Tag Archives: endocannabinoids

Fatty-acid-binding protein inhibition produces analgesic effects through peripheral and central mechanisms.

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“Fatty-acid-binding proteins (FABPs) are intracellular carriers for endocannabinoids, N-acylethanolamines, and related lipids. Previous work indicates that systemically administered FABP5 inhibitors produce analgesia in models of inflammatory pain. It is currently not known whether FABP inhibitors exert their effects through peripheral or central mechanisms. Here, we examined FABP5 distribution in dorsal root ganglia and spinal cord and examined the analgesic effects of peripherally and centrally administered FABP5 inhibitors.

Results: Immunofluorescence revealed robust expression of FABP5 in lumbar dorsal root ganglia. FABP5 was distributed in peptidergic calcitonin gene-related peptide-expressing dorsal root ganglia and non-peptidergic isolectin B4-expressing dorsal root ganglia. In addition, the majority of dorsal root ganglia expressing FABP5 also expressed transient receptor potential vanilloid 1 (TRPV1) and peripherin, a marker of nociceptive fibers. Intraplantar administration of FABP5 inhibitors reduced thermal and mechanical hyperalgesia in the complete Freund’s adjuvant model of chronic inflammatory pain. In contrast to its robust expression in dorsal root ganglia, FABP5 was sparsely distributed in the lumbar spinal cord and intrathecal administration of FABP inhibitor did not confer analgesic effects. Administration of FABP inhibitor via the intracerebroventricular (i.c.v.) route reduced thermal hyperalgesia. Antagonists of peroxisome proliferator-activated receptor alpha blocked the analgesic effects of peripherally and i.c.v. administered FABP inhibitor while antagonism of cannabinoid receptor 1 blocked the effects of peripheral FABP inhibition and a TRPV1 antagonist blocked the effects of i.c.v. administered inhibitor. Although FABP5 and TRPV1 were co-expressed in the periaqueductal gray region of the brain, which is known to modulate pain, knockdown of FABP5 in the periaqueductal gray using adeno-associated viruses and pharmacological FABP5 inhibition did not produce analgesic effects.

Conclusions: This study demonstrates that FABP5 is highly expressed in nociceptive dorsal root ganglia neurons and FABP inhibitors exert peripheral and supraspinal analgesic effects. This indicates that peripherally restricted FABP inhibitors may serve as a new class of analgesic and anti-inflammatory agents.”

https://www.ncbi.nlm.nih.gov/pubmed/28326944

2-Arachidonoylglycerol ameliorates inflammatory stress-induced insulin resistance in cardiomyocytes.

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“Several studies have linked impaired glucose uptake and insulin resistance (IR) to functional impairment of the heart. Recently, endocannabinoids have been implicated in cardiovascular disease. However, the mechanisms involving endocannabinoid signaling, glucose uptake and IR in cardiomyocytes are understudied.

Here, we report the endocannabinoid 2-Arachidonoylglycerol (2-AG) via stimulation of cannabinoid type-1 (CB1) receptor and Ca2+/Calmodulin-dependent protein kinase β (CaMKKβ) activates AMPK leading to increased glucose uptake. Interestingly, we have observed that the mRNA expression of CB1 and CB2 receptors was decreased in diabetic mice, indicating reduced endocannabinoid signaling in diabetic heart. We further establish that TNFα induces IR in cardiomyocytes.

Treatment with 2-AG suppresses TNFα-induced pro-inflammatory markers, and improves IR and glucose uptake. Conversely, pharmacological inhibition or knockdown of AMPK attenuates the anti-inflammatory effect and reversal of IR elicited by 2-AG. Additionally, in human embryonic stem cell-derived cardiomyocytes challenged with TNFα or free fatty acid (FFA), we demonstrate that 2-AG improves insulin sensitivity and glucose uptake.

In conclusion, 2-AG abates inflammatory responses, increases glucose uptake and overcomes IR in an AMPK-dependent manner in cardiomyocytes.”

https://www.ncbi.nlm.nih.gov/pubmed/28320859

The Ratio of 2-AG to Its Isomer 1-AG as an Intrinsic Fine Tuning Mechanism of CB1 Receptor Activation.

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Image result for Front Cell Neurosci.“Endocannabinoids are pleiotropic lipid messengers that play pro-homeostatic role in cellular physiology by strongly influencing intracellular Ca2+ concentration through the activation of cannabinoid receptors. One of the best-known endocannabinoid ‘2-AG’ is chemically unstable in aqueous solutions, thus its molecular rearrangement, resulting in the formation of 1-AG, may influence 2-AG-mediated signaling depending on the relative concentration and potency of the two isomers.

To predict whether this molecular rearrangement may be relevant in physiological processes and in experiments with 2-AG, here we studied if isomerization of 2-AG has an impact on 2-AG-induced, CB1-mediated Ca2+ signaling in vitro.

We found that the isomerization-dependent drop in effective 2-AG concentration caused only a weak diminution of Ca2+ signaling in CB1 transfected COS7 cells. We also found that 1-AG induces Ca2+transients through the activation of CB1, but its working concentration is threefold higher than that of 2-AG. Decreasing the concentration of 2-AG in parallel to the prevention of 1-AG formation by rapid preparation of 2-AG solutions, caused a significant diminution of Ca2+ signals. However, various mixtures of the two isomers in a fix total concentration – mimicking the process of isomerization over time – attenuated the drop in 2-AG potency, resulting in a minor decrease in CB1 mediated Ca2+ transients.

Our results indicate that release of 2-AG into aqueous medium is accompanied by its isomerization, resulting in a drop of 2-AG concentration and simultaneous formation of the similarly bioactive isomer 1-AG. Thus, the relative concentration of the two isomers with different potency and efficacy may influence CB1 activation and the consequent biological responses.

In addition, our results suggest that may play role in stabilizing the strength of cannabinoid signal in case of prolonged 2-AG dependent cannabinoid mechanisms.”

 https://www.ncbi.nlm.nih.gov/pubmed/28265242

Cell-Autonomous Excitation of Midbrain Dopamine Neurons by Endocannabinoid-Dependent Lipid Signaling.

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“The major endocannabinoid in the mammalian brain is the bioactive lipid 2-arachidonoylglycerol (2-AG). The best-known effects of 2-AG are mediated by G-protein-coupled cannabinoid receptors. In principle, 2-AG could modify neuronal excitability by acting directly on ion channels, but such mechanisms are poorly understood.

Using a preparation of dissociated mouse midbrain dopamine neurons to isolate effects on intrinsic excitability, we found that 100 nM 2-AG accelerated pacemaking and steepened the frequency-current relationship for burst-like firing. In voltage-clamp experiments, 2-AG reduced A-type potassium current (IA) through a cannabinoid receptor-independent mechanism mimicked by arachidonic acid, which has no activity on cannabinoid receptors. Activation of orexin, neurotensin, and metabotropic glutamate Gq/11-linked receptors mimicked the effects of exogenous 2-AG and their actions were prevented by inhibiting the 2-AG-synthesizing enzyme diacylglycerol lipase α.

The results show that 2-AG and related lipid signaling molecules can directly tune neuronal excitability in a cell-autonomous manner by modulating IA.”

https://www.ncbi.nlm.nih.gov/pubmed/28262417

Endocannabinoids: A Promising Impact for Traumatic Brain Injury.

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“The endogenous cannabinoid (endocannabinoid) system regulates a diverse array of physiological processes and unsurprisingly possesses considerable potential targets for the potential treatment of numerous disease states, including two receptors (i.e., CB1 and CB2 receptors) and enzymes regulating their endogenous ligands N-arachidonoylethanolamine (anandamide) and 2-arachidonyl glycerol (2-AG).

Increases in brain levels of endocannabinoids to pathogenic events suggest this system plays a role in compensatory repair mechanisms.

Traumatic brain injury (TBI) pathology remains mostly refractory to currently available drugs, perhaps due to its heterogeneous nature in etiology, clinical presentation, and severity. Here, we review pre-clinical studies assessing the therapeutic potential of cannabinoids and manipulations of the endocannabinoid system to ameliorate TBI pathology.

Specifically, manipulations of endocannabinoid degradative enzymes (e.g., fatty acid amide hydrolase, monoacylglycerol lipase, and α/β-hydrolase domain-6), CB1and CB2 receptors, and their endogenous ligands have shown promise in modulating cellular and molecular hallmarks of TBI pathology such as; cell death, excitotoxicity, neuroinflammation, cerebrovascular breakdown, and cell structure and remodeling.

TBI-induced behavioral deficits, such as learning and memory, neurological motor impairments, post-traumatic convulsions or seizures, and anxiety also respond to manipulations of the endocannabinoid system.

As such, the endocannabinoid system possesses potential drugable receptor and enzyme targets for the treatment of diverse TBI pathology.

Yet, full characterization of TBI-induced changes in endocannabinoid ligands, enzymes, and receptor populations will be important to understand that role this system plays in TBI pathology.

Promising classes of compounds, such as the plant-derived phytocannabinoids, synthetic cannabinoids, and endocannabinoids, as well as their non-cannabinoid receptor targets, such as TRPV1 receptors, represent important areas of basic research and potential therapeutic interest to treat TBI.”

 https://www.ncbi.nlm.nih.gov/pubmed/28261100

It’s Colorectal Cancer Awareness Month. Please Be Aware:

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“Prevention and Treatment of Colorectal Cancer by Natural Agents From Mother Nature. This review clearly demonstrates that various nutraceuticals provided by the Mother Nature have a huge potential for both prevention and treatment of Colorectal cancer (CRC). Since these agents can be administered chronically without any concern for safety and are highly affordable, their use has been the wave of the past and is likely to continue as the wave of the future.” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3693477/
“Inflammatory Diet Linked to Colon Cancer, Metabolic Risk” https://www.psychologytoday.com/blog/nourish/201410/inflammatory-diet-linked-colon-cancer-metabolic-risk
“Links between inflammation and colon cancer metastasis” https://www.sciencedaily.com/releases/2015/08/150825094923.htm
“Inflammation and colon cancer. The connection between inflammation and tumorigenesis is well-established. Inflammation is also likely to be involved with other forms of sporadic as well as heritable colon cancer.” https://www.ncbi.nlm.nih.gov/pubmed/20420949
“Cannabis-derived substances in cancer therapy–an emerging anti-inflammatory role for the cannabinoids. Chronic inflammation has been associated with neoplasia for sometime, and as a consequence, reducing inflammation as a way of impacting cancer presents a new role for these compounds. ” https://www.ncbi.nlm.nih.gov/pubmed/20925645
“Cannabinoids as gastrointestinal anti-inflammatory drugs.” https://www.ncbi.nlm.nih.gov/pubmed/28239924
“Colon Cancer Risk Linked To High-Fat Diet: How Eating More Fat Can Increase Intestinal Tumors” http://www.medicaldaily.com/colon-cancer-high-fat-diet-intestinal-tumors-376664
 
“Study: Red and Processed Meats Linked With Colon Cancer Risk” http://healthland.time.com/2011/05/27/study-red-and-processed-meats-linked-with-colon-cancer-risk/
 
“Eating hot dogs, ham and other processed meat can cause colorectal cancer, and eating red meat “probably” can cause cancer, the World Health Organization’s cancer agency reported” http://www.usatoday.com/story/news/nation/2015/10/26/experts-processed-meats-can-cause-cancer/74615390/
 
“Mediterranean Diet Reduces Risk of Colon Cancer”
 
 
“More evidence a veg diet might lower cancer risk” http://www.today.com/health/veggie-diet-lowers-colon-cancer-risk-t7671
 
 
 
“Omegas linked with colon cancer survival. A large, observational study has linked higher intake of omega-3s with a lower risk of dying from colon cancer.” http://www.newhope.com/breaking-news/omegas-linked-colon-cancer-survival
 
 “Study shows how high-fat diets increase colon cancer risk” http://news.temple.edu/news/2012-03-06/study-shows-how-high-fat-diets-increase-colon-cancer-risk
 
 
 
“Poor metabolic health linked to increased risk for colorectal cancer in normal-weight women” http://www.news-medical.net/news/20170201/Poor-metabolic-health-linked-to-increased-risk-for-colorectal-cancer-in-normal-weight-women.aspx
 
 
“Cheese, Milk, and Fatty Fish Can Help Fight Colon Cancer” https://munchies.vice.com/en_us/article/cheese-milk-and-fatty-fish-can-help-fight-colon-cancer
 
“Diet, exercise and aspirin: 3 tools to fight colon cancer” http://ktar.com/story/1314810/diet-exercise-aspirin-3-tools-fight-colon-cancer/
 
“Many Early Colon Cancers Linked to Inherited Genes” https://medlineplus.gov/news/fullstory_162574.html
 
“Study Supports Link Between Asbestos Exposure and Colon Cancer” http://www.asbestosnetwork.com/News/Study-Supports-Link-Between-Asbestos-Exposure-and-Colon-Cancer.shtml
 
“E.coli Bacteria Linked to Colon Cancer” http://www.ibtimes.co.uk/e-coli-bateria-linked-colon-cancer-375102
 
“Colorectal cancer prevalence linked to human papillomavirus: a systematic review with meta-analysis” http://www.scielo.br/scielo.php?pid=S1415-790X2016000400791&script=sci_arttext&tlng=en
 
“Colon cancer linked to viruses in beef, Nobel-winning scientist contends” http://www.scmp.com/lifestyle/health/article/1695757/colon-cancer-linked-viruses-beef-nobel-winning-scientist-contends
 
 
“Diet High in Choline Linked with Increased Risk of Colorectal Polyps. According to the results of a study published in the Journal of the National Cancer Institute, high intake of choline-a nutrient found in foods such as red meat, eggs, poultry, and dairy products-may be linked with an increased risk of colorectal polyps.” http://news.cancerconnect.com/diet-high-in-choline-linked-with-increased-risk-of-colorectal-polyps/
 
“High-Glycemic Foods Linked to Colon Cancer. These foods include breads, pastas, pancakes, and other carbohydrates made from refined “white” grains, as well as other processed or sugary foods such as cakes, cookies, and other snacks.” http://www.webmd.com/colorectal-cancer/news/20040203/high-glycemic-foods-linked-to-colon-cancer#1
 
“Low-carb diet cuts risk of colon cancer” https://www.utoronto.ca/news/low-carb-diet-cuts-risk-colon-cancer
 
“Common food additive promotes colon cancer in mice. Emulsifiers, which are added to most processed foods to aid texture and extend shelf life, can alter intestinal bacteria in a manner that promotes intestinal inflammation and colorectal cancer” https://www.sciencedaily.com/releases/2016/11/161107110639.htm
 
“Processed meats including bacon, hot dogs linked to colon cancer” http://www.cp24.com/news/processed-meats-including-bacon-hot-dogs-linked-to-colon-cancer-1.2627498
 
“Processed meat can cause colon cancer, World Health Organization says” http://www.cbc.ca/news/health/meat-cancer-world-health-organization-1.3288355
 
“Sweets, sugary snacks linked to colorectal cancer” http://www.cbsnews.com/news/sweets-sugary-snacks-linked-to-colorectal-cancer/
 
“Eating Nuts Linked to Lower Risk of Colon Cancer” http://www.livescience.com/54448-eating-nuts-may-lower-colon-cancer-risk.html
 
“Diabetes, high blood pressure linked to colon cancer recurrence” http://www.mcknights.com/news/diabetes-high-blood-pressure-linked-to-colon-cancer-recurrence/article/274064/
 
“Coffee consumption linked to lower risk of colorectal cancer” http://www.ctvnews.ca/health/coffee-consumption-linked-to-lower-risk-of-colorectal-cancer-1.2841834
“Alcohol Linked to Colorectal Cancer Risk” http://www.medscape.com/viewarticle/749886
 
“Excessive alcohol consumption favours high risk polyp or colorectal cancer occurrence among patients with adenomas: a case control study” http://gut.bmj.com/content/50/1/38.full
 
 
 
“High vitamin D levels linked to lower risk of colon cancer” http://www3.imperial.ac.uk/newsandeventspggrp/imperialcollege/newssummary/news_22-1-2010-13-46-0
 
 
 
 
“Anthocyanins in Purple, Blue and Red Foods Fight Colon Cancer” http://reliawire.com/anthocyanins-purple-blue-red-foods-fight-colon-cancer/
 
“Purple Potatoes Could Fight Colon Cancer” http://www.emaxhealth.com/1275/purple-potatoes-could-fight-colon-cancer
 
“Prunes reduce colon cancer risk by benefiting healthy gut bacteria” http://www.belmarrahealth.com/prunes-reduce-colon-cancer-risk-by-benefiting-healthy-gut-bacteria/
 
“BLACK RASPBERRIES A POTENTIALLY POWERFUL AGENT IN FIGHT AGAINST COLON CANCER” https://researchnews.osu.edu/archive/brberry.htm
 
 
 
 
 
 
 
“G‐protein coupled receptor 55 (GPR55), a lysophospholipid receptor, has been shown to play an important role in carcinogenesis. GPR55 is involved in the migratory behaviour of colon carcinoma cells and may serve as a pharmacological target for the prevention of metastasis.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4688947/
“The putative cannabinoid receptor GPR55 promotes cancer cell proliferation.” http://www.ncbi.nlm.nih.gov/pubmed/21057532
 “L-α-lysophosphatidylinositol meets GPR55: a deadly relationship. Evidence points to a role of L-α-lysophosphatidylinositol (LPI) in cancer.” http://www.ncbi.nlm.nih.gov/pubmed/21367464
“Modulation of l-α-Lysophosphatidylinositol/GPR55 Mitogen-activated Protein Kinase (MAPK) Signaling by Cannabinoids*. Here, we report that the little investigated cannabis constituents CBDV, CBGA, and CBGV are potent inhibitors of LPI-induced GPR55 signaling. The phytocannabinoids Δ9-tetrahydrocannabivarin, cannabidivarin, and cannabigerovarin are also potent inhibitors of LPI. Our findings also suggest that GPR55 may be a new pharmacological target for the following C. sativa constituents: Δ9-THCV, CBDV, CBGA, and CBGV. These Cannabis sativa constituents may represent novel therapeutics targeting GPR55.” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3249141/
 “Cannabinoids and cancer: potential for colorectal cancer therapy.” https://www.ncbi.nlm.nih.gov/pubmed/16042581
 “The endogenous cannabinoid system protects against colonic inflammation”  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC385396/
 “Cannabinoids in intestinal inflammation and cancer. In vivo, cannabinoids – via direct or indirect activation of CB(1) and/or CB(2) receptors – exert protective effects in well-established models of intestinal inflammation and colon cancer. Pharmacological elevation of endocannabinoid levels may be a promising strategy to counteract intestinal inflammation and colon cancer.” http://www.ncbi.nlm.nih.gov/pubmed/19442536
 “Cannabinoids have become a novel therapeutic approach against colon cancer with protective and anti-tumoral effects on colorectal carcinoma cell lines and in animal models of colon cancer” http://impactjournals.com/oncoscience/index.php?pii=119 
 “Possible endocannabinoid control of colorectal cancer growth. Inhibitors of endocannabinoid inactivation may prove useful anticancer agents.” https://www.ncbi.nlm.nih.gov/pubmed/12949714
“Increased endocannabinoid levels reduce the development of precancerous lesions in the mouse colon. Cannabinoids have been licensed for clinical use as palliative treatment of chemotherapy, but increasing evidence shows antitumor actions of cannabinoid agonists on several tumor cells in vitro and in animal models” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2755791/

“Loss of cannabinoid receptor 1 accelerates intestinal tumor growth”  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2561258/

“Turned-off Cannabinoid Receptor Turns On Colorectal Tumor Growth” https://www.sciencedaily.com/releases/2008/08/080801074056.htm

“Turning CB1 back on and then treating with a cannabinoid agonist could provide a new approach to colorectal cancer treatment or prevention. Cannabinoids are a group of ligands that serve a variety of cell-signaling roles. Some are produced by the body internally (endocannabinoids). External cannabinoids include manmade versions and those present in plants, most famously the active ingredient in marijuana (THC).” http://www.news-medical.net/news/2008/08/03/40485.aspx

“Cannabinoid Receptor Activation Induces Apoptosis through Tumor Necrosis Factor α–Mediated Ceramide De novo Synthesis in Colon Cancer Cells. The present study shows that either CB1 or CB2 receptor activation induces apoptosis through ceramide de novo synthesis in colon cancer cells. ” http://clincancerres.aacrjournals.org/content/14/23/7691.long

“The cannabinoid delta(9)-tetrahydrocannabinol inhibits RAS-MAPK and PI3K-AKT survival signalling and induces BAD-mediated apoptosis in colorectal cancer cells. Here, we report that CB1 and CB2 cannabinoid receptors are expressed in human colorectal adenoma and carcinoma cells, and show for the first time that THC induces apoptosis in colorectal cancer cells. The use of THC, or selective targeting of the CB1 receptor, may represent a novel strategy for colorectal cancer therapy.” http://www.ncbi.nlm.nih.gov/pubmed/17583570

“Programmed Cell Death (Apoptosis)” http://www.ncbi.nlm.nih.gov/books/NBK26873/

“Cannabis-Linked Cell Receptor Might Help Prevent Colon Cancer” http://www.medicinenet.com/script/main/art.asp?articlekey=91511

“Chemopreventive effect of the non-psychotropic phytocannabinoid cannabidiol on experimental colon cancer. Cannabidiol, a safe and non-psychotropic ingredient of Cannabis sativa, exerts pharmacological actions (antioxidant and intestinal antinflammatory) and mechanisms (inhibition of endocannabinoid enzymatic degradation) potentially beneficial for colon carcinogenesis. It is concluded that cannabidiol exerts chemopreventive effect in vivo and reduces cell proliferation through multiple mechanisms.” https://www.ncbi.nlm.nih.gov/pubmed/22231745

“CBD-Rich Marijuana Fights Colon Cancer, New Study Finds” http://blog.sfgate.com/smellthetruth/2014/01/06/cbd-rich-marijuana-fights-colon-cancer-new-study-finds/

“Inhibition of colon carcinogenesis by a standardized Cannabis sativa extract with high content of cannabidiol. Cannabis-based medicines are useful adjunctive treatments in cancer patients.” http://www.ncbi.nlm.nih.gov/pubmed/24373545

“Cannabigerol (CBG) is a safe non-psychotropic Cannabis-derived cannabinoid. CBG hampers colon cancer progression in vivo and selectively inhibits the growth of colorectal cancer cells. CBG should be considered translationally in colorectal cancer prevention and cure.” http://www.ncbi.nlm.nih.gov/pubmed/25269802

“According to researchers at the University of Texas in Houston chemicals in marijuana could be a potential cure in the treatment of colon cancer.” http://www.digitaljournal.com/article/258161

“Cannabis compound clue to colon cancer”  https://www.newscientist.com/article/mg19926685.000-cannabis-compound-clue-to-colon-cancer/

“Marijuana takes on colon cancer” https://www.newscientist.com/article/dn14451-marijuana-takes-on-colon-cancer/

“Cannabinoids appear to kill tumor cells but do not affect their nontransformed counterparts and may even protect them from cell death. Tumor specimens revealed that THC had antiangiogenic and antiproliferative effects. CBD has also been demonstrated to exert a chemopreventive effect in a mouse model of colon cancer. In in vitro experiments involving colorectal cancer cell lines, the investigators found that CBD protected DNA from oxidative damage, increased endocannabinoid levels, and reduced cell proliferation. In addition, both plant-derived and endogenous cannabinoids have been studied for anti-inflammatory effects. A mouse study demonstrated that endogenous cannabinoid system signaling is likely to provide intrinsic protection against colonic inflammation. As a result, a hypothesis that phytocannabinoids and endocannabinoids may be useful in the risk reduction and treatment of colorectal cancer has been developed.” http://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#section/_7

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The role of exercise training and the endocannabinoid system in atherosclerotic plaque burden and composition in Apo-E-deficient mice.

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“We investigated the effect of combining exercise training and treatment with an endocannabinoid receptor 1 inhibitor (Rimonabant) on atherosclerosis burden and composition.

Both exercise and rimonabant treatments induced plaque regression and promoted plaque stability. The combined treatment failed to show additive or synergistic benefits relative to either intervention alone.”

https://www.ncbi.nlm.nih.gov/pubmed/28254386

CB1 receptor-mediated respiratory depression by endocannabinoids.

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“Endocannabinoids (ECs) are bioactive lipid mediators acting on two distinct cannabinoid receptors (CB1 and CB2), which are ubiquitously expressed in many tissues including the respiratory system. Despite numerous experimental data showing that cannabinomimetics influence respiration, the role of endogenously produced ECs in respiratory control has not been verified yet. Pulse oximetry was used in the present study to directly measure changes in respiratory parameters during elevation of EC levels. The cannabinoid reuptake inhibitor AM-404 (10mgkg-1, i.v.), but not its vehicle, induced a transient reduction of respiratory rate with a concomitant depression of arterial oxygen saturation and increase in breath distension in wild-type mice. In contrast, CB1 knock-out mice showed no alteration in any of these parameters upon administration of AM-404. Our results imply that the EC system has an important role in the physiological control of respiration by modulating the respiratory rate and consequently influencing arterial oxygen saturation. Furthermore, this mechanism is entirely dependent on CB1 receptors.”

https://www.ncbi.nlm.nih.gov/pubmed/28254562

The Direct Actions of Cannabidiol and 2-Arachidonoyl Glycerol at GABAA Receptors.

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“Cannabidiol (CBD) is a major non-intoxicating component of cannabis and possesses anti-epileptic, anxiolytic and anti-hyperalgesic properties.

Despite evidence that some endogenous and synthetic cannabinoids interact with GABAA receptors, no-one has yet investigated the effects of CBD.

Here we used two-electrode voltage clamp electrophysiology to compare the actions of CBD with those of the major central endocannabinoid, 2-arachidonoyl glycerol (2-AG) on human recombinant GABAA receptors (synaptic α1-6βg2 and extrasynaptic α4β2δ) expressed on Xenopus oocytes.

Taken together these results reveal a mode of action of CBD on specifically configured GABAA receptors that may be relevant to the anticonvulsant and anxiolytic effects of the compound.”

https://www.ncbi.nlm.nih.gov/pubmed/28249817

Changes in the Brain Endocannabinoid System in Rat Models of Depression.

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“A growing body of evidence implicates the endocannabinoid (eCB) system in the pathophysiology of depression.

The aim of this study was to investigate the influence of changes in the eCB system, such as levels of neuromodulators, eCB synthesizing and degrading enzymes, and cannabinoid (CB) receptors, in different brain structures in animal models of depression using behavioral and biochemical analyses.

These findings suggest that dysregulation in the eCB system is implicated in the pathogenesis of depression, although neurochemical changes were linked to the particular brain structure and the factor inducing depression (surgical removal of the olfactory bulbs vs. genetic modulation).”

https://www.ncbi.nlm.nih.gov/pubmed/28247204