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Endocannabinoid Receptors in Human 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 Pharmacology".

Deadline for manuscript submissions: closed (15 March 2024) | Viewed by 14193

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Special Issue Editors

Dr. Cristoforo Silvestri

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Guest Editor

Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec (CRIUCPQ), Université Laval, Quebec City, QC G1V 0A6, Canada
Interests: cannabinoids/endocannabinoids and related bioactive lipids; obesity; metabolism; adipogenesis; lipid and glucose metabolism
Special Issues, Collections and Topics in MDPI journals

Dr. Robert B. Laprairie

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Guest Editor

College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada
Interests: cannabinoids/endocannabinoids; epilepsy; pain; molecular pharmacology; G protein-coupled receptors

Special Issue Information

Dear Colleagues,

While endocannabinoids (N-arachidonoylethanolamine; AEA and 2-arachidonoyl glycerol; 2-AG) were initially found to activate the cannabinoid receptors CB1 and CB2, it is now understood that they bind to, and modulate the activity of, several different classes of receptors, including G protein-coupled receptors, transient receptor potential channels and nuclear receptors. Additionally, AEA and 2-AG are now viewed as the canonical ligands of a broader family of bioactive lipids that constitute the endocannabinoidome, which includes a plethora of N-acylamines and 2-monoacyl glycerols. These ligands, despite their structural similarities to AEA and 2-AG, often display distinct (and sometimes opposing) receptor activity profiles to endocannabinoids. Research into this growing family, their receptor activity profiles, pharmacology and involvement in the regulation of various physiological and pathological processes is still in its infancy. However, it is becoming clear that these bioactive lipids play important roles that are relevant to several disease states. This Special Issue aims to highlight recent advances in our understanding of the function of endocannabinoid-related receptors in physiological processes and diseases at CB1, CB2, and beyond to the many other receptors that comprise the wide endogenous cannabinoid system.

Suitable topics include, but are not limited to: ligand–receptor interactions and modeling, signal transduction, physiological activity, altered activity within disease states.

Dr. Cristoforo Silvestri
Dr. Robert B. Laprairie
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

endocannaibnoid
cannabinoid
receptors
GPCR
TRP channels
nuclear receptors
PPARS
physiology
pathophysiology

Published Papers (7 papers)

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Research

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15 pages, 4693 KiB

Open AccessArticle

URB447 Is Neuroprotective in Both Male and Female Rats after Neonatal Hypoxia–Ischemia and Enhances Neurogenesis in Females

by Gorane Beldarrain, Marc Chillida, Enrique Hilario, Borja Herrero de la Parte, Antonia Álvarez and Daniel Alonso-Alconada

Int. J. Mol. Sci. 2024, 25(3), 1607; https://doi.org/10.3390/ijms25031607 - 28 Jan 2024

Viewed by 691

Abstract

The need for new and effective treatments for neonates suffering from hypoxia–ischemia is urgent, as the only implemented therapy in clinics is therapeutic hypothermia, only effective in 50% of cases. Cannabinoids may modulate neuronal development and brain plasticity, but further investigation is needed to better describe their implication as a neurorestorative therapy after neonatal HI. The cannabinoid URB447, a CB1 antagonist/CB2 agonist, has previously been shown to reduce brain injury after HI, but it is not clear whether sex may affect its neuroprotective and/or neurorestorative effect. Here, URB447 strongly reduced brain infarct, improved neuropathological score, and augmented proliferative capacity and neurogenic response in the damaged hemisphere. When analyzing these effects by sex, URB447 ameliorated brain damage in both males and females, and enhanced cell proliferation and the number of neuroblasts only in females, thus suggesting a neuroprotective effect in males and a double neuroprotective/neurorestorative effect in females. Full article

(This article belongs to the Special Issue Endocannabinoid Receptors in Human Health and Disease)

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16 pages, 5392 KiB

Open AccessArticle

Renal Endocannabinoid Dysregulation in Obesity-Induced Chronic Kidney Disease in Humans

by Anna Permyakova, Ariel Rothner, Sarah Knapp, Alina Nemirovski, Danny Ben-Zvi and Joseph Tam

Int. J. Mol. Sci. 2023, 24(17), 13636; https://doi.org/10.3390/ijms241713636 - 04 Sep 2023

Viewed by 1130

Abstract

The endocannabinoid system (ECS) regulates various physiological processes, including energy homeostasis and kidney function. ECS upregulation in obese animals and humans suggests a potential link to obesity-induced chronic kidney disease (CKD). However, obesity-induced ECS changes in the kidney are mainly studied in rodents, leaving the impact on obese humans unknown. In this study, a total of 21 lean and obese males (38–71 years) underwent a kidney biopsy. Biochemical analysis, histology, and endocannabinoid (eCB) assessment were performed on kidney tissue and blood samples. Correlations between different parameters were evaluated using a comprehensive matrix. The obese group exhibited kidney damage, reflected in morphological changes, and elevated kidney injury and fibrotic markers. While serum eCB levels were similar between the lean and obese groups, kidney eCB analysis revealed higher anandamide in obese patients. Obese individuals also exhibited reduced expression of cannabinoid-1 receptor (CB1R) in the kidney, along with increased activity of eCB synthesizing and degrading enzymes. Correlation analysis highlighted connections between renal eCBs, kidney injury markers, obesity, and related pathologies. In summary, this study investigates obesity’s impact on renal eCB “tone” in humans, providing insights into the ECS’s role in obesity-induced CKD. Our findings enhance the understanding of the intricate interplay among obesity, the ECS, and kidney function. Full article

(This article belongs to the Special Issue Endocannabinoid Receptors in Human Health and Disease)

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14 pages, 2268 KiB

Open AccessArticle

New Insights into Bitopic Orthosteric/Allosteric Ligands of Cannabinoid Receptor Type 2

by Rebecca Ferrisi, Beatrice Polini, Caterina Ricardi, Francesca Gado, Kawthar A. Mohamed, Giovanna Baron, Salvatore Faiella, Giulio Poli, Simona Rapposelli, Giuseppe Saccomanni, Giancarlo Aldini, Grazia Chiellini, Robert B. Laprairie, Clementina Manera and Gabriella Ortore

Int. J. Mol. Sci. 2023, 24(3), 2135; https://doi.org/10.3390/ijms24032135 - 21 Jan 2023

Cited by 4 | Viewed by 1593

Abstract

Very recently, we have developed a new generation of ligands targeting the cannabinoid receptor type 2 (CB2R), namely JR compounds, which combine the pharmacophoric portion of the CB2R positive allosteric modulator (PAM), EC21a, with that of the CB2R selective orthosteric agonist LV62, both synthesized in our laboratories. The functional examination enabled us to identify JR14a, JR22a, and JR64a as the most promising compounds of the series. In the current study, we focused on the assessment of the bitopic (dualsteric) nature of these three compounds. Experiments in cAMP assays highlighted that only JR22a behaves as a CB2R bitopic (dualsteric) ligand. In parallel, computational studies helped us to clarify the binding mode of these three compounds at CB2R, confirming the bitopic (dualsteric) nature of JR22a. Finally, the potential of JR22a to prevent neuroinflammation was investigated on a human microglial cell inflammatory model. Full article

(This article belongs to the Special Issue Endocannabinoid Receptors in Human Health and Disease)

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15 pages, 5727 KiB

Open AccessArticle

Preeclampsia Correlates with an Increase in Cannabinoid Receptor 1 Levels Leading to Macromolecular Alterations in Chorionic Villi of Term Placenta

by Marta Lombó, Christian Giommi, Michela Paolucci, Valentina Notarstefano, Nina Montik, Giovanni Delli Carpini, Andrea Ciavattini, Antonio Ragusa, Francesca Maradonna, Elisabetta Giorgini and Oliana Carnevali

Int. J. Mol. Sci. 2022, 23(21), 12931; https://doi.org/10.3390/ijms232112931 - 26 Oct 2022

Cited by 7 | Viewed by 1568

Abstract

Preeclampsia is a human pregnancy-specific disease characterized by abnormal placentation that usually presents with maternal hypertension and proteinuria. The main hallmark of preeclampsia, impaired trophoblast migration, and the subsequent disruption of uterine arteries remodeling lead to several molecular alterations in the placental compartments with those occurring in the chorionic villi being of the utmost importance. Given the essential role of the endocannabinoid system during preimplantation and trophoblast migration, we have combined the histological and hyperspectral imaging analyses to shed light on the involvement of two cannabinoid receptors in the macromolecular alterations related to preeclampsia. The results obtained by immunohistochemistry showed a significant increase in the protein levels of cannabinoid receptor 1 (CB1) in the preeclamptic chorionic villi. However, no changes were reported regarding transient receptor potential vanilloid 1 (TRPV-1) levels either in the bulk placental samples or chorionic villi when comparing control and preeclamptic patients. Histological analysis and Fourier-transform infrared spectroscopy (FTIRI) showed an increase in collagen deposition together with higher levels of lipid peroxidation and phosphorylated compounds in the pathological villi. Since CB1 enhancement has been described as promoting fibrosis and oxidative stress in several tissues, we proposed that the higher receptor abundance in preeclampsia could be triggering similar molecular effects in preeclamptic term placentas. Full article

(This article belongs to the Special Issue Endocannabinoid Receptors in Human Health and Disease)

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15 pages, 2118 KiB

Open AccessArticle

Anti-Inflammatory and Analgesic Properties of the Cannabis Terpene Myrcene in Rat Adjuvant Monoarthritis

by Jason J. McDougall and Meagan K. McKenna

Int. J. Mol. Sci. 2022, 23(14), 7891; https://doi.org/10.3390/ijms23147891 - 17 Jul 2022

Cited by 12 | Viewed by 5150

Abstract

Cannabis-based terpenes are believed to modulate physiological responses to disease and alter the efficacy of cannabinoids in the so-called “entourage effect”. The monoterpene myrcene can reduce nociception produced by noxious thermal and mechanical stimuli as well as reducing acute inflammation. The current study examined the role of myrcene and cannabidiol (CBD) in controlling chronic joint inflammation and pain. Chronic arthritis was induced in male Wistar rats by intra-articular injection of Freund’s complete adjuvant into the right knee. On days 7 and 21 after arthritis induction, joint pain (von Frey hair algesiometry), inflammation (intravital microscopy, laser speckle contrast analysis) and joint histopathology were assessed. Local application of myrcene (1 and 5 mg/kg s.c.) reduced joint pain and inflammation via a cannabinoid receptor mechanism. The combination of myrcene and CBD (200 μg) was not significantly different from myrcene alone. Repeated myrcene treatment had no effect on joint damage or inflammatory cytokine production. These data suggest that topical myrcene has the potential to reduce chronic arthritis pain and inflammation; however, it has no synergistic effect with CBD. Full article

(This article belongs to the Special Issue Endocannabinoid Receptors in Human Health and Disease)

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Review

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16 pages, 724 KiB

Open AccessReview

Cannabinoids, Endocannabinoids, and Synthetic Cannabimimetic Molecules in Neuromuscular Disorders

by Fabio Arturo Iannotti

Int. J. Mol. Sci. 2024, 25(1), 238; https://doi.org/10.3390/ijms25010238 - 23 Dec 2023

Cited by 2 | Viewed by 1173

Abstract

Neuromuscular disorders (NMDs) encompass a large heterogeneous group of hereditary and acquired diseases primarily affecting motor neurons, peripheral nerves, and the skeletal muscle system. The symptoms of NMDs may vary depending on the specific condition, but some of the most common ones include muscle weakness, pain, paresthesias, and hyporeflexia, as well as difficulties with swallowing and breathing. NMDs are currently untreatable. Therapeutic options include symptomatic and experimental medications aimed at delaying and alleviating symptoms, in some cases supplemented by surgical and physical interventions. To address this unmet medical need, ongoing research is being conducted on new treatments, including studies on medical cannabis, endocannabinoids, and related molecules with cannabimimetic properties. In this context, a significant amount of knowledge about the safety and effectiveness of cannabinoids in NMDs has been obtained from studies involving patients with multiple sclerosis experiencing pain and spasticity. In recent decades, numerous other preclinical and clinical studies have been conducted to determine the potential benefits of cannabinoids in NMDs. This review article aims to summarize and provide an unbiased point of view on the current knowledge about the use of cannabinoids, endocannabinoids, and synthetic analogs in NMDs, drawing from an array of compelling studies. Full article

(This article belongs to the Special Issue Endocannabinoid Receptors in Human Health and Disease)

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19 pages, 1892 KiB

Open AccessReview

Pharmacohistory of Cannabis Use—A New Possibility in Future Drug Development for Gastrointestinal Diseases

by Dinesh Thapa, Leon N. Warne and Marco Falasca

Int. J. Mol. Sci. 2023, 24(19), 14677; https://doi.org/10.3390/ijms241914677 - 28 Sep 2023

Viewed by 2085

Abstract

Humans have employed cannabis for multiple uses including medicine, recreation, food, and fibre. The various components such as roots, flowers, seeds, and leaves have been utilized to alleviate pain, inflammation, anxiety, and gastrointestinal disorders like nausea, vomiting, diarrhoea, and inflammatory bowel diseases (IBDs). It has occupied a significant space in ethnomedicines across cultures and religions. Despite multi-dimensional uses, the global prohibition of cannabis by the USA through the introduction of the Marijuana Tax Act in 1937 led to prejudice about the perceived risks of cannabis, overshadowing its medicinal potential. Nevertheless, the discovery of tetrahydrocannabinol (THC), the primary psychoactive compound in cannabis, and the endocannabinoid system renewed scientific interest in understanding the role of cannabis in modulating different conditions, including gastrointestinal disorders. Preparations combining cannabidiol and THC have shown promise in mitigating gut symptoms through anti-inflammatory and motility-enhancing effects. This review revisits the ethnomedicinal use of cannabis in gastrointestinal diseases and emphasizes the need for further research to determine optimal dosages, formulations, and safety profiles of cannabis-based medicines. It also underscores the future potential of cannabinoid-based therapies by leveraging the role of the expanded endocannabinoid system, an endocannabinoidome, in the modulation of gastrointestinal ailments. Full article

(This article belongs to the Special Issue Endocannabinoid Receptors in Human Health and Disease)

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