Endocannabinoid System Research Articles

Comparative targeted lipidomics between serum and cerebrospinal fluid of multiple sclerosis patients shows sex and age-specific differences of endocannabinoids and glucocorticoids

Multiple sclerosis (MS) is a complex chronic neuroinflammatory disease characterized by demyelination leading to neuronal dysfunction and neurodegeneration manifested by various neurological impairments. The endocannabinoid system (ECS) is a lipid signalling network, which plays multiple roles in the central nervous system and the periphery, including synaptic signal transmission and modulation of inflammation. The ECS has been identified as a potential target for the development of novel therapeutic interventions in MS patients. It remains unclear whether ECS-associated metabolites are changed in MS and could serve as biomarkers in blood or cerebrospinal fluid (CSF). In this retrospective study we applied targeted lipidomics to matching CSF and serum samples of 74 MS and 80 non-neuroinflammatory control patients. We found that MS-associated lipidomic changes overall did not coincide between CSF and serum. While glucocorticoids correlated positively, only the endocannabinoid (eCB) 2-arachidonoyl glycerol (2-AG) showed a weak positive correlation (r = 0.3, p < 0.05) between CSF and serum. Peptide endocannabinoids could be quantified for the first time in CSF but did not differ between MS and controls. MS patients showed elevated levels of prostaglandin E2 and steaorylethanolamide in serum, and 2-oleoylglycerol and cortisol in CSF. Sex-specific differences were found in CSF of MS patients showing increased levels of 2-AG and glucocorticoids in males only. Overall, arachidonic acid was elevated in CSF of males. Interestingly, CSF eCBs correlated positively with age only in the control patients due to the increased levels of eCBs in young relapsing-remitting MS patients. Our findings reveal significant discrepancies between CSF and serum, underscoring that measuring eCBs in blood matrices is not optimal for detecting MS-associated changes in the central nervous system. The identified sex and age-specific changes of analytes of the stress axis and ECS specifically in the CSF of MS patients supports the role of the ECS in MS and may be relevant for drug development strategies.

Exploring Novel Pharmacotherapy Candidates for Cannabis Use Disorder: Uncovering Promising Agents on the Horizon by Mechanism of Action.

With rapid expansion of cannabis legalization worldwide, rates of cannabis use and cannabis use disorder (CUD) are increasing; the need for safe and effective medications to treat CUD is urgent. This narrative review evaluates evidence for promising pharmacotherapies to treat CUD from randomized, placebo-controlled trials. Pharmacotherapies for CUD are categorized based on compound targets (e.g., cannabinoid receptor 1 [CB1] agonists such as nabilone, serotonergic compounds such as bupropion, GABAergic compounds such as zolpidem) and outcomes are organized by predetermined withdrawal symptoms, cannabis craving, and cannabis relapse/use. Most promising pharmacotherapies for CUD are drugs that act on the endocannabinoid system and specifically at the CB1 receptor. Priority populations such as females, certain racial/ethnic groups, and age groups experience a different course of CUD progression, symptoms, and drug effects that are important to consider when evaluating outcomes related to CUD. Possible explanations for these disparities are explored, along with the clinical trials that explore these demographics in treating CUD with pharmacotherapies.

Decoding the Therapeutic Potential of Cannabis and Cannabinoids in Neurological Disorders.

For millennia, Cannabis sativa has served diverse roles, from medicinal applications to recreational use. Despite its extensive historical use, only a fraction of its components have been explored until recent times. The therapeutic potential of Cannabis and its constituents has garnered attention, with suggestions for treating various conditions such as Parkinson's disease, epilepsy, Alzheimer's disease, and other Neurological disorders. Recent research, particularly on animal experimental models, has unveiled the neuroprotective properties of cannabis. This neuroprotective effect is orchestrated through numerous G protein-coupled receptors (GPCRs) and the two cannabinoid receptors, CB1 and CB2. While the capacity of cannabinoids to safeguard neurons is evident, a significant challenge lies in determining the optimal cannabinoid receptor agonist and its application in clinical trials. The intricate interplay of cannabinoids with the endocannabinoid system, involving CB1 and CB2 receptors, underscores the need for precise understanding and targeted approaches. Unravelling the molecular intricacies of this interaction is vital to harness the therapeutic potential of cannabinoids effectively. As the exploration of cannabis components accelerates, there is a growing awareness of the need for nuanced strategies in utilizing cannabinoid receptor agonists in clinical settings. The evolving landscape of cannabis research presents exciting possibilities for developing targeted interventions that capitalize on the neuroprotective benefits of cannabinoids while navigating the complexities of receptor specificity and clinical applicability.

Attenuation of 1-chloro-2,4-dinitrobenzene-induced inflammation in atopic dermatitis-like skin lesions in rats by a pyrrole containing FELL-NH 2 bioconjugate: Cannabinoid receptor type 1 involvement

Atopic dermatitis (AD) is a chronic inflammatory skin condition of significant health and social importance, which justifies the search for new means of treatment. Since the endogenous cannabinoid system appears to be involved in the pathogenesis of AD, the proposed article summarizes the clinical impact on skin inflammation in a rat model of 1-chloro-2,4-dinitrobenzene-induced atopic dermatitis-like condition after exogenous systemic administration of the cannabinoid receptor type 1 (CB1r) agonist anandamide, as well as after local treatment with a newly synthesized pyrrole moiety containing bioconjugate of FELL tetrapeptide with CB1r-dependent analgesic activity. The changes in skin lesions and ear thickness were estimated along with the CB1r expression immunohistochemically determined on skin punch biopsies. The results showed attenuation of skin lesions by anandamide and lack of positive effect after introduction of CB1r antagonist, accompanied by a change in CB1r expression, suggesting the involvement of the cannabinoid system in the defensive functions of the skin. The topically applied newly synthesized bioconjugate also favorably affected skin manifestations of inflammation, but without a change in CB1r expression, suggesting the involvement of other mechanisms in the reported effects.

Genetic and Neurodevelopmental Markers in Schizophrenia-Spectrum Disorders: Analysis of the Combined Role of the CNR1 Gene and Dermatoglyphics.

Background: Dermatoglyphic pattern deviances have been associated with schizophrenia-spectrum disorders (SSD) and are considered neurodevelopment vulnerability markers based on the shared ectodermal origin of the epidermis and the central nervous system. The endocannabinoid system participates in epidermal differentiation, is sensitive to prenatal insults and is associated with SSD. Objective: We aimed to investigate whether the Cannabinoid Receptor 1 gene (CNR1) modulates the dermatoglyphics-SSD association. Methods: In a sample of 112 controls and 97 patients with SSD, three dermatoglyphic markers were assessed: the total palmar a-b ridge count (TABRC), the a-b ridge count fluctuating asymmetry (ABRC-FA), and the pattern intensity index (PII). Two CNR1 polymorphisms were genotyped: rs2023239-T/C and rs806379-A/T. We tested: (i) the CNR1 association with SSD and dermatoglyphic variability within groups; and (ii) the CNR1 × dermatoglyphic measures interaction on SSD susceptibility. Results: Both polymorphisms were associated with SSD. The polymorphism rs2023239 modulated the relationship between PII and SSD: a high PII score was associated with a lower SSD risk within C-allele carriers and a higher SSD risk within TT-homozygotes. This result indicates an inverse relationship between the PII and the SSD predicted probability conditional to the rs2023239 genotype. Conclusions: These novel findings suggest the endocannabinoid system's role in the development and variability of dermatoglyphic patterns. The identified interaction encourages combining genetic and dermatoglyphics to assess neurodevelopmental alterations predisposing to SSD in future studies.

No Evidence for Endocannabinoid-Induced G Protein Subtype Selectivity at Human and Rodent Cannabinoid CB1 Receptors.

Introduction: The endocannabinoid system (ECS) is a widespread neurotransmitter system. A key characteristic of the ECS is that there are multiple endogenous ligands (endocannabinoids). Of these, the most extensively studied are arachidonoyl ethanolamide (AEA) and 2-arachidonoyl-glycerol (2-AG), both act as agonists at the cannabinoid CB1 receptor. In humans, three CB1 variants have been identified: hCB1, considered the most abundant G protein-coupled receptor in the brain, alongside the less abundant and studied variants, hCB1a and hCB1b. CB1 exhibits a preference for coupling with inhibitory Gi/o proteins, although its interactions with specific members of the Gi/o family remain poorly characterized. This study aimed to compare the AEA and 2-AG-induced activation of various G protein subtypes at CB1. Furthermore, we compared the response of human CB1 (hCB1, hCB1a, hCB1b) and explored species differences by examining rodent receptors (mCB1, rCB1). Materials and Methods: Activation of individual G protein subtypes in HEK293 cells transiently expressing CB1 was measured with G protein dissociation assay utilizing TRUPATH biosensors. The performance of the TRUPATH biosensors was evaluated using Z-factor analysis. Pathway potencies and efficacies were analyzed using the operational analysis of bias to determine G protein subtype selectivity for AEA and 2-AG. Results: Initial screening of TRUPATH biosensors performance revealed variable sensitivities within our system. Based on the biosensor performance, the G protein subtypes pursued for further characterization were Gi1, Gi3, GoA, GoB, GZ, G12, and G13. Across all pathways, AEA demonstrated partial agonism, whereas 2-AG exhibited full or high-efficacy agonism. Notably, we provide direct evidence that the hCB1 receptor couples to G12 and G13 proteins. Our findings do not indicate any evidence of G protein subtype selectivity. Similar observations were made across the human receptor variants (hCB1, hCB1a, hCB1b), as well as at mCB1 and rCB1. Discussion: There was no evidence suggesting G protein subtype selectivity for AEA and 2-AG at CB1, and this finding remained consistent across human receptor variants and different species.

The Interplay of Exogenous Cannabinoid Use on Anandamide and 2-Arachidonoylglycerol in Anxiety: Results from a Quasi-Experimental Ad Libitum Study

The public is increasingly reporting using cannabis for anxiety relief. Both cannabis use and the endocannabinoid system have been connected with anxiety relief/anxiolytic properties, but these relationships are complex, and the underlying mechanisms for them are unclear. Background/Objectives: Work is needed to understand how the endocannabinoid system, including the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG), may be impacted by the main constituents of cannabis, Δ9-tetrahydrocannabinol (THC), and cannabidiol (CBD). Methods: The current study examined how the ab libitum use of products differing in THC and CBD affected AEA and 2-AG among 292 individuals randomly assigned to THC-dominant use (N = 92), CBD-dominant use (N = 97), THC + CBD use (N = 74), or non-use (N = 29). Results: The findings suggest that AEA levels do not change differently based on 4 weeks of cannabis use or by cannabinoid content, as AEA similarly increased across all conditions from study weeks 2 to 4. In contrast, AEA decreased at an acute administration session with product conditions containing any THC having greater AEA levels on average than the non-use condition. With regard to 2-AG, its levels appeared to primarily be affected by THC-dominant use, both acutely and over 4 weeks, when controlling for baseline cannabis use and examining study product use frequency among use conditions. Conclusions: Overall, the results continue to shed light on the complicated relationship between cannabinoid content and endocannabinoid production, and highlight the need for continued research on their interplay in human subjects.

An overview of major depression disorder: The endocannabinoid system as a potential target for therapy.

Major depressive disorder is the psychiatric disease with the highest global prevalence, impacting social functioning and decreasing the quality of life. The partial pathophysiological knowledge of the disease, the economic burden and the low remission rates are sufficient justification to carry out an update on the subject in the search for new therapeutic approaches and targets. The endocannabinoid system has been linked to the development of depression, and its stimulation or antagonism is a promising approach in the treatment of major depressive disorder. Cannabidiol (CBD) and its properties have been widely studied recently; its analgesic, anti-inflammatory, antineoplastic and neuroprotective roles have even been reported in animal models and clinical trials, achieving its approved use for certain neurodegenerative pathologies. The use of CBD in depression biomodels and clinical trials has not been the exception, and here we contrast the current evidence of its administration and pharmacology against the pathological mechanisms of major depressive disorder.

The Potential Role of Cannabidiol in Cosmetic Dermatology: A Literature Review.

Cannabidiol (CBD) is a non-psychotropic cannabinoid with multiple pharmacological properties. Cannabidiol has attracted growing attention in the cosmetic industry, with an increasing number of CBD-containing skincare products on the market in recent years. The aim of this review is to evaluate the current evidence on the use of CBD for cosmetic purposes. Following an overview of CBD and the endocannabinoid system in the skin, we summarize pre-clinical and clinical studies that address the potential of CBD in cosmetic dermatology. Available in vitro and in vivo evidence suggests that CBD has anti-oxidant, anti-inflammatory, moisturizing, anti-acne, wound-healing, and anti-aging properties. However, only a few clinical studies have been conducted on the use of CBD in the skin. In addition, there is a critical need to develop an efficient drug-delivery system for topical/transdermal application of CBD. Further research, including clinical and pharmacokinetic studies, are needed to fully evaluate the role of CBD in cosmetic dermatology.

Inulin may prevent the high-fat diet induced-obesity via suppressing endocannabinoid system in the prefrontal cortex in Wistar rats

High-fat diets contribute to various metabolic disorders. Inulin supplementation has been shown to reduce appetite, lower food intake, and promote weight loss. Although there is evidence that the endocannabinoid system has metabolic effects in the prefrontal cortex, studies investigating the effects of inulin on the endocannabinoid system are limited. This study investigated the impact of inulin on obesity through the endocannabinoid system in the prefrontal cortex. Twenty-four male Wistar rats were fed one of four diets over 12 weeks. Findings indicated that a high-fat diet led to obesity, whereas inulin reduced food intake and supported weight loss. Consequently, inulin supplementation both prevented obesity and significantly decreased the expressions of Adrb3 and Adcy1, and anandamide and 2-arachidonylglycerol levels in the prefrontal cortex. Additionally, inulin lowered leptin in circulation and stimulated Trpv1. Thus, inulin may mitigate obesity development, possibly by modulating gene expressions linked to obesity in the prefrontal cortex via endocannabinoids.

New peripherally-restricted CB1 receptor antagonists, PMG-505–010 and −013 ameliorate obesity-associated NAFLD and fibrosis

The endocannabinoid system plays a crucial role in metabolic regulation, prompting the investigation of cannabinoid type 1 receptor (CB1R) antagonists for obesity and its complications like non-alcoholic fatty liver disease (NAFLD). Concerns over psychiatric side effects led to the development of peripheral CB1R antagonists that circumvent the blood-brain barrier (BBB). In this study, we synthesized PMG-505–010 and PMG-505–013 as peripherally restricted CB1 receptor antagonists by modifying rimonabant to minimize BBB penetration. Physicochemical analysis confirmed their reduced lipophilicity and increased polarity compared to rimonabant, indicating limited brain exposure. Molecular docking studies revealed similar binding modes to rimonabant at CB1R, characterized by robust hydrophobic interactions. Functionally, they acted as CB1R antagonists and inverse agonists, effectively reversing CP55,940-induced cAMP inhibition. In a murine model of obesity-related NAFLD, PMG-505–010 and −013 improved metabolic profiles, including fasting blood glucose levels and dyslipidemia. They also ameliorated hepatic injury, steatosis, and inflammation, evidenced by reduced liver enzymes, lipid peroxidation, hepatic lipid levels, and inflammatory cytokine levels. Notably, these compounds inhibited hepatic fibrosis by reducing extracellular matrix (ECM) deposition and altering fibrosis-related gene and protein expressions. In conclusion, PMG-505–010 and PMG-505–013 hold promise for treating obesity-related liver diseases, including NAFLD and fibrosis, through selective peripheral CB1R targeting, potentially avoiding CNS-related side effects seen with earlier CB1R antagonists.

Visualization of membrane localization and the functional state of CB2R pools using matched agonist and inverse agonist probe pairs.

The diversity of physiological roles of the endocannabinoid system has turned it into an attractive yet elusive therapeutic target. However, chemical probes with various functionalities could pave the way for a better understanding of the endocannabinoid system at the cellular level. Notably, inverse agonists of CB2R - a key receptor of the endocannabinoid system - lagged behind despite the evidence regarding the therapeutic potential of its antagonism. Herein, we report a matched fluorescent probe pair based on a common chemotype to address and visualize both the active and inactive states of CB2R, selectively. Alongside extensive cross-validation by flow cytometry, time-lapse confocal microscopy, and super-resolution microscopy, we successfully visualize the intracellular localization of CB2R pools in live cells. The synthetic simplicity, together with the high CB2R-selectivity and specificity of our probes, turns them into valuable tools in chemical biology and drug development that can benefit the clinical translatability of CB2R-based drugs.

Modulation of chemotherapy-induced peripheral neuropathy by JZL195 through glia and the endocannabinoid system

Chemotherapy-induced peripheral neuropathy (CIPN) used to treat cancer, is a significant side effect with a complex pathophysiology, and its mechanisms remain unclear. Recent research highlights neuroinflammation, which is modulated by the endocannabinoid system (ECS) and associated with glial activation, and the role of toll-like receptor 4 (TLR4) in CIPN. This study aimed to investigate the effects of JZL195, an inhibitor of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), and explore the connection between cannabinoid receptors and TLR4 in glial cells. A CIPN animal model was developed using cisplatin-injected male C57BL/6 mice. Mechanical and cold allodynia were assessed through von Frey and acetone tests. Western blot analysis was used to examine the expression of catabolic enzymes, cannabinoid receptors, glial cells, and neuroinflammatory factors in the dorsal root ganglia (DRGs) and spinal cord. Immunohistochemistry was used to investigate the colocalization of cannabinoid receptors and TLR4 in glial cells. JZL195 alleviated pain by inhibiting FAAH/MAGL, modulating the ECS and neuroinflammatory factors, and suppressing glial cell activity. Additionally, cannabinoid receptors and TLR4 colocalized with astrocytes and microglia in the spinal cord. This study highlights the therapeutic potential of JZL195 in modulating the ECS and suggests a correlation between cannabinoid receptors and TLR4 in spinal glial cells, providing insight into alleviating pain and neuroinflammation in CIPN.

The endocannabinoid system in appetite regulation and treatment of obesity.

The endocannabinoid system (ECS) is a complex cell-signaling system that is responsible for maintaining homeostasis by modulating various regulatory reactions in response to internal and environmental changes. The influence of ECS on appetite regulation has been a subject of much recent research, however, the full extent of its impact remains unknown. Current evidence links human obesity to ECS activation, increased endocannabinoid levels in both central and peripheral tissues, along with cannabinoid receptor type 1 (CBR1) up-regulation. These findings imply the potential pharmacological use of the ECS in the treatment of obesity. Here, we present various pathophysiological processes in obesity involving the ECS, highlighting different pharmacological options for modulating endocannabinoid activity to treat obesity. However, the potential of those pharmacological possibilities remains under investigation and requires further research.

Hemoglobin α-derived peptides VD-hemopressin (α) and RVD-hemopressin (α) are involved in electroacupuncture inhibition of chronic pain.

Knee osteoarthritis (KOA) is a chronic degenerative bone metabolic disease that primarily affects older adults, leading to chronic pain and disability that affect patients' daily activities. Electroacupuncture (EA) is a commonly used method for the treatment of chronic pain in clinical practice. Previous studies indicate that the endocannabinoid system is involved in EA analgesia, but whether endocannabinopeptide VD-hemopressin (α) and RVD-hemopressin (α) derived from hemoglobin chains are involved in EA analgesia is unclear. RNA-seq technology was used to screen which genes involved in EA analgesia. The expression of hemoglobin α chain and 26S proteasome were determined by Western blotting. The level of VD-hemopressin (α) and RVD-hemopressin (α) were measured by UPLC-MS/MS. Microinjection VD-Hemopressin (α), RVD-Hemopressin (α) and 26S proteasome inhibitor MG-132 into vlPAG, then observe mechanical and thermal pain thresholds. Therefore, we used RNA-seq to obtain differentially expressed genes Hba-a1 and Hba-a2 involved in EA analgesia in the periaqueductal gray (PAG), which were translated into the hemoglobin α chain. EA significantly increased the expression of the hemoglobin α chain and the level of hemopressin (α) and RVD-hemopressin (α). Microinjection of VD-hemopressin (α) and RVD-hemopressin (α) into the ventrolateral periaqueductal gray (vlPAG) mimicked the analgesic effect of EA, while CB1 receptor antagonist AM251 reversed this effect. EA significantly increased the expression of 26S proteasome in KOA mice. Microinjection of 26S proteasome inhibitor MG132 before EA prevented both the anti-allodynic effect and upregulation of the concentration of RVD-hemopressin (α) by EA treatment and upregulated the expression of the hemoglobin α chain. Our data suggest that EA upregulated the concentration of VD-hemopressin (α) and RVD-hemopressin (α) through enhancement of the hemoglobin α chain degradation by 26S proteasome in the PAG, then activated the CB1 receptor, thereby exerting inhibition of chronic pain in a mouse model of KOA. These results provide new insights into the EA analgesic mechanisms and reveal possible targets for EA treatment of chronic pain.

Assessment of the effects of cannabidiol and a CBD-rich hemp extract in Caenorhabditis elegans.

Consumer use of cannabidiol (CBD) is growing, but there are still data gaps regarding its possible adverse effects on reproduction and development. Multiple pathways and signaling cascades involved in organismal development and neuronal function, including endocannabinoid synthesis and signaling systems, are well conserved across phyla, suggesting that Caenorhabditis elegans can model the in vivo effects of exogenous cannabinoids. The effects in C. elegans on oxidative stress response (OxStrR), developmental timing, juvenile and adult spontaneous locomotor activity, reproductive output, and organismal CBD concentrations were assessed after exposure to purified CBD or a hemp extract suspended in 0.5% sesame oil emulsions. In C. elegans, this emulsion vehicle is equivalent to a high-fat diet (HFD). As in mammals, HFD was associated with oxidative-stress-related gene expression in C. elegans adults. CBD reduced HFD-induced OxStrR in transgenic adults and counteracted the hypoactivity observed in HFD-exposed wild-type adults. In C. elegans exposed to CBD from the onset of feeding, delays in later milestone acquisition were irreversible, while later juvenile locomotor activity effects were reversible after the removal of CBD exposure. CBD-induced reductions in mean juvenile population body size were cumulative when chronic exposures were initiated at parental reproductive maturity. Purified CBD was slightly more toxic than matched concentrations of CBD in hemp extract for all tested endpoints, and both were more toxic to juveniles than to adults. Dosimetry indicated that all adverse effect levels observed in C. elegans far exceeded recommended CBD dosages for humans.

Gut symbiont-derived anandamide promotes reward learning in honeybees by activating the endocannabinoid pathway.

Polyunsaturated fatty acids (PUFAs) are dietary components participating in neurotransmission and cell signaling. Pollen is a source of PUFAs for honeybees, and disruptions in dietary PUFAs reduce the cognitive performance of honeybees. We reveal that gut bacteria of honeybees contribute to fatty acid metabolism, impacting reward learning. Gut bacteria possess Δ-6 desaturases that mediate fatty acid elongation andcompensate for the absence of honeybee factors required for fatty acid metabolism. Colonization with Gilliamella apicola, but not a mutant lacking the Δ-6 desaturase FADS2, increases the production of anandamide (AEA), a ligand of the endocannabinoid system, and alters learning and memory. AEA activates the Hymenoptera-specific transient receptor AmHsTRPA in astrocytes, which induces Ca2+ influx and regulates glutamate re-uptake of glial cells to enhance reward learning. These findings illuminate the roles of gut symbionts in host fatty acid metabolism and the impacts of endocannabinoid signaling on the reward system of social insects.

FAAH inhibitor URB597 shows anti-hyperalgesic action and increases brain and intestinal tissues fatty acid amides in a model of CRF1 agonist mediated visceral hypersensitivity in male rats.

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. 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. 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. 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.

The Expression of Cannabinoid and Cannabinoid-Related Receptors on the Gustatory Cells of the Piglet Tongue.

The gustatory system is responsible for detecting and evaluating the palatability of the various chemicals present in food and beverages. Taste bud cells, located primarily on the tongue, communicate with the gustatory sensory neurons by means of neurochemical signals, transmitting taste information to the brain. It has also been found that the endocannabinoid system (ECS) may modulate food intake and palatability, and that taste bud cells express cannabinoid receptors. The purpose of this study was to investigate the expression of cannabinoid and cannabinoid-related receptors in the gustatory cells of the papillae vallatae and foliatae of ten piglets. Specific antibodies against the cannabinoid receptors (CB1R and CB2R), G protein-coupled receptor 55 (GPR55), transient receptor potential vanilloid 1 (TRPV1) and ankyrin 1 (TRPA1) were applied on cryosections of lingual tissue; the lingual tissue was also processed using Western blot analysis. Cannabinoid and cannabinoid-related receptors were found to be expressed in the taste bud cells and the surrounding epithelial cells. The extra-papillary epithelium also showed strong immunolabeling for these receptors. The results showed that these receptors were present in both the taste bud cells and the extra-gustatory epithelial cells, indicating their potential role in taste perception and chemesthesis. These findings contributed to understanding the complex interactions between cannabinoids and the gustatory system, highlighting the role of the ECS within taste perception and its potential use in animal production in order to enhance food intake.

Cannabinoids and the heart-apsychiatrist's perspective.

The partial legalization of cannabis in Germany in 2024 will affect both medical and recreational use of cannabis. Tetrahydrocannabinol (THC), the main psychoactive component of the cannabis plant, influences heart rate and blood pressure through the endocannabinoid system. Acute and chronic use can pose cardiovascular risks. There is evidence of alink between cannabis use and cardiovascular events such as stroke and myocardial infarction, although studies show conflicting results. The non-psychoactive cannabidiol (CBD) could have anti-inflammatory and antioxidant effects. Smoking cannabis poses additional cardiovascular risks similar to tobacco. Given these risks, cardiologists should routinely ask their patients about possible cannabis use and inform them about the potential cardiovascular dangers. The article also highlights the psychiatric risks of cannabis use, including dependence and psychosis, and emphasizes the need for interdisciplinary collaboration between cardiologists and psychiatrists to effectively manage cannabis-related health problems.