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Molecular Advances on Cannabinoid and Endocannabinoid Research

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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 (31 January 2023) | Viewed by 26238

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Prof. Dr. Rosaria Meccariello

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Department of Movement and Wellness Sciences, Parthenope University of Naples, Via Medina 40, I-80133 Naples, Italy
Interests: endocannabinoid system; endocannabinoids–GnRH–steroids crosstalk; kisspeptins; reproduction; HPG axis; spermatogenesis; spermatozoa; endocrine disruptors; epigenetics
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Dear Colleagues,

Marijuana has been used for recreational and medical use since ancient times. In 1964 Raphael Mechoulam and Yechiel Gaoni, two pioneers of cannabinoid research, first reported the structure of Δ9-tetrahydrocannabinol (Δ9-THC), the main psychotropic phytocannabinoid in Cannabis L. sativa, revealing the pharmacological and therapeutic potential of plant-derived cannabinoids. Studies on Δ9-THC were pivotal to the discovery of cannabinoid receptors and endogenous cannabinoids (i.e., endocannabinoids), revealing the existence of a conserved endogenous signaling system that is involved in many biological functions. Endocannabinoids and endocannabinoid-like substances, canonical and non-canonical cannabinoid receptors, biosynthetic/hydrolyzing enzymes and transporters have been discovered in biological systems, and the endocannabinoid system (ECS) has a recognized role in synaptic plasticity, learning and memory, neuroinflammation, pain control, stress response, mood and behavior, energy homeostasis, food intake and metabolism, reproduction, fertility and pregnancy, immune response, cardiac functions, cancer progression, etc. Furthermore, the isolation of several psychotropic and non-psychotropic plant-derived cannabinoids in parallel to the development of agonists/antagonists/inhibitors of the ECS has gathered attention with regard to the development of cannabinoid-based therapies. Recreational/medical use of cannabinoids is gaining traction and legitimacy in many countries, but the large distribution of cannabinoid receptors in biological systems and the pleiotropic activity of the ECS require further investigation.

This Special Issue aims to update knowledge of the molecular advances in cannabinoid and endocannabinoid research in physiological and pathological conditions, with focus on molecular and epigenetic regulatory mechanisms and possible therapeutic exploitation. Experimental studies in in vitro and in vivo models, review articles and clinical studies are all welcome.

Prof. Dr. Rosaria Meccariello
Guest Editor

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Molecular Advances on Cannabinoid and Endocannabinoid Research 2.0 in International Journal of Molecular Sciences (6 articles)

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Editorial

Jump to: Research, Review

5 pages, 227 KiB

Open AccessEditorial

Molecular Advances on Cannabinoid and Endocannabinoid Research

by Rosaria Meccariello

Int. J. Mol. Sci. 2023, 24(16), 12760; https://doi.org/10.3390/ijms241612760 - 14 Aug 2023

Cited by 2 | Viewed by 1277

Abstract

Since ancient times, cannabis has been used for recreational and medical purposes [...] Full article

(This article belongs to the Special Issue Molecular Advances on Cannabinoid and Endocannabinoid Research)

Research

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17 pages, 2920 KiB

Open AccessArticle

The Anti-Tumorigenic Role of Cannabinoid Receptor 2 in Colon Cancer: A Study in Mice and Humans

by Jennifer Ana Iden, Bitya Raphael-Mizrahi, Zamzam Awida, Aaron Naim, Dan Zyc, Tamar Liron, Melody Kasher, Gregory Livshits, Marilena Vered and Yankel Gabet

Int. J. Mol. Sci. 2023, 24(4), 4060; https://doi.org/10.3390/ijms24044060 - 17 Feb 2023

Cited by 5 | Viewed by 3196

Abstract

The endocannabinoid system, particularly cannabinoid receptor 2 (CB2 in mice and CNR2 in humans), has controversial pathophysiological implications in colon cancer. Here, we investigate the role of CB2 in potentiating the immune response in colon cancer in mice and determine the influence of CNR2 variants in humans. Comparing wild-type (WT) mice to CB2 knockout (CB2^−/−) mice, we performed a spontaneous cancer study in aging mice and subsequently used the AOM/DSS model of colitis-associated colorectal cancer and a model for hereditary colon cancer (Apc^Min/+). Additionally, we analyzed genomic data in a large human population to determine the relationship between CNR2 variants and colon cancer incidence. Aging CB2^−/− mice exhibited a higher incidence of spontaneous precancerous lesions in the colon compared to WT controls. The AOM/DSS-treated CB2^−/− and Apc^Min/+CB2^−/− mice experienced aggravated tumorigenesis and enhanced splenic populations of immunosuppressive myeloid-derived suppressor cells along with abated anti-tumor CD8+ T cells. Importantly, corroborative genomic data reveal a significant association between non-synonymous variants of CNR2 and the incidence of colon cancer in humans. Taken together, the results suggest that endogenous CB2 activation suppresses colon tumorigenesis by shifting the balance towards anti-tumor immune cells in mice and thus portray the prognostic value of CNR2 variants for colon cancer patients. Full article

(This article belongs to the Special Issue Molecular Advances on Cannabinoid and Endocannabinoid Research)

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13 pages, 1316 KiB

Open AccessArticle

CB2 Receptor as Emerging Anti-Inflammatory Target in Duchenne Muscular Dystrophy

by Maura Argenziano, Vincenzo Pota, Alessandra Di Paola, Chiara Tortora, Maria Maddalena Marrapodi, Giulia Giliberti, Domenico Roberti, Maria Caterina Pace and Francesca Rossi

Int. J. Mol. Sci. 2023, 24(4), 3345; https://doi.org/10.3390/ijms24043345 - 7 Feb 2023

Cited by 3 | Viewed by 2482

Abstract

Duchenne Muscular Dystrophy (DMD) is a very severe X-linked dystrophinopathy. It is due to a mutation in the DMD gene and causes muscular degeneration in conjunction with several secondary co-morbidities, such cardiomyopathy and respiratory failure. DMD is characterized by a chronic inflammatory state, and corticosteroids represent the main therapy for these patients. To contradict drug-related side effects, there is need for novel and more safe therapeutic strategies. Macrophages are immune cells stringently involved in both physiological and pathological inflammatory processes. They express the CB2 receptor, one of the main elements of the endocannabinoid system, and have been proposed as an anti-inflammatory target in several inflammatory and immune diseases. We observed a lower expression of the CB2 receptor in DMD-associated macrophages, hypothesizing its involvement in the pathogenesis of this pathology. Therefore, we analyzed the effect of JWH-133, a CB2 receptor selective agonist, on DMD-associated primary macrophages. Our study describes the beneficial effect of JWH-133 in counteracting inflammation by inhibiting pro-inflammatory cytokines release and by directing macrophages’ phenotype toward the M2 anti-inflammatory one. Full article

(This article belongs to the Special Issue Molecular Advances on Cannabinoid and Endocannabinoid Research)

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24 pages, 4477 KiB

Open AccessArticle

Endocannabinoid 2-Arachidonoylglycerol Synthesis and Metabolism at Neuronal Nuclear Matrix Fractions Derived from Adult Rat Brain Cortex

by Xabier Aretxabala, Gontzal García del Caño, Sergio Barrondo, Maider López de Jesús, Imanol González-Burguera, Miquel Saumell-Esnaola, María Aranzazu Goicolea and Joan Sallés

Int. J. Mol. Sci. 2023, 24(4), 3165; https://doi.org/10.3390/ijms24043165 - 5 Feb 2023

Cited by 3 | Viewed by 2231

Abstract

In this report, we describe the kinetics characteristics of the diacylglycerol lipase-α (DGLα) located at the nuclear matrix of nuclei derived from adult cortical neurons. Thus, using high-resolution fluorescence microscopy, classical biochemical subcellular fractionation, and Western blot techniques, we demonstrate that the DGLα enzyme is located in the matrix of neuronal nuclei. Furthermore, by quantifying the 2-arachidonoylglycerol (2-AG) level by liquid chromatography and mass spectrometry when 1-stearoyl-2-arachidonoyl-sn-glycerol (SAG) was exogenously added as substrate, we describe the presence of a mechanism for 2-AG production through DGLα dependent biosynthesis with an apparent K_m (K_m^app) of 180 µM and a V_max of 1.3 pmol min⁻¹ µg⁻¹ protein. We also examined the presence of enzymes with hydrolytic and oxygenase activities that are able to use 2-AG as substrate, and described the localization and compartmentalization of the major 2-AG degradation enzymes, namely monoacylglycerol lipase (MGL), fatty acid amide hydrolase (FAAH), α/β-hydrolase domain 12 protein (ABHD12) and cyclooxygenase-2 (COX2). Of these, only ABHD12 exhibited the same distribution with respect to chromatin, lamin B1, SC-35 and NeuN as that described for DGLα. When 2-AG was exogenously added, we observed the production of arachidonic acid (AA), which was prevented by inhibitors (but not specific MGL or ABHD6 inhibitors) of the ABHD family. Overall, our results expand knowledge about the subcellular distribution of neuronal DGLα, and provide biochemical and morphological evidence to ensure that 2-AG is produced in the neuronal nuclear matrix. Thus, this work paves the way for proposing a working hypothesis about the role of 2-AG produced in neuronal nuclei. Full article

(This article belongs to the Special Issue Molecular Advances on Cannabinoid and Endocannabinoid Research)

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9 pages, 2435 KiB

Open AccessCommunication

Cannabinoid Biosynthesis Using Noncanonical Cannabinoid Synthases

by Maybelle Kho Go, Tingting Zhu, Kevin Jie Han Lim, Yossa Dwi Hartono, Bo Xue, Hao Fan and Wen Shan Yew

Int. J. Mol. Sci. 2023, 24(2), 1259; https://doi.org/10.3390/ijms24021259 - 9 Jan 2023

Cited by 6 | Viewed by 2690

Abstract

We report enzymes from the berberine bridge enzyme (BBE) superfamily that catalyze the oxidative cyclization of the monoterpene moiety in cannabigerolic acid (CBGA) to form cannabielsoin (CBE). The enzymes are from a variety of organisms and are previously uncharacterized. Out of 232 homologues chosen from the enzyme superfamily, four orthologues were shown to accept CBGA as a substrate and catalyze the biosynthesis of CBE. The four enzymes discovered in this study were recombinantly expressed and purified in Pichia pastoris. These enzymes are the first report of heterologous expression of BBEs that did not originate from the Cannabis plant that catalyze the production of cannabinoids using CBGA as substrate. This study details a new avenue for discovering and producing natural and unnatural cannabinoids. Full article

(This article belongs to the Special Issue Molecular Advances on Cannabinoid and Endocannabinoid Research)

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12 pages, 1721 KiB

Open AccessArticle

Synaptoproteomic Analysis of the Prefrontal Cortex Reveals Spatio-Temporal Changes in SYNGAP1 Following Cannabinoid Exposure in Rat Adolescence

by Johanna S. Qvist, Maria Scherma, Nitya Jayaram-Lindström, Walter Fratta, Denise B. Kandel, Eric R. Kandel, Paola Fadda and Philippe A. Melas

Int. J. Mol. Sci. 2023, 24(1), 698; https://doi.org/10.3390/ijms24010698 - 31 Dec 2022

Cited by 3 | Viewed by 3148

Abstract

The regular use of cannabis during adolescence has been associated with a number of negative life outcomes, including psychopathology and cognitive impairments. However, the exact molecular mechanisms that underlie these outcomes are just beginning to be understood. Moreover, very little is known about the spatio-temporal molecular changes that occur following cannabinoid exposure in adolescence. To understand these changes, we exposed mid-adolescent male rats to a synthetic cannabinoid (WIN 55,212-2 mesylate; WIN) and, following drug abstinence through late adolescence, we subjected the synaptosomal fractions of the prefrontal cortex (PFC) to proteomic analyses. A total of N = 487 differentially expressed proteins were found in WIN-exposed animals compared to controls. Gene ontology analyses revealed enrichment of terms related to the gamma-aminobutyric acid (GABA)-ergic neurotransmitter system. Among the top differentially expressed proteins was the synaptic Ras GTPase-activating protein 1 (SYNGAP1). Using Western blotting experiments, we found that the WIN-induced upregulation of SYNGAP1 was spatio-temporal in nature, arising only in the synaptosomal fractions (not in the cytosol) and only following prolonged drug abstinence (not on abstinence day 1). Moreover, the SYNGAP1 changes were found to be specific to WIN-exposure in adolescence and not adulthood. Adolescent animals exposed to a natural cannabinoid (Δ⁹-tetrahydrocannabinol; THC) were also found to have increased levels of SYNGAP1 in the PFC. THC exposure also led to a pronounced upregulation of SYNGAP1 in the amygdala, but without any changes in the dorsal striatum, hippocampus, or nucleus accumbens. To our knowledge, this is the first study to uncover a link between cannabinoid exposure and changes in SYNGAP1 that are spatio-temporal and developmental in nature. Future studies are needed to investigate the putative role of SYNGAP1 in the negative behavioral consequences of cannabis use in adolescence. Full article

(This article belongs to the Special Issue Molecular Advances on Cannabinoid and Endocannabinoid Research)

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15 pages, 85276 KiB

Open AccessArticle

Hippocampal Deletion of CB1 Receptor Impairs Social Memory and Leads to Age-Related Changes in the Hippocampus of Adult Mice

by Michela Palmisano, Alessandra Gargano, Bolanle Fatimat Olabiyi, Beat Lutz and Andras Bilkei-Gorzo

Int. J. Mol. Sci. 2023, 24(1), 26; https://doi.org/10.3390/ijms24010026 - 20 Dec 2022

Cited by 8 | Viewed by 3173

Abstract

Endocannabinoid system activity declines with age in the hippocampus, along with the density of the cannabinoid receptor type-1 (CB1). This process might contribute to brain ageing, as previous studies showed that the constitutive deletion of the CB1 receptor in mice leads to early onset of memory deficits and histological signs of ageing in the hippocampus including enhanced pro-inflammatory glial activity and reduced neurogenesis. Here we asked whether the CB1 receptor exerts its activity locally, directly influencing hippocampal ageing or indirectly, accelerating systemic ageing. Thus, we deleted the CB1 receptor site-specifically in the hippocampus of 2-month-old CB1^flox/flox mice using stereotaxic injections of rAAV-Cre-Venus viruses and assessed their social recognition memory four months later. Mice with hippocampus-specific deletion of the CB1 receptor displayed a memory impairment, similarly as observed in constitutive knockouts at the same age. We next analysed neuroinflammatory changes in the hippocampus, neuronal density and cell proliferation. Site-specific mutant mice had enhanced glial cell activity, up-regulated levels of TNFα in the hippocampus and decreased cell proliferation, specifically in the subgranular zone of the dentate gyrus. Our data indicate that a local activity of the CB1 receptor in the hippocampus is required to maintain neurogenesis and to prevent neuroinflammation and cognitive decline. Full article

(This article belongs to the Special Issue Molecular Advances on Cannabinoid and Endocannabinoid Research)

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12 pages, 858 KiB

Open AccessArticle

Salivary Endocannabinoid Profiles in Chronic Orofacial Pain and Headache Disorders: An Observational Study Using a Novel Tool for Diagnosis and Management

by Shimrit Heiliczer, Asaf Wilensky, Tal Gaver, Olga Georgiev, Sharleen Hamad, Alina Nemirovski, Rivka Hadar, Yair Sharav, Doron J. Aframian, Joseph Tam and Yaron Haviv

Int. J. Mol. Sci. 2022, 23(21), 13017; https://doi.org/10.3390/ijms232113017 - 27 Oct 2022

Cited by 10 | Viewed by 2430

Abstract

The endocannabinoid system is involved in physiological and pathological processes, including pain generation, modulation, and sensation. Its role in certain types of chronic orofacial pain (OFP) has not been thoroughly examined. By exploring the profiles of specific salivary endocannabinoids (eCBs) in individuals with different types of OFP, we evaluated their use as biomarkers and the influence of clinical parameters and pain characteristics on eCB levels. The salivary levels of anandamide (AEA), 2-arachidonoyl glycerol (2-AG), and their endogenous breakdown product arachidonic acid (AA), as well as the eCB-like molecules N-palmitoylethanolamide (PEA) and N-oleoylethanolamide (OEA), were assessed in 83 OFP patients and 43 pain-free controls using liquid chromatography/tandem mass spectrometry. Patients were grouped by diagnosis: post-traumatic neuropathy (PTN), trigeminal neuralgia (TN), temporomandibular disorder (TMD), migraine, tension-type headache (TTH), and burning mouth syndrome (BMS). Correlation analyses between a specific diagnosis, pain characteristics, and eCB levels were conducted. Significantly lower levels of 2-AG were found in the TN and TTH groups, while significantly lower PEA levels were found in the migraine group. BMS was the only group with elevated eCBs (AEA) versus the control. Significant correlations were found between levels of specific eCBs and gender, health-related quality of life (HRQoL), BMI, pain duration, and sleep awakenings. In conclusion, salivary samples exhibited signature eCBs profiles for major OFP disorders, especially migraine, TTH, TN, and BMS. This finding may pave the way for using salivary eCBs biomarkers for more accurate diagnoses and management of chronic OFP patients. Full article

(This article belongs to the Special Issue Molecular Advances on Cannabinoid and Endocannabinoid Research)

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Review

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25 pages, 1067 KiB

Open AccessReview

The Role of Physical Exercise in Opioid Substitution Therapy: Mechanisms of Sequential Effects

by Alexandros Psarianos, Costas Chryssanthopoulos, Thomas Paparrigopoulos and Anastassios Philippou

Int. J. Mol. Sci. 2023, 24(5), 4763; https://doi.org/10.3390/ijms24054763 - 1 Mar 2023

Cited by 9 | Viewed by 4249

Abstract

It is generally accepted that chronic opioid use is associated with structural and functional changes in the human brain that lead to an enhancement of impulsive behavior for immediate satisfaction. Interestingly, in recent years, physical exercise interventions have been used as an adjunctive treatment for patients with opioid use disorders (OUDs). Indeed, exercise has positive effects on both the biological and psychosocial basis of addiction, modifying neural circuits such as the reward, inhibition, and stress systems, and thus causing behavioral changes. This review focuses on the possible mechanisms that contribute to the beneficial effects of exercise on the treatment of OUDs, with emphasis placed on the description of a sequential consolidation of these mechanisms. Exercise is thought to act initially as a factor of internal activation and self-regulation and eventually as a factor of commitment. This approach suggests a sequential (temporal) consolidation of the functions of exercise in favor of gradual disengagement from addiction. Particularly, the sequence in which the exercise-induced mechanisms are consolidated follows the pattern of internal activation—self-regulation—commitment, eventually resulting in stimulation of the endocannabinoid and endogenous opioid systems. Additionally, this is accompanied by modification of molecular and behavioral aspects of opioid addiction. Overall, the neurobiological actions of exercise in combination with certain psychological mechanisms appear to promote its beneficial effects. Given the positive effects of exercise on both physical and mental health, exercise prescription is recommended as a complement to conventional therapy for patients on opioid maintenance treatment. Full article

(This article belongs to the Special Issue Molecular Advances on Cannabinoid and Endocannabinoid Research)

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