Tag Archives: cannabinoid receptors

Circulating Endocannabinoids: From Whence Do They Come and Where are They Going?

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Related image“The goal of this review is to summarize studies in which concentrations of circulating endocannabinoids in humans have been examined in relationship to physiological measurements and pathological status. The roles of endocannabinoids in the regulation of energy intake and storage have been well studied and the data obtained consistently support the hypothesis that endocannabinoid signaling is associated with increased consumption and storage of energy. Physical exercise mobilizes endocannabinoids, which could contribute to refilling of energy stores and also to the analgesic and mood-elevating effects of exercise. Circulating concentrations of 2-arachidonoylglycerol are very significantly circadian and dysregulated when sleep is disrupted. Other conditions under which circulating endocannabinoids are altered include inflammation and pain. A second important role for endocannabinoid signaling is to restore homeostasis following stress. Circulating endocannabinoids are stress-responsive and there is evidence that their concentrations are altered in disorders associated with excessive stress, including post-traumatic stress disorder. Although determination of circulating endocannabinoids can provide important information about the state of endocannabinoid signaling and thus allow for hypotheses to be defined and tested, the large number of physiological factors that contribute to their circulating concentrations makes it difficult to use them in isolation as a biomarker for a specific disorder.” https://www.ncbi.nlm.nih.gov/pubmed/28653665

https://www.nature.com/npp/journal/vaop/naam/abs/npp2017130a.html

The cannabinoid ligand LH-21 reduces anxiety and improves glucose handling in diet-induced obese pre-diabetic mice.

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“LH-21 is a triazol derivative that has been described as a low-permeant neutral CB1 antagonist, though its pharmacology is still unclear. It has been associated with anti-obesity actions in obese rats. However, its role in preventing type 2 diabetes (T2D) onset have not been studied yet. Given CB1 receptors remain as potential pharmacological targets to fight against obesity and T2D, we wanted to explore the metabolic impact of this compound in an animal model of obesity and pre-diabetes as well as the lack of relevant actions in related central processes such as anxiety. These results suggest that LH-21 can be a new candidate to fight against diabetes onset. Indeed, this compound shows potential in counteracting obesity-related anxiety.” https://www.ncbi.nlm.nih.gov/pubmed/28638091   https://www.nature.com/articles/s41598-017-03292-w

“Anti-obesity efficacy of LH-21, a cannabinoid CB(1) receptor antagonist with poor brain penetration, in diet-induced obese rats.”  https://www.ncbi.nlm.nih.gov/pubmed/21951309

“Antiobesity effects of the novel in vivo neutral cannabinoid receptor antagonist 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-hexyl-1H-1,2,4-triazole–LH 21.”  https://www.ncbi.nlm.nih.gov/pubmed/16750544

The cannabinoid system and pain.

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“Chronic pain states are highly prevalent and yet poorly controlled by currently available analgesics, representing an enormous clinical, societal, and economic burden. Existing pain medications have significant limitations and adverse effects including tolerance, dependence, gastrointestinal dysfunction, cognitive impairment, and a narrow therapeutic window, making the search for novel analgesics ever more important. In this article, we review the role of an important endogenous pain control system, the endocannabinoid (EC) system, in the sensory, emotional, and cognitive aspects of pain. Herein, we briefly cover the discovery of the EC system and its role in pain processing pathways, before concentrating on three areas of current major interest in EC pain research; 1. Pharmacological enhancement of endocannabinoid activity (via blockade of EC metabolism or allosteric modulation of CB1receptors); 2. The EC System and stress-induced modulation of pain; and 3. The EC system & medial prefrontal cortex (mPFC) dysfunction in pain states. Whilst we focus predominantly on the preclinical data, we also include extensive discussion of recent clinical failures of endocannabinoid-related therapies, the future potential of these approaches, and important directions for future research on the EC system and pain.”

https://www.ncbi.nlm.nih.gov/pubmed/28625720

http://www.sciencedirect.com/science/article/pii/S002839081730285X

Synaptic functions of endocannabinoid signaling in health and disease.

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“Endocannabinoids (eCBs) are a family of lipid molecules that act as key regulators of synaptic transmission and plasticity. They are synthetized “on demand” following physiological and/or pathological stimuli. Once released from postsynaptic neurons, eCBs typically act as retrograde messengers to activate presynaptic type 1 cannabinoid receptors (CB1) and induce short- or long-term depression of neurotransmitter release. Besides this canonical mechanism of action, recent findings have revealed a number of less conventional mechanisms by which eCBs regulate neural activity and synaptic function, suggesting that eCB-mediated plasticity is mechanistically more diverse than anticipated. These mechanisms include non-retrograde signaling, signaling via astrocytes, participation in long-term potentiation, and the involvement of mitochondrial CB1. Focusing on paradigmatic brain areas, such as hippocampus, striatum, and neocortex, we review typical and novel signaling mechanisms, and discuss the functional implications in normal brain function and brain diseases. In summary, eCB signaling may lead to different forms of synaptic plasticity through activation of a plethora of mechanisms, which provide further complexity to the functional consequences of eCB signaling.”

https://www.ncbi.nlm.nih.gov/pubmed/28625718

http://www.sciencedirect.com/science/article/pii/S0028390817302861

Metabolism of the Endocannabinoid Anandamide: Open Questions after 25 Years.

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“Cannabis extracts have been used for centuries, but its main active principle ∆9-tetrahydrocannabinol (THC) was identified about 50 years ago. Yet, it is only 25 years ago that the first endogenous ligand of the same receptors engaged by the cannabis agents was discovered. This “endocannabinoid (eCB)” was identified as N-arachidonoylethanolamine (or anandamide (AEA)), and was shown to have several receptors, metabolic enzymes and transporters that altogether drive its biological activity. Here I report on the latest advances about AEA metabolism, with the aim of focusing open questions still awaiting an answer for a deeper understanding of AEA activity, and for translating AEA-based drugs into novel therapeutics for human diseases.”

https://www.ncbi.nlm.nih.gov/pubmed/28611591

http://journal.frontiersin.org/article/10.3389/fnmol.2017.00166/full

Endocannabinoid System in Neurodegenerative Disorders.

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Journal of Neurochemistry

“Most neurodegenerative disorders (NDDs) are characterized by cognitive impairment and other neurological defects. The definite cause of and pathways underlying the progression of these NDDs are not well defined. Several mechanisms have been proposed to contribute to the development of NDDs. These mechanisms may proceed concurrently or successively, and they differ among cell types at different developmental stages in distinct brain regions. The endocannabinoid system, which involves cannabinoid receptors type 1 (CB1R) and type 2 (CB2R), endogenous cannabinoids and the enzymes that catabolize these compounds, has been shown to contribute to the development of NDDs in several animal models and human studies. In this review, we discuss the functions of the endocannabinoid (EC) system in NDDs and converse the therapeutic efficacy of targeting the endocannabinoid system to rescue NDDs.”

https://www.ncbi.nlm.nih.gov/pubmed/28608560

http://onlinelibrary.wiley.com/doi/10.1111/jnc.14098/abstract

Cannabidiol upregulates melanogenesis through CB1 dependent pathway by activating p38 MAPK and p42/44 MAPK.

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“Melanogenesis plays a critical role in the protection of skin against external stresses such as ultraviolet irradiation and oxidative stressors. This study was aimed to investigate the effects of cannabidiol on melanogenesis and its mechanisms of action in human epidermal melanocytes. We found that cannabidiol increased both melanin content and tryrosinase activity. The mRNA levels of microphthalmia-associated transcription factor (MITF), tyrosinase, tyrosinase-related protein (TRP) 1, and TRP2 were increased following cannabidiol treatment. Likewise, cannabidiol increased the protein levels of MITF, TRP 1, TRP 2, and tyrosinase. Mechanistically, we found that cannabidiol regulated melanogenesis by upregulating MITF through phosphorylation of p38 mitogen-activated protein kinase (MAPK) and p42/44 MAPK, independent of cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) signaling. In addition, the melanogenic effect of cannabidiol was found to be mediated by cannabinoid CB1 receptor, not by CB2receptor. Taken together, these findings indicate that cannabidiol-induced melanogenesis is cannabinoid CB1 receptor-dependent, and cannabidiol induces melanogenesis through increasing MITF gene expression which is mediated by activation of p38 MAPK and p42/44 MAPK. Our results suggest that cannabidiol might be useful as a protective agent against external stresses.”

https://www.ncbi.nlm.nih.gov/pubmed/28601556

http://www.sciencedirect.com/science/article/pii/S0009279716304343

Medicinal Uses of Marijuana and Cannabinoids

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“In the past two decades, there has been increasing interest in the therapeutic potential of cannabis and single cannabinoids, mainly cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC). THC and cannabis products rich in THC exert their effects mainly through the activation of cannabinoid receptors (CB1 and CB2). Since 1975, 140 controlled clinical trials using different cannabinoids or whole-plant preparations for the treatment of a large number of disorders and symptoms have been conducted. Results have led to the approval of cannabis-based medicines [dronabinol, nabilone, and the cannabis extract nabiximols (Sativex®, THC:CBD = 1:1)] as well as cannabis flowers in several countries. Controlled clinical studies provide substantial evidence for the use of cannabinoid receptor agonists in cancer chemotherapy induced nausea and vomiting, appetite loss and cachexia in cancer and HIV patients, neuropathic and chronic pain, and in spasticity in multiple sclerosis. In addition, there is also some evidence suggesting a therapeutic potential of cannabis-based medicines in other indications including Tourette syndrome, spinal cord injury, Crohn’s disease, irritable bowel syndrome, and glaucoma. In several other indications, small uncontrolled and single-case studies reporting beneficial effects are available, for example in posttraumatic stress disorder, attention deficit hyperactivity disorder, and migraine. The most common side effects of THC and cannabis-based medicines rich in THC are sedation and dizziness (in more than 10% of patients), psychological effects, and dry mouth. Tolerance to these side effects nearly always develops within a short time. Withdrawal symptoms are hardly ever a problem in the therapeutic setting. In recent years there is an increasing interest in the medical use of CBD, which exerts no intoxicating side effects and is usually well-tolerated. Preliminary data suggest promising effects in the treatment of anxiety disorders, schizophrenia, dystonia, and some forms of epilepsy. This review gives an overview on clinical studies which have been published over the past 40 years.”

http://www.tandfonline.com/doi/abs/10.1080/07352689.2016.1265360?needAccess=true&journalCode=bpts20

“Review Identifies 140 Controlled Clinical Trials Related to Cannabis”  http://blog.norml.org/2017/06/04/review-identifies-140-controlled-clinical-trials-related-to-cannabis/

Analysis of Natural Product Regulation of Cannabinoid Receptors in the treatment of Human Disease.

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“The organized tightly regulated signaling relays engaged by the cannabinoid receptors (CBs) and their ligands, G proteins and other effectors, together constitute the endocannabinoid system (ECS). This system governs many biological functions including cell proliferation, regulation of ion transport and neuronal messaging. This review will firstly examine the physiology of the ECS, briefly discussing some anomalies in the relay of the ECS signaling as these are consequently linked to maladies of global concern including neurological disorders, cardiovascular disease and cancer.

While endogenous ligands are crucial for dispatching messages through the ECS, there are also commonalities in binding affinities with copious exogenous ligands, both natural and synthetic. Therefore, this review provides a comparative analysis of both types of exogenous ligands with emphasis on natural products given their putative safer efficacy and the role of Δ9-tetrahydrocannabinol (Δ9-THC) in uncovering the ECS.

Efficacy is congruent to both types of compounds but noteworthy is the effect of a combination therapy to achieve efficacy without the unideal side-effects. An example is Sativex that displayed promise in treating Huntington’s disease (HD) in preclinical models allowing for its transition to current clinical investigation. Despite the in vitro and preclinical efficacy of Δ9-THC to treat neurodegenerative ailments, its psychotropic effects limit its clinical applicability to treating feeding disorders.

We therefore propose further investigation of other compounds and their combinations such as the triterpene, α,β-amyrin that exhibited greater binding affinity to CB1 than CB2 and was more potent than Δ9-THC and the N-alkylamides that exhibited CB2 selective affinity, the latter can be explored towards peripherally exclusive ECS modulation. The synthetic CB1 antagonist, Rimonabant was pulled from market for the treatment of diabetes, however its analogue SR144528 maybe an ideal lead molecule towards this end and HU-210 and Org27569 are also promising synthetic small molecules.”

https://www.ncbi.nlm.nih.gov/pubmed/28583800

http://www.sciencedirect.com/science/article/pii/S0163725817301511

GPR3 and GPR6, novel molecular targets for cannabidiol.

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“GPR3 and GPR6 are members of a family of constitutively active, Gs protein-coupled receptors. Previously, it has been reported that GPR3 is involved in Alzheimer’s disease whereas GPR6 plays potential roles in Parkinson’s disease.

GPR3 and GPR6 are considered orphan receptors because there are no confirmed endogenous agonists for them. However, GPR3 and GPR6 are phylogenetically related to the cannabinoid receptors.

In this study, the activities of endocannabinoids and phytocannabinoids were tested on GPR3 and GPR6 using a β-arrestin2 recruitment assay. Among the variety of cannabinoids tested, cannabidiol (CBD), the major non-psychoactive component of marijuana, significantly reduced β-arrestin2 recruitment to both GPR3 and GPR6. In addition, the inhibitory effects of CBD on β-arrestin2 recruitment were concentration-dependent for both GPR3 and GPR6, with a higher potency for GPR6.

These data show that CBD acts as an inverse agonist at both GPR3 and GPR6 receptors. These results demonstrate for the first time that both GPR3 and GPR6 are novel molecular targets for CBD.

Our discovery that CBD acts as a novel inverse agonist on both GPR3 and GPR6 indicates that some of the potential therapeutic effects of CBD (e.g. treatment of Alzheimer’s disease and Parkinson’s disease) may be mediated through these important receptors.”

https://www.ncbi.nlm.nih.gov/pubmed/28571738

http://www.sciencedirect.com/science/article/pii/S0006291X17310744