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The Endocannabinoid System: New Insights into Its Role in Health and Disease

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 November 2023) | Viewed by 16186

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Prof. Dr. Anna Serefko

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Department of Clinical Pharmacy and Pharmaceutical Care, Medical University of Lublin, Chodźki 1, 20-093 Lublin, Poland
Interests: depression; anxiety; epilepsy; neuroscience; preclinical studies
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Aleksandra Szopa

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Special Issue Information

Dear Colleagues,

Over the last three decades, the endocannabinoid system has emerged as an important neuromodulatory system in the human body that modulates and controls a range of crucial physiological or psychological functions, including inflammatory and immune responses, emotions, learning and memory, sleep, appetite, nociception, as well as cell growth and proliferation. Based on the available data, it seems that specific cannabinoid receptors as well as enzymes responsible for the synthesis and degradation of their endogenous ligands (i.e., endocannabinoids) are promising as therapeutic targets in multiple diseases and disorders. In fact, the hemp plant (Cannabis sativa) that modulates the endocannabinoid system was widely used in the past for its curative properties. Extensive research on compounds targeting components of the endocannabinoid system in relation to the treatment of psychiatric disorders, neurodegenerative diseases, seizures, cancer, pain, metabolic diseases, cardiovascular diseases, and respiratory disorders has been carried out with varying degrees of success. Few drugs have reached the pharmaceutical market, but there are several drug candidates whose activity and safety have been verified. In our Special Issue entitled The Endocannabinoid System: New Insights into Its Role in Health and Disease, we would like to encourage scientists to share their opinions and suggestions related to new therapeutic or diagnostic approaches that affect the endocannabinoid system.

This Special Issue aims to provide a platform for molecular mechanistic research on the endocannabinoid system, with a special focus on its role in health and disease. We warmly welcome your submissions of original papers and reviews based on results from molecular viewpoints.

Dr. Anna Serefko
Dr. Aleksandra Szopa
Guest Editors

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Keywords

cannabinoids
cannabinoid receptors
drug development
diagnostics
phytocannabinoids
synthetic cannabinoids

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Published Papers (8 papers)

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23 pages, 3747 KiB

Open AccessArticle

Role of CB1 Cannabinoid Receptors in Vascular Responses and Vascular Remodeling of the Aorta in Female Mice

by Bálint Bányai, Zsolt Vass, Stella Kiss, Anikó Balogh, Dóra Brandhuber, Gellért Karvaly, Krisztián Kovács, György L. Nádasy, László Hunyady, Gabriella Dörnyei, Eszter Mária Horváth and Mária Szekeres

Int. J. Mol. Sci. 2023, 24(22), 16429; https://doi.org/10.3390/ijms242216429 - 17 Nov 2023

Cited by 1 | Viewed by 2480

Abstract

Both the endocannabinoid system (ECS) and estrogens have significant roles in cardiovascular control processes. Cannabinoid type 1 receptors (CB₁Rs) mediate acute vasodilator and hypotensive effects, although their role in cardiovascular pathological conditions is still controversial. Estrogens exert cardiovascular protection in females. We aimed to study the impact of ECS on vascular functions. Experiments were performed on CB₁R knockout (CB₁R KO) and wild-type (WT) female mice. Plasma estrogen metabolite levels were determined. Abdominal aortas were isolated for myography and histology. Vascular effects of phenylephrine (Phe), angiotensin II, acetylcholine (Ach) and estradiol (E2) were obtained and repeated with inhibitors of nitric oxide synthase (NOS, Nω-nitro-L-arginine) and of cyclooxygenase (COX, indomethacin). Histological stainings (hematoxylin-eosin, resorcin-fuchsin) and immunostainings for endothelial NOS (eNOS), COX-2, estrogen receptors (ER-α, ER-β) were performed. Conjugated E2 levels were higher in CB₁R KO compared to WT mice. Vasorelaxation responses to Ach and E2 were increased in CB₁R KO mice, attenuated by NOS-inhibition. COX-inhibition decreased Phe-contractions, while it increased Ach-relaxation in the WT group but not in the CB₁R KO. Effects of indomethacin on E2-relaxation in CB₁R KO became opposite to that observed in WT. Histology revealed lower intima/media thickness and COX-2 density, higher eNOS and lower ER-β density in CB₁R KO than in WT mice. CB₁R KO female mice are characterized by increased vasorelaxation associated with increased utilization of endothelial NO and a decreased impact of constrictor prostanoids. Our results indicate that the absence or inhibition of CB₁Rs may have beneficial vascular effects. Full article

(This article belongs to the Special Issue The Endocannabinoid System: New Insights into Its Role in Health and Disease)

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20 pages, 7172 KiB

Open AccessArticle

Effect of the Cannabinoid Agonist WIN 55,212-2 on Neuropathic and Visceral Pain Induced by a Non-Diarrheagenic Dose of the Antitumoral Drug 5-Fluorouracil in the Rat

by Gema Vera, Laura López-Gómez, Rocío Girón, María Isabel Martín-Fontelles, Kulmira Nurgali, Raquel Abalo and José Antonio Uranga

Int. J. Mol. Sci. 2023, 24(19), 14430; https://doi.org/10.3390/ijms241914430 - 22 Sep 2023

Viewed by 1603

Abstract

5-fluorouracil (5-FU) is an antineoplastic drug used to treat colorectal cancer, but it causes, among other adverse effects, diarrhea and mucositis, as well as enteric neuropathy, as shown in experimental animals. It might also cause neuropathic pain and alterations in visceral sensitivity, but this has not been studied in either patients or experimental animals. Cannabinoids have antimotility and analgesic effects and may alleviate 5-FU-induced adverse effects. Our aim was to evaluate the effects of the cannabinoid agonist WIN 55,212-2 on neuropathic and visceral pain induced by a non-diarrheagenic dose of 5-FU. Male Wistar rats received a dose of 5-FU (150 mg/kg, ip) and gastrointestinal motility, colonic sensitivity, gut wall structure and tactile sensitivity were evaluated. WIN 55,212-2 (WIN) was administered to evaluate its effect on somatic (50–100 µg ipl; 1 mg/kg, ip) and visceral (1 mg/kg, ip) sensitivity. The cannabinoid tetrad was used to assess the central effects of WIN (1 mg/kg, ip). 5-FU decreased food intake and body weight gain, produced mucositis and thermal hyperalgesia, but these effects were reduced afterwards, and were not accompanied by diarrhea. Tactile mechanical allodynia was also evident and persisted for 15 days. Interestingly, it was alleviated by WIN. 5-FU tended to increase colonic sensitivity whereas WIN reduced the abdominal contractions induced by increasing intracolonic pressure in both control and 5-FU-treated animals. Importantly, the alleviating effects of WIN against those induced by 5-FU were not accompanied by any effect in the cannabinoid tetrad. The activation of the peripheral cannabinoid system may be useful to alleviate neuropathic and visceral pain associated with antitumoral treatment. Full article

(This article belongs to the Special Issue The Endocannabinoid System: New Insights into Its Role in Health and Disease)

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13 pages, 2714 KiB

Open AccessArticle

Activity of FAAH-Inhibitor JZP327A in an Experimental Rat Model of Migraine

by Rosaria Greco, Miriam Francavilla, Chiara Demartini, Anna Maria Zanaboni, Sara Facchetti, Michela Palmisani, Valentina Franco and Cristina Tassorelli

Int. J. Mol. Sci. 2023, 24(12), 10102; https://doi.org/10.3390/ijms241210102 - 14 Jun 2023

Cited by 3 | Viewed by 1517

Abstract

Increased anandamide levels via fatty acid amide hydrolase (FAAH) inhibition can decrease the pronociceptive responses and inflammatory mediators in animal models of migraine. Here, we profile the pharmacological activity of the FAAH inhibitor JZP327A, a chiral 1,3,4-oxadiazol-2(3H)-one compound, in the mediation of spontaneous and nocifensive behaviour in the animal models of migraine based on nitroglycerin (NTG) administration. JZP327A (0.5 mg/kg, i.p.) or vehicle was administered to male rats 3 h after NTG (10 mg/kg, i.p.) or NTG vehicle injection. The rats were then exposed to the open field test and an orofacial formalin test 1 h later. The levels of endocannabinoids and lipid-related substances, and the expression of pain and inflammatory mediators were evaluated in cranial tissues and serum. The findings show that JZP327A did not affect NTG-induced changes in the spontaneous behaviour of rats, while it inhibited NTG-induced hyperalgesia at the orofacial formalin test. Furthermore, JZP327A dramatically decreased the gene expression of calcitonin gene-related peptide (CGRP), tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) in the trigeminal ganglia and medulla-pons, while it did not change endocannabinoids or lipids levels nor CGRP serum levels in the same tissues. These data suggest an anti-hyperalgesic role for JZP327A in the NTG model, which is mediated by the inhibition of the inflammatory cascade of events. This activity does not seem mediated by a change in the levels of endocannabinoids and lipid amides. Full article

(This article belongs to the Special Issue The Endocannabinoid System: New Insights into Its Role in Health and Disease)

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16 pages, 1240 KiB

Open AccessArticle

Antipsychotic Medication Influences the Discriminative Value of Acylethanolamides as Biomarkers of Substance Use Disorder

by Jesús Herrera-Imbroda, María Flores-López, Nerea Requena-Ocaña, Pedro Araos, Jessica Ropero, Nuria García-Marchena, Antonio Bordallo, Juan Suarez, Francisco Javier Pavón-Morón, Antonia Serrano, Fermín Mayoral and Fernando Rodríguez de Fonseca

Int. J. Mol. Sci. 2023, 24(11), 9371; https://doi.org/10.3390/ijms24119371 - 27 May 2023

Cited by 1 | Viewed by 1837

Abstract

Plasma acylethanolamides (NAEs), including the endocannabinoid anandamide (AEA), have been proposed as circulating biomarkers of substance use disorders. However, the concentration of these lipid transmitters might be influenced by the use of drugs prescribed for either the treatment of addiction or the associated psychiatric co-morbidities such as psychosis. As an example, neuroleptics, used for attenuation of psychotic symptoms and sedation, might theoretically interfere with the monoamine-mediated production of NAEs, obstructing the interpretation of plasma NAEs as clinical biomarkers. To solve the lack of information on the impact of neuroleptics on the concentration of NAEs, we evaluated the concentrations of NAEs in a control group and compared them to those present in (a) substance use disorders (SUD) patients that are not prescribed with neuroleptics, and (b) SUD patients (both alcohol use disorder and cocaine use disorder patients) using neuroleptics. The results demonstrate that SUD patients exhibited greater concentrations of NAEs than the control population, affecting all species with the exception of stearoylethanolamide (SEA) and palmitoleoylethanolamide (POEA). Neuroleptic treatment enhanced the concentrations of NAEs, especially those of AEA, linoleoylethanolamide (LEA), and oleoylethanolamide (OEA). This effect of neuroleptic treatment was observed independently of the drug addiction that motivated the demand for treatment (either alcohol or cocaine). This study remarks the need to control the current use of psychotropic medication as a potential confounding variable when considering the use of NAEs as biomarkers in SUD. Full article

(This article belongs to the Special Issue The Endocannabinoid System: New Insights into Its Role in Health and Disease)

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19 pages, 2422 KiB

Open AccessArticle

Novel GPR18 Ligands in Rodent Pharmacological Tests: Effects on Mood, Pain, and Eating Disorders

by Małgorzata Frankowska, Karolina Wydra, Agata Suder, Magdalena Zaniewska, Dawid Gawliński, Joanna Miszkiel, Anna Furgała-Wojas, Kinga Sałat, Małgorzata Filip, Christa E. Müller, Katarzyna Kieć-Kononowicz and Magdalena Kotańska

Int. J. Mol. Sci. 2023, 24(10), 9046; https://doi.org/10.3390/ijms24109046 - 20 May 2023

Cited by 2 | Viewed by 2152

Abstract

The lack of selective pharmacological tools has limited the full unraveling of G protein-coupled receptor 18 (GPR18) functions. The present study was aimed at discovering the activities of three novel preferential or selective GPR18 ligands, one agonist (PSB-KK-1415) and two antagonists (PSB-CB-5 and PSB-CB-27). We investigated these ligands in several screening tests, considering the relationship between GPR18 and the cannabinoid (CB) receptor system, and the control of endoCB signaling over emotions, food intake, pain sensation, and thermoregulation. We also assessed whether the novel compounds could modulate the subjective effects evoked by Δ⁹-tetrahydrocannabinol (THC). Male mice or rats were pretreated with the GPR18 ligands, and locomotor activity, depression- and anxiety-like symptoms, pain threshold, core temperature, food intake, and THC-vehicle discrimination were measured. Our screening analyses indicated that GPR18 activation partly results in effects that are similar to those of CB receptor activation, considering the impact on emotional behavior, food intake, and pain activity. Thus, the orphan GPR18 may provide a novel therapeutic target for mood, pain, and/or eating disorders, and further investigation is warranted to better discern its function. Full article

(This article belongs to the Special Issue The Endocannabinoid System: New Insights into Its Role in Health and Disease)

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Review

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11 pages, 1182 KiB

Open AccessReview

Linking the Autotaxin-LPA Axis to Medicinal Cannabis and the Endocannabinoid System

by Mathias C. Eymery, Ahcène Boumendjel, Andrew A. McCarthy and Jens Hausmann

Int. J. Mol. Sci. 2024, 25(6), 3212; https://doi.org/10.3390/ijms25063212 - 12 Mar 2024

Viewed by 1519

Abstract

Over the past few decades, many current uses for cannabinoids have been described, ranging from controlling epilepsy to neuropathic pain and anxiety treatment. Medicines containing cannabinoids have been approved by both the FDA and the EMA for the control of specific diseases for which there are few alternatives. However, the molecular-level mechanism of action of cannabinoids is still poorly understood. Recently, cannabinoids have been shown to interact with autotaxin (ATX), a secreted lysophospholipase D enzyme responsible for catalyzing lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA), a pleiotropic growth factor that interacts with LPA receptors. In addition, a high-resolution structure of ATX in complex with THC has recently been published, accompanied by biochemical studies investigating this interaction. Due to their LPA-like structure, endocannabinoids have been shown to interact with ATX in a less potent manner. This finding opens new areas of research regarding cannabinoids and endocannabinoids, as it could establish the effect of these compounds at the molecular level, particularly in relation to inflammation, which cannot be explained by the interaction with CB1 and CB2 receptors alone. Further research is needed to elucidate the mechanism behind the interaction between cannabinoids and endocannabinoids in humans and to fully explore the therapeutic potential of such approaches. Full article

(This article belongs to the Special Issue The Endocannabinoid System: New Insights into Its Role in Health and Disease)

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13 pages, 21828 KiB

Open AccessReview

Role of the CB2 Cannabinoid Receptor in the Regulation of Food Intake: A Systematic Review

by Luis Miguel Rodríguez-Serrano and María Elena Chávez-Hernández

Int. J. Mol. Sci. 2023, 24(24), 17516; https://doi.org/10.3390/ijms242417516 - 15 Dec 2023

Cited by 2 | Viewed by 1669

Abstract

The CB2 cannabinoid receptor has been found in brain areas that are part of the reward system and has been shown to play a role in food intake regulation. Herein, we conducted a systematic review of studies assessing the role of the CB2 receptor in food intake regulation. Records from the PubMed, Scopus, and EBSCO databases were screened, resulting in 13 studies that were used in the present systematic review, following the PRISMA guidelines. A risk of bias assessment was carried out using the tool of the Systematic Review Center for Laboratory Animal Experimentation (SYRCLE). The studies analyzed used two main strategies: (1) the intraperitoneal or intracerebroventricular administration of a CB2 agonist/antagonist; and (2) depletion of CB2 receptors via knockout in mice. Both strategies are useful in identifying the role of the CB2 receptor in food intake in standard and palatable diets. The conclusions derived from animal models showed that CB2 receptors are necessary for modulating food intake and mediating energy balance. Full article

(This article belongs to the Special Issue The Endocannabinoid System: New Insights into Its Role in Health and Disease)

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19 pages, 356 KiB

Open AccessReview

Zebrafish as an Animal Model in Cannabinoid Research

by Joanna Lachowicz, Aleksandra Szopa, Katarzyna Ignatiuk, Katarzyna Świąder and Anna Serefko

Int. J. Mol. Sci. 2023, 24(13), 10455; https://doi.org/10.3390/ijms241310455 - 21 Jun 2023

Cited by 4 | Viewed by 2511

Abstract

Cannabinoids are active substances present in plants of the Cannabis genus. Both the Food and Drug Administration (FDA) and European Medicines Agency (EMA) have approved several medicinal products containing natural cannabinoids or their synthetic derivatives for the treatment of drug-resistant epilepsy, nausea and vomiting associated with cancer chemotherapy, anorexia in AIDS patients, and the alleviation of symptoms in patients with multiple sclerosis. In fact, cannabinoids constitute a broad group of molecules with a possible therapeutic potential that could be used in the management of much more diseases than mentioned above; therefore, multiple preclinical and clinical studies on cannabinoids have been carried out in recent years. Danio rerio (zebrafish) is an animal model that has gained more attention lately due to its numerous advantages, including easy and fast reproduction, the significant similarity of the zebrafish genome to the human one, simplicity of genetic modifications, and body transparency during the early stages of development. A number of studies have confirmed the usefulness of this model in toxicological research, experiments related to the impact of early life exposure to xenobiotics, modeling various diseases, and screening tests to detect active substances with promising biological activity. The present paper focuses on the current knowledge of the endocannabinoid system in the zebrafish model, and it summarizes the results and observations from studies investigating the pharmacological effects of natural and synthetic cannabinoids that were carried out in Danio rerio. The presented data support the notion that the zebrafish model is a suitable animal model for use in cannabinoid research. Full article

(This article belongs to the Special Issue The Endocannabinoid System: New Insights into Its Role in Health and Disease)

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