogenous cannabinoid system, (ii) exogenous activation of cannabinoid CB(1) receptors produces a reduction in intestinal motility in the upper gastrointestinal tract but not in defaecation, (iii) endogenous or exogenous activation of cannabinoid CB(2) receptors does not affect defaecation or intestinal motility and (iv) the cannabinoid receptor agonist, CP 55, 940, possesses a weak and transient antidiarrhoeal effect while the cannabinoid receptor agonist, WIN 55,212-2, does not possess antidiarrhoeal activity.
The endogenous cannabinoid ligand anandamide (arachidonylethanolamide) inhibited the intestinal passage of a charcoal meal when administered s.c. in mice at doses ranging from 0.1 to 50 mg/kg. This effect was prevented by the cannabinoid CB1 receptor antagonist SR141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-me thyl-1H-pyrazole-3-carboxamide x HCl] (1 mg/kg s.c.), but it was not affected by the anandamide transport inhibitor, N-(4-hydroxyphenyl) arachidonylethanolamide (AM404) (50 mg/kg, s.c.). The results indicate that anandamide modulates intestinal motility in mice by activating cannabinoid CB1 receptors. They also suggest that anandamide transport, which was previously shown to participate in terminating neural and vascular responses to anandamide, does not contribute to anandamide inactivation in intestinal tissue.
GPR55 has recently attracted much attention as another member of the cannabinoid family, potentially explaining physiological effects that are non-CB1/CB2 mediated. However, the data gathered so far are conflicting with respect to its pharmacology. We review the primary literature to date on GPR55, describing its discovery, structure, pharmacology and potential physiological functions. The CB1 receptor antagonist/inverse agonist AM251 has been shown to be a GPR55 agonist in all reports in which it was evaluated, as has the lysophospholipid, lysophosphatidylinositol (LPI). Whether GPR55 responds to the endocannabinoid ligands anandamide and 2-arachidonylglycerol and the phytocannabinoids, delta-9-tetrahydrocannabidiol and cannabidiol, is cell type and tissue-dependent. GPR55 has been shown to utilize G(q), G(12), or G(13) for signal transduction; RhoA and phospholipase C are activated. Experiments with mice in which GPR55 has been inactivated reveal a role for this receptor in neuropathic and inflammatory pain as well as in bone physiology. Thus delineating the pharmacology of this receptor and the discovery of selective agonists and antagonists merits further study and could lead to new therapeutics.
Cannabinoid use is prevalent in the United States, with recent reports of increased usage among younger Americans. Traditionally, cannabinoids have been used recreationally or as antiemetics; however, recent reports suggest that chronic abuse can result in the paradoxical effect of a cyclic vomiting syndrome, termed cannabinoid hyperemesis.
We report on this recently described clinical syndrome characterized by severe nausea and hyperemesis in the setting of chronic cannabinoid use.
We report the cases of 3 patients who presented to two academic emergency departments (EDs) on multiple occasions with nausea and vomiting in the setting of chronic cannabinoid use. There were extensive medical evaluations and frequent inpatient hospital admissions before the diagnosis of cannabinoid hyperemesis was considered.
With the relatively high prevalence of cannabinoid use in the United States and increasing interest in the applications of marijuana for therapeutic purposes, this entity may be encountered in the ED. Cannabinoid hyperemesis should be considered in the differential diagnosis of patients presenting with similar symptoms.
Delta(9)-tetrahydrocannabinol binds cannabinoid (CB(1) and CB(2)) receptors, which are activated by endogenous compounds (endocannabinoids) and are involved in a wide range of physiopathological processes (e.g. modulation of neurotransmitter release, regulation of pain perception, and of cardiovascular, gastrointestinal and liver functions). The well-known psychotropic effects of Delta(9)-tetrahydrocannabinol, which are mediated by activation of brain CB(1) receptors, have greatly limited its clinical use. However, the plant Cannabis contains many cannabinoids with weak or no psychoactivity that, therapeutically, might be more promising than Delta(9)-tetrahydrocannabinol. Here, we provide an overview of the recent pharmacological advances, novel mechanisms of action, and potential therapeutic applications of such non-psychotropic plant-derived cannabinoids. Special emphasis is given to cannabidiol, the possible applications of which have recently emerged in inflammation, diabetes, cancer, affective and neurodegenerative diseases, and to Delta(9)-tetrahydrocannabivarin, a novel CB(1) antagonist which exerts potentially useful actions in the treatment of epilepsy and obesity.
Cannabinoid signalling is an important mechanism of synaptic modulation in the nervous system. Endogenous cannabinoids (anandamide and 2-arachidonyl-glycerol) are synthesized and released via calcium-activated biosynthetic pathways. Exogenous cannabinoids and endocannabinoids act on CB1 and CB2 receptors. CB1 receptors are neuronal receptors which couple via G-proteins to inhibition of adenylate cyclase or to activation or inhibition of ion channels. CB2 receptors are expressed by immune cells and cannabinoids can suppress immune function. In the central nervous system, the endocannabinoids may function as retrograde signals released by the postsynaptic neuron to inhibit neurotransmitter release from presynaptic nerve terminals. Enteric neurons also express CB receptors. Exogenously applied CB receptor agonists inhibit enteric neuronal activity but it is not clear if endocannabinoids released by enteric neurons can produce similar responses in the enteric nervous system (ENS). In this issue of Neurogastroenterology and Motility, Boesmans et al. show that CB1 receptor activation on myenteric neurons maintained in primary culture can suppress neuronal activity, inhibit synaptic transmission and mitochondrial transport along axons. They also provide initial evidence that myenteric neurons (or other cell types present in the cultures) release endocannabinoids and which activate CB1 receptors constitutively. These data provide new information about targets for cannabinoid signalling in the ENS and highlight the potential importance of CB receptors as drug targets. It is necessary that future work extends these interesting findings to intact tissues and ideally to the in vivo setting.
Considerable preclinical research has demonstrated the efficacy of Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the primary psychoactive constituent of Cannabis sativa, in a wide variety of animal models of pain, but few studies have examined other phytocannabinoids. Indeed, other plant-derived cannabinoids, including cannabidiol (CBD), cannabinol (CBN), and cannabichromene (CBC) elicit antinociceptive effects in some assays. In contrast, tetrahydrocannabivarin (THCV), another component of cannabis, antagonizes the pharmacological effects of Delta(9)-THC. These results suggest that various constituents of this plant may interact in a complex manner to modulate pain. The primary purpose of the present study was to assess the antinociceptive effects of these other prevalent phytocannabinoids in the acetic acid stretching test, a rodent visceral pain model. Of the cannabinoid compounds tested, Delta(9)-THC and CBN bound to the CB(1) receptor and produced antinociceptive effects. The CB(1) receptor antagonist, rimonabant, but not the CB(2) receptor antagonist, SR144528, blocked the antinociceptive effects of both compounds. Although THCV bound to the CB(1) receptor with similar affinity as Delta(9)-THC, it had no effects when administered alone, but antagonized the antinociceptive effects of Delta(9)-THC when both drugs were given in combination. Importantly, the antinociceptive effects of Delta(9)-THC and CBN occurred at lower doses than those necessary to produce locomotor suppression, suggesting motor dysfunction did not account for the decreases in acetic acid-induced abdominal stretching. These data raise the intriguing possibility that other constituents of cannabis can be used to modify the pharmacological effects of Delta(9)-THC by either eliciting antinociceptive effects (i.e., CBN) or antagonizing (i.e., THCV) the actions of Delta(9)-THC.
Endocannabinoids modulate eating behavior; hence, endocannabinoid genes may contribute to the biological vulnerability to eating disorders. The rs1049353 (1359 G/A) single nucleotide polymorphism (SNP) of the gene coding the endocannabinoid CB1 receptor (CNR1) and the rs324420 (cDNA 385C to A) SNP of the gene coding fatty acid amide hydrolase (FAAH), the major degrading enzyme of endocannabinoids, have been suggested to have functional effects on mature proteins. Therefore, we explored the possibility that those SNPs were associated to anorexia nervosa and/or bulimia nervosa. The distributions of the CNR1 1359 G/A SNP and of the FAAH cDNA 385C to A SNP were investigated in 134 patients with anorexia nervosa, 180 patients with bulimia nervosa and 148 normal weight healthy controls. Additive effects of the two SNPs in the genetic susceptibility to anorexia nervosa and bulimia nervosa were also tested. As compared to healthy controls, anorexic and bulimic patients showed significantly higher frequencies of the AG genotype and the A allele of the CNR1 1359 G/A SNP. Similarly, the AC genotype and the A allele of the FAAH cDNA 385C to A SNP were significantly more frequent in anorexic and bulimic individuals. A synergistic effect of the two SNPs was evident in anorexia nervosa but not in bulimia nervosa. Present findings show for the first time that the CNR1 1359 G/A SNP and the FAAH cDNA 385C to A SNP are significantly associated to anorexia nervosa and bulimia nervosa, and demonstrate a synergistic effect of the two SNPs in anorexia nervosa.
The major active ingredient of the plant Salvia divinorum, salvinorin A (SA) has been used to treat gastrointestinal (GI) symptoms. As the action of SA on the regulation of colonic function is unknown, our aim was to examine the effects of SA on mouse colonic motility and secretion in vitro and in vivo. The effects of SA on GI motility were studied using isolated preparations of colon, which were compared with preparations from stomach and ileum. Colonic epithelial ion transport was evaluated using Ussing chambers. Additionally, we studied GI motility in vivo by measuring colonic propulsion, gastric emptying, and upper GI transit. Salvinorin A inhibited contractions of the mouse colon, stomach, and ileum in vitro, prolonged colonic propulsion and slowed upper GI transit in vivo. Salvinorin A had no effect on gastric emptying in vivo. Salvinorin A reduced veratridine-, but not forskolin-induced epithelial ion transport. The effects of SA on colonic motility in vitro were mediated by kappa-opioid receptors (KORs) and cannabinoid (CB) receptors, as they were inhibited by the antagonists nor-binaltorphimine (KOR), AM 251 (CB(1) receptor) and AM 630 (CB(2) receptor). However, in the colon in vivo, the effects were largely mediated by KORs. The effects of SA on veratridine-mediated epithelial ion transport were inhibited by nor-binaltorphimine and AM 630. Salvinorin A slows colonic motility in vitro and in vivo and influences neurogenic ion transport. Due to its specific regional action, SA or its derivatives may be useful drugs in the treatment of lower GI disorders associated with increased GI transit and diarrhoea.
Acylethanolamides are lipid substances widely distributed in the body, generated from a membrane phospholipid precursor, N-acylphosphatidylethanolamine (NAPE). The recent identification of arachidonoyl ethanolamide (anandamide or AEA) as an endogenous cannabinoid ligand has focused attention on acylethanolamides, which has further increased with the subsequent identification of related additional acylethanolamides with signaling function, such as oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). Most of the biological functions of anandamide are mediated by the two G protein-coupled cannabinoid receptors identified to date, CB(1) and CB(2), with the transient receptor potential vanilloid-1 receptor being an additional potential target. There has been increasing pharmacological evidence for the existence of additional cannabinoid receptors, with the orphan G protein-coupled receptor GPR55 being the most actively scrutinized, and is one of the subjects of this review. The other receptor reviewed here is GPR119, which can recognize OEA and PEA. These two acylethanolamides, although structurally related to anandamide, do not interact with classical cannabinoid receptors. Instead, they have high affinity for the nuclear receptor PPARalpha, which is believed to mediate many of their biological effects.
The endocannabinoid signalling system includes: (1) at least two G-protein-coupled receptors, known as the cannabinoid CB(1) and CB(2) receptors and discovered following studies on the mechanism of action of Delta(9)-tetrahydrocannabinol, the major psychoactive principle of the hemp plant Cannabis sativa; (2) the endogenous agonists at these receptors, known as endocannabinoids, of which anandamide and 2-arachidonoylglycerol are the best known; and (3) proteins and enzymes for the regulation of endocannabinoid levels and action at receptors. The endocannabinoid system is quite widespread in mammalian tissues and cells and appears to play a pro-homeostatic role by being activated following transient or chronic perturbation of homeostasis, and by regulating in a local way the levels and action of other chemical signals. Compounds that selectively manipulate the action and levels of endocannabinoids at their targets have been and are being developed, and represent templates for potential new therapeutic drugs.
Although it is well accepted that cannabinoids modulate intestinal motility by reducing cholinergic neurotransmission mediated by CB(1) receptors, it is not known whether the endocannabinoids are involved in more complex circuits and if they interact with other systems. The aim of the present study was to examine possible interactions between cannabinoid CB(1) receptors and purines in the control of spontaneous contractility of longitudinal muscle in mouse ileum.
The mechanical activity of longitudinally oriented ileal segments from mice was recorded as isometric contractions.
The selective CB(1) receptor agonist, N-(2-chloroethyl)5,8,11,14-eicosaetraenamide (ACEA) reduced, concentration dependently, spontaneous contractions in mouse ileum. This effect was almost abolished by tetrodotoxin (TTX) or atropine. Inhibition by ACEA was not affected by theophylline (P1 receptor antagonist) or by P2Y receptor desensitization with adenosine 5'[beta-thio]diphosphate trilithium salt, but was significantly reversed by pyridoxal phosphate-6-azo(benzene-2,4-disulphonic acid) (P2 receptor antagonist), by P2X receptor desensitization with alpha,beta-methyleneadenosine 5'-triphosphate lithium salt (alpha,beta-MeATP) or by 8,8'-[carbonylbis(imino-4,1-phenylenecarbonylimino-4,1-phenylenecarbonylimino) bis(1,3,5-naphthalenetrisulphonic acid)] (P2X receptor antagonist). Contractile responses to alpha,beta-MeATP (P2X receptor agonist) were virtually abolished by TTX or atropine, suggesting that they were mediated by acetylcholine released from neurones, and significantly reduced by ACEA.
In mouse ileum, activation of CB(1) receptors, apart from reducing acetylcholine release from cholinergic nerves, was able to modulate negatively, endogenous purinergic effects, mediated by P2X receptors, on cholinergic neurons. Our study provides evidence for a role of cannabinoids in the modulation of interneuronal purinergic transmission.
The majority of polymodal nociceptors express the non-selective cationic channel, transient receptor potential vanilloid type 1 receptor, which plays a pivotal role in the development of inflammatory heat hyperalgesia and visceral hyper-reflexia. Thus, blocking transient receptor potential vanilloid type 1 receptor-mediated signalling in primary sensory neurons would provide significant pain relief and reduced visceral hyperactivity in inflammatory conditions. Here, we report that cannabinoids including the endogenous agent, anandamide (3-30 nM) and the synthetic compounds, arachidonyl-2-chloroethylamide (500 nM) and 1,1-dimethylheptyl-11-hydroxytetrahydrocannabinol (1 microM) significantly reduce cobalt influx that is mediated through the transient receptor potential vanilloid type 1 receptor in rat cultured primary sensory neurons. The cannabinoid-evoked inhibitory effect can be reversed by rimonabant (200 nM), an antagonist of the cannabinoid 1 receptor. While anandamide- and arachidonyl-2-chloroethylamide fail to evoke inhibitory effects on the transient receptor potential vanilloid type 1 receptor-mediated responses, the inhibitory effect of 1,1-dimethylheptyl-11-hydroxytetrahydrocannabinol is maintained, when the cannabinoids are applied together with the inflammatory mediators, prostaglandin E(2) (10 microM) and bradykinin (10 microM). These results indicate that activation of the cannabinoid 1 receptor can reduce the activity of the transient receptor potential vanilloid type 1 receptor in primary sensory neurons, though the inhibitory effect of agents, which activate both the cannabinoid 1 and the transient receptor potential vanilloid type 1 receptor could be reduced in inflammatory conditions.
The identification of the major psychoactive constituent of Cannabis and marijuana, Delta(9)-tetrahydrocannabinol, opened the way first to the cloning of the G-protein-coupled cannabinoid CB(1) and CB(2) receptors, and then to the isolation and characterisation of their endogenous agonists, the endocannabinoids. Considerable progress has been made in the characterisation of pathways and enzymes for the biosynthesis and degradation of anandamide and 2-arachidonoylglycerol, the two best-known endocannabinoids, as well as of endocannabinoid-related molecules, such as the N-acylethanolamines, which, as in the case of N-palmitoylethanolamine and N-oleoylethanolamine, may interact with other receptor types. However, it is still not fully understood how other plant cannabinoids, of which cannabidiol is the most studied representative, exert their pharmacological effects. Together with these issues, this first review article on the endocannabinoids describes the synthetic pharmacological tools that have been designed so far to interact with the proteins of the 'endocannabinoid system' and that can potentially be used as templates for the development of new therapies.
The cannabinoid receptor-1 (CNR-1) and endogenous agonists of this receptor are present in the central and peripheral nervous systems including the gastrointestinal nervous system. The surgically rejected specimens of human colorectal cancers and paired normal tissues were studied to detect mutations in the CNR1 gene by sequencing method. The results were compared to clinicopathological parameters and correlated with overall survival time. Sixty-three colorectal cancer patients, who underwent surgical excision of colorectal carcinoma, were included in this study. The coding region of the CNR1 gene was studied: a nucleotide change (G-->A) at position 1359 was identified by direct sequencing of PCR. Thirty-eight patients had the G/G genotype (wild type) in tumor areas and 25 patients had G/A heterozygous or A/A homozygous genotype. Univariate analysis revealed 2 independent variables associated with CNR1 gene mutation. The results show that the patients with Dukes stage C and D had a 2.9 times (p = 0.04) and patients that were lymph node positive had 2.8 times (p = 0.05) greater probability of nucleotide change in CNR1 gene. Genotype G/A plus A/A had a shorter overall survival time than G/G wild-type patients (p < 0.05). Indeed nontumor paired colorectal tissues showed nucleotide change. A large number of patients with mutation in the CNR1 gene were observed. These preliminary findings highlight the importance of further studies in the use of cannabinoid analogs as receptor ligands to analyze potential therapeutic effects.
Anandamide and the other N-acylethanolamines, e.g. oleoylethanolamide (OEA), palmitoylethanolamide (PEA), and linoleoylethanolamide (LEA), may be formed by several enzymatic pathways from their precursors, which are the N-acylated ethanolamine phospholipids. The exact enzymatic pathways involved in their biosynthesis in specific tissues are not clarified. It has been suggested that endogenous anandamide could stimulate food intake by activation of cannabinoid receptors in the brain and/or in the intestinal tissue. On the other hand, endogenous OEA and PEA have been suggested to inhibit food intake by acting on receptors in the intestine. At present, there is no clear role for endogenous anandamide in controlling food intake via cannabinoid receptors, neither centrally nor in the gastrointestinal tract. However, OEA, PEA and perhaps also LEA may be involved in regulation of food intake by selective prolongation of feeding latency and post-meal interval. These N-acylethanolamines seem to be formed locally in the intestine, where they can activate PPARalpha located in close proximity to their site of synthesis. The rapid onset of OEA response and its reliance on an intact vagus nerve suggests that activation of PPARalpha does not result in formation of a transcription-dependent signal but must rely on an unidentified non-genomic signal that translates to activation of vagal afferents. Whether GPR119, TRPV1 and/or intestinal ceramide levels also contribute to the anorectic and weight-reducing effect of exogenous OEA is less clear. Prolonged intake of dietary fat (45 energy%) may promote over-consumption of food by decreasing the endogenous levels of OEA, PEA and LEA in the intestine.
The use of cannabinoids to treat gastrointestinal (GI) motor disorders has considerable potential. However, it is not clear if tolerance to their actions develops peripherally, as it does centrally. The aim of this study was to examine the chronic effects of the cannabinoid agonist WIN 55,212-2 (WIN) on GI motility, as well as those in the central nervous and cardiovascular systems. WIN was administered for 14 days, at either non-psychoactive or psychoactive doses. Cardiovascular parameters were measured in anaesthetized rats, whereas central effects and alterations in GI motor function were assessed in conscious animals using the cannabinoid tetrad and non-invasive radiographic methods, respectively. Tests were performed after first (acute effects) and last (chronic effects) administration of WIN, and 1 week after discontinuing treatment (residual effects). Food intake and body weight were also recorded throughout treatment. Blood pressure and heart rate remained unchanged after acute or chronic administration of WIN. Central activity and GI motility were acutely depressed at psychoactive doses, whereas non-psychoactive doses only slightly reduced intestinal transit. Most effects were reduced after the last administration. However, delayed gastric emptying was not and could, at least partially, account for a concomitant reduction in food intake and body weight gain. The remaining effects of WIN administration in GI motility were blocked by the CB1 antagonist AM 251, which slightly accelerated motility when administered alone. No residual effects were found 1 week after discontinuing cannabinoid treatment. The different systems show differential sensitivity to cannabinoids and tolerance developed at different rates, with delayed gastric emptying being particularly resistant to attenuation upon chronic treatment.
Activation of cannabinoid (CB)(1) receptors results in attenuation of experimental colitis. Our aim was to examine the role of CB(2) receptors in experimental colitis using agonists (JWH133, AM1241) and an antagonist (AM630) in trinitrobenzene sulfonic acid (TNBS)-induced colitis in wildtype and CB(2) receptor-deficient (CB(2) (-/-)) mice.
Mice were treated with TNBS to induce colitis and then given intraperitoneal injections of the CB(2) receptor agonists JWH133, AM1241, or the CB(2) receptor antagonist AM630. Additionally, CB(2) (-/-) mice were treated with TNBS and injected with JWH133 or AM1241. Animals were examined 3 days after the induction of colitis. The colons were removed for macroscopic and microscopic evaluation, as well as the determination of myeloperoxidase activity. Quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) for CB(2) receptor was also performed in animals with TNBS and dextran sodium sulfate colitis.
Intracolonic installation of TNBS caused severe colitis. CB(2) mRNA expression was significantly increased during the course of experimental colitis. Three-day treatment with JWH133 or AM1241 significantly reduced colitis; AM630 exacerbated colitis. The effect of JWH133 was abolished when animals were pretreated with AM630. Neither JWH133 nor AM1241 had effects in CB(2) (-/-) mice.
We show that activation of the CB(2) receptor protects against experimental colitis in mice. Increased expression of CB(2) receptor mRNA and aggravation of colitis by AM630 suggests a role for this receptor in normally limiting the development of colitis. These results support the idea that the CB(2) receptor may be a possible novel therapeutic target in inflammatory bowel disease.
Orally applicable Delta9-tetrahydrocannabinol and its synthetic derivatives have been used as antiemetic drugs during chemotherapy in cancer patients. However, it is not well known how cannabinoids influence the effects of chemotherapeutic agents on malignant tumors. In this study, we investigated how the endogenous cannabinoid anandamide (AEA) changes the effect of paclitaxel on gastric cancer cell lines. In the human gastric cancer cell line, HGC-27, which express cannabinoid receptor 1 (CB1), AEA stimulated proliferation at concentrations under 1 microM, while it strongly suppressed proliferation through the induction of apoptosis at 10 microM. This bimodal effect was reproduced by a selective CB1 agonist, arachidonyl-2-chloroethylamide, although the effects were less marked. When AEA was used with paclitaxel, AEA at 10 microM synergistically enhanced the cytotoxic effect of paclitaxel, whereas it showed no significant effect at lower concentrations. Flow cytometric analysis revealed that addition of 10 microM AEA synergistically enhanced paclitaxel-induced apoptosis, possibly through the activation of caspase-3, -8, and -9. Our results suggest that cannabinoids could be a good palliative agent for cancer patients receiving paclitaxel.
Obesity is a severe health problem in the modernized world and understanding the central nervous mechanisms underlying food-seeking behaviour and reward are at the forefront of medical research. Cannabinoid receptors have proven an efficient target to suppress hunger and weight gain by their pharmacological inactivation.
A standard fasted protocol and a novel long-term home-cage observation system with free-feeding animals were used to assess the feeding behaviour of mice treated with the CB1 antagonist AM251. Similarly, the effects of the phytocannabinoid Delta9-tetrahydrocannabivarin (Delta9-THCV), which behaves like a CB1 antagonist, were also determined in free-feeding animals.
AM251 suppressed food intake and weight gain in fasted and non-fasted animals. The suppression of food intake by AM251 (10 mg.kg-1) endured for a period of 6-8 h when administered acutely, and was continuous when injected for four consecutive days. Pure Delta9-THCV also induced hypophagia and weight reduction at doses as low as 3 mg.kg-1. No rebound was observed on the following day with all drug groups returning to normal activity and feeding regimes. However, a Delta9-THCV-rich cannabis-extract failed to suppress food intake and weight gain, possibly due to residual Delta9-tetrahydrocannabinol (Delta9-THC) in the extract. This Delta9-THC effect was overcome by the co-administration of cannabidiol.
The data strongly suggest (i) the long-term home-cage observation system is a sensitive and obesity-relevant tool, and (ii) the phytocannabinoid Delta9-THCV is a novel compound with hypophagic properties and a potential treatment for obesity
Cannabinoid (CB) receptors are expressed in the enteric nervous system (ENS) and CB(1) receptor activity slows down motility and delays gastric emptying. This receptor system has become an important target for GI-related drug development such as in obesity treatment. The aim of the study was to investigate how CB(1) ligands and antagonists affect ongoing activity in enteric neurone networks, modulate synaptic vesicle cycling and influence mitochondrial transport in nerve processes. Primary cultures of guinea-pig myenteric neurones were loaded with different fluorescent markers: Fluo-4 to measure network activity, FM1-43 to image synaptic vesicles and Mitotracker green to label mitochondria. Synaptic vesicle cluster density was assessed by immunohistochemistry and expression of CB(1) receptors was confirmed by RT-PCR. Spontaneous network activity, displayed by both excitatory and inhibitory neurones, was significantly increased by CB(1) receptor antagonists (AM-251 and SR141716), abolished by CB(1) activation (methanandamide, mAEA) and reduced by two different inhibitors (arachidonylamide serotonin, AA-5HT and URB597) of fatty acid amide hydrolase. Antagonists reduced the number of synaptic vesicles that were recycled during an electrical stimulus. CB(1) agonists (mAEA and WIN55,212) reduced and antagonists enhanced the fraction of transported mitochondria in enteric nerve fibres. We found immunohistochemical evidence for an enhancement of synaptophysin-positive release sites with SR141716, while WIN55,212 caused a reduction. The opposite effects of agonists and antagonists suggest that enteric nerve signalling is under the permanent control of CB(1) receptor activity. Using inhibitors of the endocannabinoid degrading enzyme, we were able to show there is endogenous production of a CB ligand in the ENS.