We also examined a form of excitatory long-term depression that is dependent on CB1 receptors (eCB-eLTD) and found that it was completely lacking in the animals that consumed EtOH during adolescence.
These findings indicate that repeated exposure to EtOH during adolescence leads to long-term deficits in CB1 receptor expression, eCB-eLTD, and reduced recognition memory, but that these functional deficits can be restored by treatments that increase endogenous 2-arachidonoylglycerol.”
“Abusive alcohol consumption is a health problem, worldwide.
There is extensive literature indicating that cannabinoid 1 receptor (CB1R) plays a crucial role in mediating alcohol’s reward effects.
Maternal care deprivation (MCD) is a reliable rodent model of early life stress that leads to high levels of anxiety and alterations in motivation, which may increase vulnerability to alcohol consumption.
The present study researched whether anxiety-like behaviors and the level of motivation for a natural reward, and CB1R expression in the prefrontal cortex (PFC) and nucleus accumbens (NAcc) can predict alcohol consumption in non-MCD and MCD male rats.
Results indicate that MCD increases anxiety-like behaviors, i.e., reduces time in open arms in the elevated plus maze and increases alcohol intake. In turn, the motivation for a palatable reward, i.e., a chocolate flavored pellet, was not affected by MCD.
MCD reduces CB1R expression in the PFC and increases it in the NAcc. Hence, both higher anxiety-like behaviors and higher CB1R expression in the NAcc and lower CB1R expression in the PFC are associated with higher alcohol intake.
These results suggest that early life adverse experiences induce a reprogramming of the brain’s endocannabinoid system that very likely contributes to making the brain vulnerable to develop alcohol abuse and dependence.”
https://www.ncbi.nlm.nih.gov/pubmed/31568767
https://www.sciencedirect.com/science/article/abs/pii/S0006899319305396?via%3Dihub
“Muscle pain affects approximately 11-24% of the global population.
Several studies have shown that exercise is a non-pharmacological therapy to pain control. It has been suggested that the endocannabinoid system is involved in this antinociceptive effect.
The present study aimed to investigate whether spinal cannabinoid CB2 receptors participate in the exercise-induced antinociception.
The present study suggests that activation of spinal cannabinoid CB2 receptors and reduction of activated microglia are involved in exercise-induced antinociception.”
https://www.ncbi.nlm.nih.gov/pubmed/31473278
https://www.sciencedirect.com/science/article/abs/pii/S0306452219306165?via%3Dihub
“The endogenous lipid metabolism network is associated with the occurrence and progression of malignancies.
Endocannabinoids and ceramides have demonstrated their anti-proliferative and pro-apoptotic properties in a series of cancer studies.
The aim of the present study was to evaluate the expression patterns of endocannabinoids and endogenous ceramides in 67 pairs of human hepatocellular carcinoma (HCC) tissues and non-cancerous counterpart controls.
Anandamide (AEA), the major endocannabinoid, was reduced in tumor tissues, probably due to the high expression and activity of fatty acid amide hydrolase. Another important endocannabinoid, 2-arachidonylglycerol (2-AG), was elevated in tumor tissues compared with non-tumor controls, indicating that the biosynthesis of 2-AG is faster than the degradation of 2-AG in tumor cells.
Furthermore, western blot analysis demonstrated that cannabinoid receptor 1 was downregulated, while cannabinoid receptor 2 was elevated in HCC tissues, in accordance with the alterations in the levels of AEA and 2-AG, respectively. For HCC tissues, the expression levels of C18:0, 20:0 and 24:0-ceramides decreased significantly, whereas C12:0, 16:0, 18:1 and 24:1-ceramides were upregulated, which may be associated with cannabinoid receptor activation and stearoyl-CoA desaturase protein downregulation.
The exact role of endocannabinoids and ceramides in regulating the fate of HCC cells requires further investigation.”
https://www.ncbi.nlm.nih.gov/pubmed/31423220
https://www.spandidos-publications.com/10.3892/ol.2019.10399
“Cannabinoid receptors have been detected in human gliomas and cannabinoids have been proposed as novel drug candidates in the treatment of brain tumors.
Aim of this study was to test the in vitro antitumor activity of COR167, a novel cannabinoid CB2-selective agonist displaying high binding affinity for human CB2 receptors, on tumor cells isolated from human glioblastoma multiforme and anaplastic astrocytoma.
COR167 was found to significantly reduce the proliferation of both glioblastoma and anaplastic astrocytoma in a dose-dependent manner at lower doses than other known, less specific CB2 agonists. This activity is independent of apoptosis and is associated with significant reduction of TGF-beta 1 and 2 levels in supernatants of glioma cell cultures.
These findings add to the role of cannabinoid CB2 receptor as a possible pharmacological target to counteract glial tumor growth and encourage further work to explore any other pharmacological effect of this novel CB2 agonist useful in the treatment of human gliomas.”
“Substance use disorder (SUD) is a major public health crisis worldwide, and effective treatment options are limited.
During the past 2 decades, researchers have investigated the impact of a variety of pharmacological approaches to treat SUD, one of which is the use of medical cannabis or cannabinoids.
Significant progress was made with the discovery of rimonabant, a selective CB1 receptor (CB1R) antagonist (also an inverse agonist), as a promising therapeutic for SUDs and obesity. However, serious adverse effects such as depression and suicidality led to the withdrawal of rimonabant (and almost all other CB1R antagonists/inverse agonists) from clinical trials worldwide in 2008.
Since then, much research interest has shifted to other cannabinoid-based strategies, such as peripheral CB1R antagonists/inverse agonists, neutral CB1R antagonists, allosteric CB1R modulators, CB2R agonists, fatty acid amide hydrolase (FAAH) inhibitors, monoacylglycerol lipase (MAGL) inhibitors, fatty acid binding protein (FABP) inhibitors, or nonaddictive phytocannabinoids with CB1R or CB2R-binding profiles, as new therapeutics for SUDs.
In this article, we first review recent progress in research regarding the endocannabinoid systems, cannabis reward versus aversion, and the underlying receptor mechanisms. We then review recent progress in cannabinoid-based medication development for the treatment of SUDs.
As evidence continues to accumulate, neutral CB1R antagonists (such as AM4113), CB2R agonists (JWH133, Xie2-64), and nonselective phytocannabinoids (cannabidiol, β-caryophyllene, ∆9-tetrahydrocannabivarin) have shown great therapeutic potential for SUDs, as shown in experimental animals.
Several cannabinoid-based medications (e.g., dronabinol, nabilone, PF-04457845) that entered clinical trials have shown promising results in reducing withdrawal symptoms in cannabis and opioid users.”
https://www.ncbi.nlm.nih.gov/pubmed/31549358
https://link.springer.com/article/10.1007%2Fs40263-019-00664-w
“The endocannabinoid system has been a target of interest for agitation in Alzheimer disease (AD) because of potential behavioral effects and its potential impact on mechanisms implicated in AD such as oxidative stress (OS) and neuroinflammation.
We explored whether serum markers of OS and neuroinflammation were associated with response to the cannabinoid nabilone in agitated patients with AD (N = 38).
These findings suggest that OS and neuroinflammation may be associated with agitation severity, while nabilone may have anti-inflammatory effects.”
https://www.ncbi.nlm.nih.gov/pubmed/31547752
https://journals.sagepub.com/doi/abs/10.1177/0891988719874118?journalCode=jgpb
“Cannabinoid-based therapies have long been used to treat pain, but there remain questions about their actual mechanisms and efficacy. From an evolutionary perspective, the cannabinoid system would appear to be highly conserved given that the most prevalent endogenous cannabinoid (endocannabinoid) transmitters, 2-arachidonyl glycerol and anandamide, have been found throughout the animal kingdom, at least in the species that have been analysed to date. This review will first examine recent findings regarding the potential conservation across invertebrates and chordates of the enzymes responsible for endocannabinoid synthesis and degradation and the receptors that these transmitters act on. Next, comparisons of how endocannabinoids modulate nociception will be examined for commonalities between vertebrates and invertebrates, with a focus on the medicinal leech Hirudo verbana. Evidence is presented that there are distinct, evolutionarily conserved anti-nociceptive and pro-nociceptive effects. The combined studies across various animal phyla demonstrate the utility of using comparative approaches to understand conserved mechanisms for modulating nociception. This article is part of the Theo Murphy meeting issue ‘Evolution of mechanisms and behaviour important for pain’.”
https://www.ncbi.nlm.nih.gov/pubmed/31544609
https://royalsocietypublishing.org/doi/10.1098/rstb.2019.0279
“The cannabinoid 2 receptor (CB2R) is a promising anti-inflammatory drug target and development of selective CB2R ligands may be useful for treating sight-threatening ocular inflammation. This study examined the pharmacology of three novel chemically-diverse selective CB2R ligands. These unique ligands are potent and selective for CB2R and have good immunomodulating actions in the eye. The data generated with these three structurally-diverse and highly-selective CB2R agonists support selective targeting of CB2R for treating ocular inflammatory diseases.”
https://www.ncbi.nlm.nih.gov/pubmed/31540271
https://www.mdpi.com/1420-3049/24/18/3338
“Neutrophil trafficking into damaged or infected tissues is essential for the initiation of inflammation, clearance of pathogens and damaged cells, and ultimately tissue repair. Neutrophil recruitment is highly dependent on the stepwise induction of adhesion molecules and promigratory chemokines and cytokines.
A number of studies in animal models have shown the efficacy of cannabinoid receptor 2 (CB2) agonists in limiting inflammation in a range of preclinical models of inflammation, including colitis, atherosclerosis, multiple sclerosis, and ischemia-reperfusion injury.
Recent work in preclinical models of inflammation raises two questions: by what mechanisms do CB2 agonists provide anti-inflammatory effects during acute inflammation and what challenges exist in the translation of CB2 modulating therapeutics into the clinic.”