Tag Archives: CB1

Regional changes in the type 1 cannabinoid receptor are associated with cognitive dysfunction in Parkinson’s disease.

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 “The endocannabinoid system plays a regulatory role in a number of physiological functions, including motor control but also mood, emotion, and cognition.

A number of preclinical studies in Parkinson’s disease (PD) models demonstrated that modulating the type 1 cannabinoid receptor (CB1R) may improve motor symptoms and components of cognitive processing. However, the relation between CB1R, cognitive decline and behavioral symptoms has not been investigated in PD patients so far.

The aim of this study was to examine whether CB1R availability is associated with measures of cognitive and behavioral function in PD patients.

CONCLUSIONS:

Decreased CB1R availability in the prefrontal and midcingulate cortex in PD patients is strongly correlated with disturbances in executive functioning, episodic memory, and visuospatial functioning. Further investigation of regional CB1R expression in groups of PD patients with mild cognitive impairment or dementia is warranted in order to further investigate the role of CB1R expression in different levels of cognitive impairment in PD.”

https://www.ncbi.nlm.nih.gov/pubmed/31342135

https://link.springer.com/article/10.1007%2Fs00259-019-04445-x

Cannabidiol binding and negative allosteric modulation at the cannabinoid type 1 receptor in the presence of delta-9-tetrahydrocannabinol: An In Silico study.

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Image result for plos one “Recent evidence has raised in discussion the possibility that cannabidiol can act as a negative allosteric modulator of the cannabinoid type 1 receptor. Here we have used computational methods to study the modulation exerted by cannabidiol on the effects of delta-9-tetrahydrocannabinol in the cannabinoid receptor type 1 and the possibility of direct receptor blockade. We propose a putative allosteric binding site that is located in the N-terminal region of receptor, partially overlapping the orthosteric binding site. Molecular dynamics simulations reveled a coordinated movement involving the outward rotation of helixes 1 and 2 and subsequent expansion of the orthosteric binding site upon cannabidiol binding. Finally, changes in the cytoplasmic region and high helix 8 mobility were related to impaired receptor internalization. Together, these results offer a possible explanation to how cannabidiol can directly modulate effects of delta-9-tetrahydrocannabinol on the cannabinoid receptor type 1.”

https://www.ncbi.nlm.nih.gov/pubmed/31335889

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0220025

Endocannabinoids and endocannabinoid-like compounds modulate hypoxia-induced permeability in CaCo-2 cells via CB1, TRPV1, and PPARα.

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Biochemical Pharmacology“We have previously reported that endocannabinoids modulate permeability in Caco-2 cells under inflammatory conditions and hypothesised in the present study that endocannabinoids could also modulate permeability in ischemia/reperfusion.

CONCLUSIONS AND IMPLICATIONS:

A variety of endocannabinoids and endocannabinoid-like compounds modulate Caco-2 permeability in hypoxia/reoxygenation, which involves multiple targets, depending on whether the compounds are applied to the basolateral or apical membrane. CB1 antagonism and TRPV1 or PPARα agonism may represent novel therapeutic targets against several intestinal disorders associated with increased permeability.”

https://www.ncbi.nlm.nih.gov/pubmed/31325449

https://www.sciencedirect.com/science/article/abs/pii/S0006295219302722?via%3Dihub

Overcoming the psychiatric side effects of the cannabinoid CB1 receptor antagonists: Current approaches for therapeutics development.

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“The cannabinoid receptor 1 (CBR1) is involved in a variety of physiological pathways and has long been considered a golden target for therapeutic manipulation. A large body of evidence in both animal and human studies suggests that CB1R antagonism is highly effective for the treatment of obesity, metabolic disorders and drug addiction. However, the first-in-class CB1R antagonist/inverse agonist, rimonabant, though demonstrating effectiveness for obesity treatment and smoking cessation, displays serious psychiatric side effects, including anxiety, depression and even suicidal ideation, resulting in its eventual withdrawal from the European market. Several strategies are currently being pursued to circumvent the mechanisms leading to these side effects by developing neutral antagonists, peripherally restricted ligands, and allosteric modulators. In this review, we describe the progress in the development of therapeutics targeting the cannabinoid receptor 1 in the last two decades.”

https://www.ncbi.nlm.nih.gov/pubmed/31284863

http://www.eurekaselect.com/173316/article

Cannabinoids reduce hyperalgesia and inflammation via interaction with peripheral CB1 receptors.

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“Central antinociceptive effects of cannabinoids have been well documented.

Our results indicate that cannabinoids produce antihyperalgesia via interaction with a peripheral CB1 receptor.

This hypothesis is supported by the finding that anandamide inhibited capsaicin-evoked release of calcitonin gene-related peptide from isolated hindpaw skin.

Collectively, these results indicate that cannabinoids reduce inflammation via interaction with a peripheral CB1 receptor.”

 https://www.ncbi.nlm.nih.gov/pubmed/9539680/
https://insights.ovid.com/pubmed?pmid=9539680

“The Endocannabinoid System and Pain. Cannabis has been used for more than twelve thousand years and for many different purposes (i.e. fiber, medicinal, recreational). However, the endocannabinoid signaling system has only recently been the focus of medical research and considered a potential therapeutic target. Cannabinoid receptors and their endogenous ligands are present at supraspinal, spinal and peripheral levels. Cannabinoids suppress behavioral responses to noxious stimulation and suppress nociceptive processing through activation of cannabinoid CB1 and CB2 receptor subtypes. These studies suggest that manipulation of peripheral endocannabinoids may be promising strategy for the management of pain.”
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2834283/

“The Analgesic Potential of Cannabinoids. Historically and anecdotally cannabinoids have been used as analgesic agents. Moreover, cannabinoids act synergistically with opioids and act as opioid sparing agents, allowing lower doses and fewer side effects from chronic opioid therapy. Thus, rational use of cannabis based medications deserves serious consideration to alleviate the suffering of patients due to severe pain.”  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3728280/

Cannabinoid receptor CB1-immunoreactive nerve fibres in painful and non-painful human tooth pulp.

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Journal of Clinical Neuroscience Home“The cannabinoid receptor CB1 is involved in modulation of neuronal hypersensitivity and pain. The aim of this study was to evaluate CB1 receptor levels for the first time in dental pain. A total of 19 patients due for molar extraction were divided into two groups, those with existing dental pain (n=9), and those with no history of pain (n=10). Immunohistochemistry and computer image analysis was used to evaluate CB1-positive nerve fibres in tooth pulp, with neurofilament-immunostaining as a structural nerve marker. CB1-immunoreactive nerve fibres were scattered throughout the tooth pulp and often seen in nerve bundles, but the fibres did not penetrate the subodontoblastic layer. There was no statistically significant change in the CB1 nerve fibre percentage area in the painful group compared to the non-painful group (p=0.146); the neurofilament fibres were significantly reduced in the painful group compared to the controls (p=0.028), but there was no difference in the ratio of CB1 to neurofilaments between the two groups. Thus, CB1 expression is maintained by nerve fibres in painful human dental pulp, and peripherally-restricted CB1 agonists currently in development may advance the treatment of dental pain.”

https://www.ncbi.nlm.nih.gov/pubmed/20705472

https://www.jocn-journal.com/article/S0967-5868(10)00289-4/fulltext

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

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

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