Therapeutic Potential of Cannabinoid Receptors Type 1 and 2—Novel Insights for Enhancing the Chance of Clinical Success
A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".
Deadline for manuscript submissions: 20 October 2024 | Viewed by 13628
Special Issue Editor
Special Issue Information
Dear Colleagues,
The endocannabinoid system (ECS) is an important lipid signaling system ubiquitous to all vertebrates, and is involved in mediating key processes of central and peripheral diseases, including chronic pain, multiple sclerosis, Alzheimer’s disease, obesity, diabetes, and kidney diseases, all of which cause a significant health and socioeconomic burden. The ECS’s key elements include lipid signaling molecules termed ‘endocannabinoids’, their respective receptors, biosynthetic as well as hydrolytic enzymes, and transporters. In particular, cannabinoid receptor type 1 (CB1R) and type 2 (CB2R) hold great therapeutic potential. While Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the most prominent plant-derived cannabinoids, numerous further phytocannabinoids and synthetic ligands targeting CB1R and CB2R have been identified and generated within recent decades. Although multiple of these ligands have been evaluated in humans, clinical success is still limited. Recent developments, including the generation of CB1R and CB2R 3D structures, the identification of allosteric binding pockets, the synthesis of organ-system-selective ligands, a better understanding of biased signaling, and mechanisms of action, could facilitate the design of next-generation drugs, thus, unlocking the receptors’ full therapeutic potential. In this Special Issue of Pharmaceuticals, authors are invited to submit original and review articles covering preclinical and clinical findings enhancing the chance of clinical success of CB1R and CB2R therapies. The proposed topics can cover novel ligands, chemical probes, and mechanistic, translational and biomarker in vitro and in vivo studies. We look forward to your valuable contributions.
Dr. Uwe M. Grether
Guest Editor
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Keywords
- endocannabinoid system (ECS)
- cannabinoid receptor type 1 (CB1R)
- cannabinoid receptor type 2 (CB2R)
- cannabinoids
- ligand
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Planned Papers
The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.
1. Title: 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.
Prof. Raquel Abalo Delgado; etc.
Abstract:
5-fluorouracil is an antineoplastic drug frequently used to treat colorectal cancer, but it causes diarrhea and mucositis as relevant side effects. In murine models, it produces enteric neuropathy and gastrointestinal dysmotility. Our aim is 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- fluorouracil in rats. Adult male Wistar rats receiving a dose of 5-fluorouracil (150 mg/kg, ip) or saline were monitored for 15 days. Gastrointestinal function (motility, colonic sensitivity), gut wall structure and tactile sensitivity were evaluated throughout the study. WIN 55,212-2 was administered to evaluate its alleviating effect on somatic (50-100 µg ipl; 1 mg/kg, ip) and visceral (1 mg/kg, ip) hypersensitivity. The cannabinoid tetrad was used to assess the central effects of WIN 55,212-2 (1 mg/kg, ip). 5-fluorouracil acutely decreased food intake and body weight gain and produced mucositis and thermal hyperalgesia, but these effects were reduced afterwards, and were not accompanied by diarrhea. Tactile mechanical allodynia (a sign of somatic peripheral neuropathy) was evident and alleviated by WIN 55,212-2, regardless of the route or dose administered, without causing alterations in the cannabinoid tetrad. Finally, 5-fluorouracil tended to increase the sensitivity to intracolonic mechanical stimulation, whereas WIN 55,212-2 reduced the abdominal contractions induced by increasing intracolonic pressure in both control and 5-fluorouracil-treated animals. The activation of the cannabinoid system at non-psychotropic doses may be useful to alleviate neuropathic and visceral pain associated with antitumoral drug treatments.
2. Title: Potential Drug Interactions with Cannabinoids in selected Chronic Diseases: Epilepsy, Autism Spectrum Disorders, Oncology, Multiple Sclerosis and Pain
Maria G. Campos1,2*, Maria China1, Mariana Claudio1, Miguel Capinha1, Rita Torres1, Simão Oliveira1, and Ana Fortuna 1,3,4*
Abstract: The clinical practice implies a research translation that will help the use of scientific data and therapeutic evidence for patient benefits. This review critically summarizes the potential impact of cannabinoids in concomitance with other drugs in chronic diseases that seem to be ameliorated with cannabinoids: Epilepsy, Autism Spectrum Disorders (ASD), Oncology, Multiple Sclerosis, and Chronic Pain. The potential interactions are able to change the predicted outcomes of therapeutic protocols and need to be evaluated. Some of the effects would be additive or synergistic, antagonistic, but can also enroll changes in absorption, distribution, metabolism, particularly via cytochrome P450 (CYP) isoenzymes (e.g CYP2C9 and CYP3A4) and excretion. For instance, the combination of cannabis-derived compounds and the antifungal drug ketoconazole, a CYP3A4 inhibitor, was reported to increase plasma concentration of Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Opposable, rifampicin, a CYP3A4 inducer, stands out for the approximately 20-40% reduction in plasma THC levels and 50% to 60% for CBD. Other CYP3A4 inhibitors and inducers are likely to have a similar effect on plasma concentrations if co-administered. Indeed, pharmacokinetic interactions have been also reported with antiepileptic drugs. Moreover, pharmacodynamic interactions between cannabinoids and drugs with sympathomimetic effects (eg tachycardia, hypertension), central nervous system depressants (eg drowsiness, ataxia), and anticholinergics (eg tachycardia and drowsiness) should also be expected. Even though pending further studies, there is currently clinical evidence supporting drug interaction with cannabinoids, demanding doctors who evaluate the risk of drug combinations with cannabinoids. The tables herein provided were designed to facilitate the identification of biorelevant interactions that may compromise therapeutic efficacy and toxicity.