Category Archives: Endocannabinoid System

Cannabinoid CB1 receptors in the amygdalar cholecystokinin glutamatergic afferents to nucleus accumbens modulate depressive-like behavior.

Posted on by

 Image result for nature medicine“Major depressive disorder is a devastating psychiatric disease that afflicts up to 17% of the world’s population. Postmortem brain analyses and imaging studies of patients with depression have implicated basal lateral amygdala (BLA) dysfunction in the pathophysiology of depression. However, the circuit and molecular mechanisms through which BLA neurons modulate depressive behavior are largely uncharacterized. Here, in mice, we identified that BLA cholecystokinin (CCK) glutamatergic neurons mediated negative reinforcement via D2 medium spiny neurons (MSNs) in the nucleus accumbens (NAc) and that chronic social defeat selectively potentiated excitatory transmission of the CCKBLA-D2NAc circuit in susceptible mice via reduction of presynaptic cannabinoid type-1 receptor (CB1R). Knockdown of CB1R in the CCKBLA-D2NAc circuit elevated synaptic activity and promoted stress susceptibility. Notably, selective inhibition of the CCKBLA-D2NAc circuit or administration of synthetic cannabinoids in the NAc was sufficient to produce antidepressant-like effects. Overall, our studies reveal the circuit and molecular mechanisms of depression.”

https://www.ncbi.nlm.nih.gov/pubmed/30643290

https://www.nature.com/articles/s41591-018-0299-9

“Antidepressant-like effect of delta9-tetrahydrocannabinol and other cannabinoids isolated from Cannabis sativa L. Results of this study show that Delta(9)-THC and other cannabinoids exert antidepressant-like actions, and thus may contribute to the overall mood-elevating properties of cannabis.”  https://www.ncbi.nlm.nih.gov/pubmed/20332000

Crystal Structure of the Human Cannabinoid Receptor CB2.

Posted on by

Image result for cell journal

“The cannabinoid receptor CB2 is predominately expressed in the immune system, and selective modulation of CB2 without the psychoactivity of CB1 has therapeutic potential in inflammatory, fibrotic, and neurodegenerative diseases.

Here, we report the crystal structure of human CB2 in complex with a rationally designed antagonist, AM10257, at 2.8 Å resolution. The CB2-AM10257 structure reveals a distinctly different binding pose compared with CB1. However, the extracellular portion of the antagonist-bound CB2 shares a high degree of conformational similarity with the agonist-bound CB1, which led to the discovery of AM10257’s unexpected opposing functional profile of CB2 antagonism versus CB1 agonism.

Further structural analysis using mutagenesis studies and molecular docking revealed the molecular basis of their function and selectivity for CB2 and CB1. Additional analyses of our designed antagonist and agonist pairs provide important insight into the activation mechanism of CB2. The present findings should facilitate rational drug design toward precise modulation of the endocannabinoid system.”

https://www.ncbi.nlm.nih.gov/pubmed/30639103

https://linkinghub.elsevier.com/retrieve/pii/S0092867418316258

Structure of a Signaling Cannabinoid Receptor 1-G Protein Complex.

Posted on by

Image result for cell journal

“Cannabis elicits its mood-enhancing and analgesic effects through the cannabinoid receptor 1 (CB1), a G protein-coupled receptor (GPCR) that signals primarily through the adenylyl cyclase-inhibiting heterotrimeric G protein Gi. Activation of CB1-Gi signaling pathways holds potential for treating a number of neurological disorders and is thus crucial to understand the mechanism of Giactivation by CB1.

Here, we present the structure of the CB1-Gi signaling complex bound to the highly potent agonist MDMB-Fubinaca (FUB), a recently emerged illicit synthetic cannabinoid infused in street drugs that have been associated with numerous overdoses and fatalities.”

https://www.ncbi.nlm.nih.gov/pubmed/30639101

https://linkinghub.elsevier.com/retrieve/pii/S0092867418315654

“Antidepressant-like effect of delta9-tetrahydrocannabinol and other cannabinoids isolated from Cannabis sativa L. Results of this study show that Delta(9)-THC and other cannabinoids exert antidepressant-like actions, and thus may contribute to the overall mood-elevating properties of cannabis.”   https://www.ncbi.nlm.nih.gov/pubmed/20332000

∆9-Tetrahydrocannabinol, a major marijuana component, enhances the anesthetic effect of pentobarbital through the CB1 receptor.

Posted on by

 “∆9 –Tetrahydrocannabinol (∆9-THC) and cannabidiol (CBD), major psychoactive constituents of marijuana, induce potentiation of pentobarbital-induced sleep in mice.

We have elucidated the mechanism of enhancement of the anesthetic effect of pentobarbital by cannabinoids.

These results suggest that binding of ∆9-THC to the CB1 receptor is involved in the synergism with pentobarbital, and that potentiating effect of CBD with pentobarbital may differ from that of ∆9-THC. We successfully demonstrated that ∆9-THC enhanced the anesthetic effect of pentobarbital through the CB1 receptor.”

https://www.ncbi.nlm.nih.gov/pubmed/30636988

“The pharmacological results indicate the effect of ∆9-THC co-administered with pentobarbital was a synergistic, but not additive, action in mice. Further evidence suggests the CB1 receptor plays an important role as a trigger in potentiating pentobarbital-induced sleep by ∆9-THC.”

https://link.springer.com/article/10.1007%2Fs11419-018-0457-2

Do Endocannabinoids Regulate Glucose Reabsorption in the Kidney?

Posted on by

Logo Nephron

“Diabetic nephropathy (DN), a distinct manifestation of diabetic kidney disease, affects approximately 30% of patients with diabetes. While most attention has been focused on glomerular changes related to DN, there is growing evidence that tubulopathy is a key feature in the pathogenesis of this disease. The renal proximal tubule cells (RPTCs) are particularly sensitive to the deleterious effect of chronic hyperglycemia. However, the cellular changes that control the dysfunction of the RPTCs are not fully understood.

Controlling glucose reabsorption in the proximal tubules via inhibition of glucose transporters (GLUT) has emerged as a promising therapeutic in ameliorating DN.

Overactivation of the renal endocannabinoid (eCB) system via the cannabinoid-1 receptor (CB1R) contributes to the development of DN, and its blockade by globally acting or peripherally restricted CB1R antagonists has been shown to ameliorate renal dysfunction in different murine models for diabetes. Recently, we have utilized various pharmacological and genetic tools to show that the eCB/CB1R system contributes to the development of DN via regulating the expression, translocation, and activity of the facilitative GLUT2 located in the RPTCs.

These findings have the potential to be translated into therapy, and support the rationale for the preclinical development of novel renal-specific CB1R and/or GLUT2 inhibitors for the treatment of DN.”

https://www.ncbi.nlm.nih.gov/pubmed/30636250

https://www.karger.com/Article/FullText/494512

Expression and Preparation of a G-Protein-Coupled Cannabinoid Receptor CB2 for NMR Structural Studies.

Posted on by

Current Protocols in Protein Science banner

“Cannabinoid receptor type II, or CB2 , is an integral membrane protein that belongs to a large class of G-protein-coupled receptors (GPCR)s. CB2 is a part of the endocannabinoid system, which plays an important role in the regulation of immune response, inflammation, and pain.

Information about the structure and function of CB2 is essential for the development of specific ligands targeting this receptor.

We present here a methodology for recombinant expression of CB2 and its stable isotope labeling, purification, and reconstitution into liposomes, in preparation for its characterization by nuclear magnetic resonance (NMR).

Correctly folded, functional CB2 labeled with [13 C,15 N]tryptophan or uniformly labeled with 13 C and 15 N is expressed in a medium of defined composition, under controlled aeration, pH, and temperature conditions.

The receptor is purified by affinity chromatography and reconstituted into lipid bilayers in the form of proteoliposomes suitable for analysis by NMR spectroscopy.”

https://www.ncbi.nlm.nih.gov/pubmed/30624864

https://currentprotocols.onlinelibrary.wiley.com/doi/abs/10.1002/cpps.83

Changes in Monoaminergic Neurotransmission in an Animal Model of Osteoarthritis: The Role of Endocannabinoid Signaling.

Posted on by

Image result for frontiers in molecular neuroscience

“Chronic pain is a main symptom of osteoarthritis (OA). Moreover, a high percentage of OA patients suffer from mental health problems.

The endocannabinoid (EC) system has attracted attention as an emerging drug target for pain treatment together with its activity on the mesolimbic reward system.

Understanding the circuits that govern the reward of pain relief is crucial for the search for effective analgesics. Therefore, we investigated the role of the EC system on dopamine (DA) and noradrenaline (NA) in an animal model of OA-related chronic pain.

Our results demonstrated that chronic pain in OA rats was reflected by the inhibition of mesolimbic and mesocortical dopaminergic transmission, and may indicate the pro-pain role of NA in the FCx.

The data provide understanding about changes in neurotransmission in chronic pain states and may explain the clinical improvement in perceived life quality following cannabinoid treatment.

Additional mechanistic studies in preclinical models examining the intersection between chronic pain and reward circuits may offer new approaches for improving pain therapy.”

https://www.ncbi.nlm.nih.gov/pubmed/30618615

https://www.frontiersin.org/articles/10.3389/fnmol.2018.00466/full

The effects of cannabinoids on the endocrine system.

Posted on by

“Cannabinoids are the derivatives of the cannabis plant, the most potent bioactive component of which is tetrahydrocannabinol (THC). The most commonly used drugs containing cannabinoids are marijuana, hashish, and hashish oil.

These compounds exert their effects via interaction with the cannabinoid receptors CB1 and CB2. Type 1 receptors (CB1) are localised mostly in the central nervous system and in the adipose tissue and many visceral organs, including most endocrine organs. Type 2 cannabinoid receptors (CB2) are positioned in the peripheral nervous system (peripheral nerve endings) and on the surface of the immune system cells.

Recently, more and more attention has been paid to the role that endogenous ligands play for these receptors, as well as to the role of the receptors themselves. So far, endogenous cannabinoids have been confirmed to participate in the regulation of food intake and energy homeostasis of the body, and have a significant impact on the endocrine system, including the activity of the pituitary gland, adrenal cortex, thyroid gland, pancreas, and gonads.

Interrelations between the endocannabinoid system and the activity of the endocrine system may be a therapeutic target for a number of drugs that have been proved effective in the treatment of infertility, obesity, diabetes, and even prevention of diseases associated with the cardiovascular system.”

 https://www.ncbi.nlm.nih.gov/pubmed/30618031
https://journals.viamedica.pl/endokrynologia_polska/article/view/58487

Cannabinoids-induced peripheral analgesia depends on activation of BK channels.

Posted on by

 Brain Research“The endogenous cannabinoid system is involved in the physiological inhibitory control of pain and is of particular interest for the development of therapeutic approaches for pain management.

Selective activation of the peripheral CB1 cannabinoid receptor has been shown to suppress the heightened firing of primary afferents, which is the peripheral mechanism underlying neuropathic pain after nerve injury. However, the mechanism underlying this effect of CB1 receptor remains unclear.

The large-conductance calcium-activated potassium (BK) channels have been reported to participate in anticonvulsant and vasorelaxant effects of cannabinoids. We asked whether BK channels participate in cannabinoids-induced analgesia and firing-suppressing effects in primary afferents after nerve injury.

Here, using mice with chronic constriction injury(CCI)-induced neuropathic pain, antinociception action and firing-suppressing effect of HU210 were measured before and after BK channel blocker application. We found that local peripheral application of HU210 alleviated CCI-induced pain behavior and suppressed the heightened firing of injured fibers. Co-administration of IBTX with HU210 significantly reversed the analgesia and the firing-suppressing effect of HU210.

This result indicated that the peripheral analgesic effects of cannabinoids depends on activation of BK channels.”

https://www.ncbi.nlm.nih.gov/pubmed/30615887

https://www.sciencedirect.com/science/article/pii/S0006899319300071?via%3Dihub

Progress in Brain Cannabinoid CB2 Receptor Research: From Genes to Behavior.

Posted on by

Neuroscience & Biobehavioral Reviews

“The type 2 cannabinoid receptor (CB2R) was initially regarded as a peripheral cannabinoid receptor. However, recent technological advances in gene detection, alongside the availability of transgenic mouse lines, indicate that CB2Rs are expressed in both neurons and glial cells in the brain under physiological and pathological conditions, and are involved in multiple functions at cellular and behavioral levels. Brain CB2Rs are inducible and neuroprotective via up-regulation in response to various insults, but display species differences in gene and receptor structures, CB2R expression, and receptor responses to various CB2R ligands. CB2R transcripts also differ between the brain and spleen. In the brain, CB2A is the major transcript isoform, while CB2A and CB2B transcripts are present at higher levels in the spleen. These new findings regarding brain versus spleen CB2R isoforms may in part explain why early studies failed to detect brain CB2R gene expression. Here, we review evidence supporting the expression and function of brain CB2R from gene and receptor levels to cellular functioning, neural circuitry, and animal behavior.”

https://www.ncbi.nlm.nih.gov/pubmed/30611802

https://www.sciencedirect.com/science/article/pii/S0149763418308297?via%3Dihub