Tag Archives: cannabinoid receptors

Nabilone administration in refractory chronic diarrhea: a case series

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“Through the years, the endocannabinoid system has been recognized in the homeostatic mechanisms of the gut, as well as in the physiological control of intestinal motility and secretion. Accordingly, cannabinoids may be a promising therapy against several gastrointestinal conditions, such as abdominal pain and motility-related disorders. After three months of therapy, oral nabilone improved the health of nearly all patients, with visible improvements in reducing diarrheal symptoms and weight gain. These findings encourage the study of cannabinoids acting on CB1 receptors in chronic gastrointestinal disorders, especially in refractory chronic diarrhea, offering a chance for a substantial improvement in the quality of life of selected patients, with a reasonable safety profile.” https://bmcgastroenterol.biomedcentral.com/articles/10.1186/s12876-019-1024-y
“Nabilone is a drug used to treat severe nausea and vomiting. It is in a family of drugs called cannabinoids (eg. marijuana).” https://hivclinic.ca/main/drugs_fact_files/nabilone.pdf

Repetitive high-frequency transcranial magnetic stimulation reverses depressive-like behaviors and protein expression at hippocampal synapses in chronic unpredictable stress-treated rats by enhancing endocannabinoid signaling.

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Pharmacology Biochemistry and Behavior“The anti-depressant effect of repetitive transcranial magnetic stimulation (rTMS), a clinically-useful treatment for depression, is associated with changes to the endocannabinoid system (ECS).

However, it is currently unknown whether different frequencies of rTMS alter the ECS differently. To test this, rats exposed to chronic unpredictable stress (CUS) were treated with rTMS at two different frequencies (5 (high) or 1 Hz (low), 1.26 Tesla) for 7 consecutive days.

Interestingly, we found that only high-frequency rTMS ameliorated depressive-like behaviors and normalized the expression of hippocampal synaptic proteins in CUS-treated rats;

Collectively, our results suggest that high-frequency rTMS exerts its anti-depressant effect by up-regulating diacylglycerol lipase alpha (DAGLα) and cannabinoid type 1 receptor (CB1R).”

https://www.ncbi.nlm.nih.gov/pubmed/31229467

https://www.sciencedirect.com/science/article/pii/S0091305719301376?via%3Dihub

Transcranial magnetic stimulation.jpg

“Transcranial magnetic stimulation (TMS), also known as repetitive transcranial magnetic stimulation (rTMS), is a noninvasive form of brain stimulation in which a changing magnetic field is used to cause electric current at a specific area of the brain through electromagnetic induction. An electric pulse generator, or stimulator, is connected to a magnetic coil, which in turn is connected to the scalp. The stimulator generates a changing electric current within the coil which induces a magnetic field; this field then causes a second inductance of inverted electric charge within the brain itself. Adverse effects of TMS are rare, and include fainting and seizure. Other potential issues include discomfort, pain, hypomania, cognitive change, hearing loss, and inadvertent current induction in implanted devices such as pacemakers or defibrillators”  https://www.sciencedirect.com/science/article/pii/S0091305719301376?via%3Dihub

Omega-3 Endocannabinoid-Epoxides Are Novel Anti-inflammatory and Anti-Pain Lipid Metabolites (FS15-01-19).

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Issue Cover“Omega-3 fatty acid derived endocannabinoids are metabolized by cytochrome P450s to form bioactive endocannabinoid epoxides that are anti-inflammatory.

RESULTS:

Cannabinoids are found in marijuana and also are produced naturally in the body from ω-3 and ω-6 fatty acids. Exocannabinoids in marijuana, are known to be responsible for some of its euphoric effects, but they also exhibit anti-inflammatory benefits. Our study revealed a cascade of enzymatic reactions that convert ω-3 fatty acids into anti-inflammatory endocannabinoid epoxides that act through the same receptors in the body as marijuana (PNAS 2017).

Endocannabinoids are ligands for cannabinoidreceptor 1 and 2 (CB1 and CB2). CB1 receptor agonists exhibit psychotropic properties while CB2 receptor agonists have anti-inflammatory effects. Consequently, there is a strong interest in the discovery of CB2 selective agonists to mitigate inflammatory pathologies. The work details the discovery and characterization of naturally occurring ω-3-derived endocannabinoid epoxides that are formed via enzymatic oxidation of ω-3 endocannabinoids by cytochrome P450 epoxygenases. These dual functional ω-3 endocannabinoid epoxides exhibit preference towards binding to CB2 receptor and are anti-inflammatory and vasodilatory and reciprocally modulate platelet aggregation. Some of the other regioisomers of ω-3 endocannabinoid epoxides are partial agonists of CB1 and stop tumor cell metastasis (J. Med. Chem 2018). By virtue of their physiological properties, they are expected to play important roles in neuroinflammation and pain.

CONCLUSIONS:

This finding demonstrates how omega-3 fatty acids can produce some of the same medicinal qualities as marijuana, but without a psychotropic effect. In summary, the ω-3 endocannabinoid epoxides are found at concentrations comparable to those of other endocannabinoids and are expected to play critical roles during inflammation in vivo.”

https://www.ncbi.nlm.nih.gov/pubmed/31223777

https://academic.oup.com/cdn/article/3/Supplement_1/nzz031.FS15-01-19/5518049

Preparation of bivalent agonists for targeting the mu opioid and cannabinoid receptors.

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European Journal of Medicinal Chemistry

“In order to obtain novel pharmacological tools and to investigate a multitargeting analgesic strategy, the CB1 and CB2 cannabinoid receptor agonist JWH-018 was conjugated with the opiate analgesic oxycodone or with an enkephalin related tetrapeptide. The opioid and cannabinoid pharmacophores were coupled via spacers of different length and chemical structure. In vitro radioligand binding experiments confirmed that the resulting bivalent compounds bound both to the opioid and to the cannabinoid receptors with moderate to high affinity. The highest affinity bivalent derivatives 11 and 19 exhibited agonist properties in [35S]GTPγS binding assays. These compounds activated MOR and CB (11 mainly CB2, whereas 19 mainly CB1) receptor-mediated signaling, as it was revealed by experiments using receptor specific antagonists. In rats both 11 and 19 exhibited antiallodynic effect similar to the parent drugs in 20 μg dose at spinal level. These results support the strategy of multitargeting G-protein coupled receptors to develop lead compounds with antinociceptive properties.”

https://www.ncbi.nlm.nih.gov/pubmed/31220675

https://www.sciencedirect.com/science/article/pii/S0223523419304477?via%3Dihub

Quetiapine induces myocardial necroptotic cell death through bidirectional regulation of cannabinoid receptors.

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Toxicology Letters

“Quetiapine is a common atypical antipsychotic used to treat mental disorders such as schizophrenia, bipolar disorder, and major depressive disorder. There has been increasing number of reports describing its cardiotoxicity. However, the molecular mechanisms underlying quetiapine-induced myocardial injury remain largely unknown.

Herein, we reported a novel cell death type, quetiapine-induced necroptosis, which accounted for quetiapine cardiotoxicity in mice and proposed novel therapeutic strategies.

Quetiapine-treated hearts showed inflammatory infiltration and evident fibrosis after 21-day continuous injection. The specific increases of protein levels of RIP3, MLKL and the phosphorylation of MLKL showed that quetiapine-induced necroptotic cell death both in vivo and in vitro. Pharmacologic blockade of necroptosis using its specific inhibitor Necrostatin-1 attenuated quetiapine-induced myocardial injury in mice.

In addition, quetiapine imbalanced the endocannabinoid system and caused opposing effects on two cannabinoid receptors (CB1R and CB2R).

Specific antagonists of CB1R (AM 281, Rimonabant), but not its agonist ACEA significantly ameliorated the heart histopathology induced by chronic quetiapine exposure. By contrast, specific agonists of CB2R (JWH-133, AM 1241), but not its antagonist AM 630 exerted beneficial roles against quetiapine cardiotoxicity.

The protective agents (AM 281, Rimonabant, AM 1241, and JWH-133) consistently inactivated the quetiapine-induced necroptosis signaling. Quetiapine bidirectionally regulates cannabinoid receptors and induces myocardial necroptosis, leading to cardiac toxic effects.

Therefore, pharmacologic inhibition of CB1R or activation of CB2R represents promising therapeutic strategies against quetiapine-induced cardiotoxicity.”

https://www.ncbi.nlm.nih.gov/pubmed/31220554

https://www.sciencedirect.com/science/article/pii/S0378427419301766?via%3Dihub

Alcohol-induced conditioned place preference is modulated by CB2 cannabinoid receptors and modifies levels of endocannabinoids in the mesocorticolimbic system.

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Pharmacology Biochemistry and Behavior

“The endocannabinoid (eCB) system is a particularly important neuronal mechanism implicated in alcohol use disorders. Animal models are key to broadening our knowledge of the neurobiological mechanisms underlying alcohol dependence.

This study has two main aims: i) to assess how eCB levels in different brain areas are modified by alcohol-induced conditioning place preference (CPP), and ii) to study how cannabinoid type 2 receptor (CB2R) is involved in alcohol-rewarding properties, using pharmacological manipulation in C57BL/6 mice.

Our results suggest that the eCB system is dysregulated throughout the mesocorticolimbic system by repeated alcohol exposure during the CPP paradigm, and that levels of anandamide (AEA) and several other N-acylethanolamines are markedly decreased in the medial prefrontal cortex and ventral midbrain of alcohol-CPP mice.

We also observed that the administering an antagonist/inverse agonist of the CB2R (AM630) during the acquisition phase of CPP reduced the rewarding effects of alcohol. However, activating CB2R signalling using the agonist JWH133 seems to reduce both alcohol- and food-rewarding behaviours. Therefore, our findings indicate that the rewarding effects of alcohol are related to its disruptive effect on AEA and other N-acylethanolamine signalling pathways.

Thus, pharmacological manipulation of CB2R is an interesting candidate treatment for alcohol use disorders.”

https://www.ncbi.nlm.nih.gov/pubmed/31220547

https://www.sciencedirect.com/science/article/pii/S0091305719300656?via%3Dihub

Opioid-Sparing Effects of Cannabinoids on Morphine Analgesia: Participation of CB1 and CB2 Receptors.

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British Journal of Pharmacology banner“Much of the opioid epidemic arose from abuse of prescription opioid drugs.

This study sought to determine if the combination of a cannabinoid with an opioid could produce additive or synergistic effects on pain, allowing reduction in the opioid dose needed for maximal analgesia.

CONCLUSIONS AND IMPLICATIONS:

The ability of a cannabinoid to produce an additive or synergistic effect on analgesia when combined with morphine varies with the pain assay and may be mediated by CB1 or CB2 receptors. These results hold the promise of using cannabinoids to reduce the dose of opioids for analgesia in certain pain conditions.”

https://www.ncbi.nlm.nih.gov/pubmed/31218677

https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bph.14769

Antitumor Cannabinoid Chemotypes: Structural Insights.

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Image result for frontiers in pharmacology“Cannabis has long been known to limit or prevent nausea and vomiting, lack of appetite, and pain. For this reason, cannabinoids have been successfully used in the treatment of some of the unwanted side effects caused by cancer chemotherapy.

Besides their palliative effects, research from the past two decades has demonstrated their promising potential as antitumor agents in a wide variety of tumors.

Cannabinoids of endogenous, phytogenic, and synthetic nature have been shown to impact the proliferation of cancer through the modulation of different proteins involved in the endocannabinoid system such as the G protein-coupled receptors CB1, CB2, and GRP55, the ionotropic receptor TRPV1, or the fatty acid amide hydrolase (FAAH).

In this article, we aim to structurally classify the antitumor cannabinoid chemotypes described so far according to their targets and types of cancer. In a drug discovery approach, their in silico pharmacokinetic profile has been evaluated in order to identify appropriate drug-like profiles, which should be taken into account for further progress toward the clinic.

This analysis may provide structural insights into the selection of specific cannabinoid scaffolds for the development of antitumor drugs for the treatment of particular types of cancer.” https://www.ncbi.nlm.nih.gov/pubmed/31214034

“The first report on the antitumor activity of phytocannabinoids was published over four decades ago. During these last years, significant research has been focused on the therapeutic potential of cannabinoids to manage palliative effects in cancer patients. Besides such palliative applications, some cannabinoids have shown anticancer properties. Since inflammation is a common risk factor for cancer, and some cannabinoids have shown anti-inflammatory properties, they could play a role in chemoprevention.” https://www.frontiersin.org/articles/10.3389/fphar.2019.00621/full
“Antitumor effects of THC.” http://www.ncbi.nlm.nih.gov/pubmed/11097557
“Antitumor effects of cannabidiol” http://www.ncbi.nlm.nih.gov/pubmed/14617682
“Anti-tumour actions of cannabinoids.” https://www.ncbi.nlm.nih.gov/pubmed/30019449
“Extensive preclinical research has demonstrated that cannabinoids, the active ingredients of Cannabis sativa, trigger antitumor responses in different models of cancer.” https://www.ncbi.nlm.nih.gov/pubmed/29940172

Cannabidiol inhibits sucrose self-administration by CB1 and CB2 receptor mechanisms in rodents.

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Addiction Biology banner

“A growing number of studies suggest therapeutic applications of cannabidiol (CBD), a recently U.S. Food and Drug Administration (FDA)-approved medication for epilepsy, in treatment of many other neuropsychological disorders. However, pharmacological action and the mechanisms by which CBD exerts its effects are not fully understood.

Here, we examined the effects of CBD on oral sucrose self-administration in rodents and explored the receptor mechanisms underlying CBD-induced behavioral effects using pharmacological and transgenic approaches.

Systemic administration of CBD produced a dose-dependent reduction in sucrose self-administration in rats and in wild-type (WT) and CB1-/- mice but not in CB2-/- mice. CBD appeared to be more efficacious in CB1-/- mice than in WT mice.

Similarly, pretreatment with AM251, a CB1R antagonist, potentiated, while AM630, a selective CB2R antagonist, blocked CBD-induced reduction in sucrose self-administration, suggesting the involvement of CB1 and CB2 receptors.

Taken together, the present findings suggest that CBD may have therapeutic potential in reducing binge eating and the development of obesity.”

https://www.ncbi.nlm.nih.gov/pubmed/31215752

https://onlinelibrary.wiley.com/doi/abs/10.1111/adb.12783

Safety and effectiveness of cannabinoids for the treatment of neuropsychiatric symptoms in dementia: a systematic review.

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SAGE Journals“Neuropsychiatric symptoms (NPS) in dementia impact profoundly on the quality of life of people living with dementia and their care givers. Evidence for the effectiveness and safety of current therapeutic options is varied.

Cannabinoids have been proposed as an alternative therapy, mainly due to their activity on CB1 receptors in the central nervous system. However, little is known regarding the safety and effectiveness of cannabinoid therapy in people with dementia.

A literature review was undertaken to identify, describe and critically appraise studies investigating cannabinoid use in treating NPS in dementia.

RESULTS:

Twelve studies met the inclusion criteria. There was considerable variability across the studies with respect to study design (50% randomized controlled trials), intervention [dronabinol (33%), nabilone (25%) or delta-9 tetrahydrocannabinol (THC; 42%)] and outcome measures.

Dronabinol (three studies) and THC (one study) were associated with significant improvements in a range of neuropsychiatric scores.

The most common adverse drug event (ADE) reported was sedation. A high risk of bias was found in eight studies. The highest-quality trial found no significant improvement in symptoms or difference in ADE rate between treatment arms. Included studies used low doses of oral cannabinoids and this may have contributed to the lack of demonstrated efficacy.

CONCLUSION:

While the efficacy of cannabinoids was not proven in a robust randomized control trial, observational studies showed promising results, especially for patients whose symptoms were refractory. In addition, the safety profile is favourable as most of the ADEs reported were mild. Future trials may want to consider dose escalation and formulations with improved bioavailability.”

https://www.ncbi.nlm.nih.gov/pubmed/31205674

https://journals.sagepub.com/doi/10.1177/2042098619846993