Tetrahydrocannabivarin (THCv) reduces Default Mode Network and increases Executive Control Network Resting State Functional Connectivity in Healthy Volunteers.

Posted on September 13, 2015 by David

“The cannabinoid CB1 Neutral Antagonist Tetrahydrocannabivarin (THCv) has been suggested as a possible treatment for obesity but without the depressogenic side-effects of inverse antagonists such as Rimonabant.

Our findings are the first to show that treatment with the CB1 neutral antagonist THCv decreases resting state functional connectivity in the Default Mode network and increases connectivity in the Cognitive Control network and Dorsal Visual Stream network.

This effect profile suggests possible therapeutic activity of THCv for obesity where functional connectivity has been found to be altered in these regions.”

http://www.ncbi.nlm.nih.gov/pubmed/26362774

Combination cannabinoid and opioid receptor antagonists improves metabolic outcomes in obese mice.

Posted on September 12, 2015 by David

“This study demonstrates that the combination of rimonabant, naloxone and norBNI is effective at producing weight loss over a sustained period of time without altering performance in standardised mouse behaviour tests. Fos expression patterns offer insight into the neuroanatomical substrates subserving these physiological and behavioural changes.

These results indicate that CB1-targeted drugs for weight loss may still be feasible.”

http://www.ncbi.nlm.nih.gov/pubmed/26360587

Cannabinoid Ligands and Alcohol Addiction: A Promising Therapeutic Tool or a Humbug?

Posted on September 12, 2015 by David

“The vast therapeutic potential of cannabinoids of both synthetic and plant-derived origins currently makes these compounds the focus of a growing interest. Although cannabinoids are still illicit drugs, their possible clinical usefulness, including treatment of acute or neuropathic pain, have been suggested by several studies.

In addition, some observations indicate that cannabinoid receptor antagonists may be useful for the treatment of alcohol dependence and addiction, which is a major health concern worldwide.

While the synergism between alcohol and cannabinoid agonists (in various forms) creates undesirable side effects when the two are consumed together, the administration of CB1 antagonists leads to a significant reduction in alcohol consumption.

Furthermore, cannabinoid antagonists also mitigate alcohol withdrawal symptoms.

Herein, we present an overview of studies focusing on the effects of cannabinoid ligands (agonists and antagonists) during acute or chronic consumption of ethanol.”

http://www.ncbi.nlm.nih.gov/pubmed/26353844

Cannabinoid-based drugs targeting CB1 and TRPV1, the sympathetic nervous system, and arthritis.

Posted on September 8, 2015 by David

“Chronic inflammation in rheumatoid arthritis (RA) is accompanied by activation of the sympathetic nervous system, which can support the immune system to perpetuate inflammation. Several animal models of arthritis already demonstrated a profound influence of adrenergic signaling on the course of RA.

Peripheral norepinephrine release from sympathetic terminals is controlled by cannabinoid receptor type 1 (CB1), which is activated by two major endocannabinoids (ECs), arachidonylethanolamine (anandamide) and 2-arachidonylglycerol.

These ECs also modulate function of transient receptor potential channels (TRPs) located on sensory nerve fibers, which are abundant in arthritic synovial tissue. TRPs not only induce the sensation of pain but also support inflammation via secretion of pro-inflammatory neuropeptides.

In addition, many cell types in synovial tissue express CB1 and TRPs.

In this review, we focus on CB1 and transient receptor potential vanilloid 1 (TRPV1)-mediated effects on RA since most anti-inflammatory mechanisms induced by cannabinoids are attributed to cannabinoid receptor type 2 (CB2) activation.

We demonstrate how CB1 agonism or antagonism can modulate arthritic disease.

The concept of functional antagonism with continuous CB1 activation is discussed.

Since fatty acid amide hydrolase (FAAH) is a major EC-degrading enzyme, the therapeutic possibility of FAAH inhibition is studied.

Finally, the therapeutic potential of ECs is examined since they interact with cannabinoid receptors and TRPs but do not produce central side effects.”

http://www.ncbi.nlm.nih.gov/pubmed/26343051

Endocannabinoid System Contributes to Liver Injury and Inflammation by Activation of Bone Marrow-Derived Monocytes/Macrophages in a CB1-Dependent Manner.

Posted on September 1, 2015 by David

“Hepatic injury undergoes significant increases in endocannabinoids and infiltrations of macrophages, yet the concrete mechanisms of changes in endocannabinoids and the functions of macrophage-expressed cannabinoid receptors (CBs) are unclear…

In the chimeric murine model, we found that blockade of CB1 by administration of a CB1 antagonist inhibited the recruitment of Bone marrow-derived monocytes/macrophages (BMM) into injured liver using immunofluorescence staining and FACS, but it did not have effects on migration of T cells and dendritic cells without CB1 expression. Furthermore, activation of CB1 enhanced cytokine expression of BMM. In vivo, inhibition of CB1 attenuated the inflammatory cytokine level through real-time RT-PCR and cytometric bead array, ameliorating hepatic inflammation and fibrosis.

In this study, we identify inactivation of BMM-expressed CB1 as a therapeutic strategy for reducing hepatic inflammation and fibrosis.”

http://www.ncbi.nlm.nih.gov/pubmed/26320250

Monoacylglycerol Lipase Regulates Fever Response.

Posted on August 21, 2015 by David

“Cyclooxygenase inhibitors such as ibuprofen have been used for decades to control fever through reducing the levels of the pyrogenic lipid transmitter prostaglandin E2 (PGE2). Historically, phospholipases have been considered to be the primary generator of the arachidonic acid (AA) precursor pool for generating PGE2 and other eicosanoids. However, recent studies have demonstrated that monoacyglycerol lipase (MAGL), through hydrolysis of the endocannabinoid 2-arachidonoylglycerol, provides a major source of AA for PGE2 synthesis in the mammalian brain under basal and neuroinflammatory states. We show here that either genetic or pharmacological ablation of MAGL leads to significantly reduced fever responses in both centrally or peripherally-administered lipopolysaccharide or interleukin-1β-induced fever models in mice. We also show that a cannabinoid CB1 receptor antagonist does not attenuate these anti-pyrogenic effects of MAGL inhibitors. Thus, much like traditional nonsteroidal anti-inflammatory drugs, MAGL inhibitors can control fever, but appear to do so through restricted control over prostaglandin production in the nervous system.”

http://www.ncbi.nlm.nih.gov/pubmed/26287872

The emerging role of the endocannabinoid system in the pathogenesis and treatment of kidney diseases.

Posted on August 19, 2015 by David

“Endocannabinoids (eCBs) are endogenous lipid ligands that bind to cannabinoid receptors that also mediate the effects of marijuana.

The eCB system is comprised of eCBs, anandamide, and 2-arachidonoyl glycerol, their cannabinoid-1 and cannabinoid-2 receptors (CB1 and CB2, respectively), and the enzymes involved in their biosynthesis and degradation.

It is present in both the central nervous system and peripheral organs including the kidney.

The current review focuses on the role of the eCB system in normal kidney function and various diseases, such as diabetes and obesity, that directly contributes to the development of renal pathologies.

Normally, activation of the CB1 receptor regulates renal vascular hemodynamics and stimulates the transport of ions and proteins in different nephron compartments. In various mouse and rat models of obesity and type 1 and 2 diabetes mellitus, eCBs generated in various renal cells activate CB1 receptors and contribute to the development of oxidative stress, inflammation, and renal fibrosis.

These effects can be chronically ameliorated by CB1 receptor blockers.

In contrast, activation of the renal CB2 receptors reduces the deleterious effects of these chronic diseases.

Because the therapeutic potential of globally acting CB1 receptor antagonists in these conditions is limited due to their neuropsychiatric adverse effects, the recent development of peripherally restricted CB1 receptor antagonists may represent a novel pharmacological approach in treating renal diseases.”

http://www.ncbi.nlm.nih.gov/pubmed/26280171

Synthesis and biological evaluation of (3′,5′-dichloro-2,6-dihydroxy-biphenyl-4-yl)-aryl/alkyl-methanone selective CB2 inverse agonist.

Posted on August 17, 2015 by David

“Cannabinoid receptor 2 (CB2) selective agonists and inverse agonists possess significant potential as therapeutic agents for regulating inflammation and immune function.

Although CB2 agonists have received the greatest attention, it is emerging that inverse agonists also manifest anti-inflammatory activity.

In process of designing new cannabinoid ligands we discovered that the 2,6-dihydroxy-biphenyl-aryl methanone scaffold imparts inverse agonist activity at CB2 receptor without functional activity at CB1. To further explore the scaffold we synthesized a series of (3′,5′-dichloro-2,6-dihydroxy-biphenyl-4-yl)-aryl/alkyl-methanone analogs and evaluated the CB1 and CB2 affinity, potency, and efficacy.

The studies reveal that an aromatic C ring is required for inverse agonist activity and that substitution at the 4 position is optimum. The resorcinol moiety is required for optimum CB2 inverse agonist activity and selectivity. Antagonist studies against CP 55,940 demonstrate that the compounds 41 and 45 are noncompetitive antagonists at CB2.”

http://www.ncbi.nlm.nih.gov/pubmed/26275680

Cannabidiol is a negative allosteric modulator of the type 1 cannabinoid receptor.

Posted on July 29, 2015 by David

“Cannabidiol has been reported to act as an antagonist of cannabinoid agonists at type 1 cannabinoid receptors (CB1 ).

We hypothesized that cannabidiol can inhibit cannabinoid agonist activity through negative allosteric modulation of CB1…

Cannabidiol behaved as a non-competitive negative allosteric modulator of CB1 .

Allosteric modulation, in conjunction with non-CB1 effects, may explain the in vivo effects of cannabidiol.

Allosteric modulators of CB1 have the potential to treat central nervous system and peripheral disorders while avoiding the adverse effects associated with orthosteric agonism or antagonism of CB1.”

http://www.ncbi.nlm.nih.gov/pubmed/26218440

Aiming for allosterism: Evaluation of allosteric modulators of CB1 in a neuronal model.

Posted on July 29, 2015 by David

“Cannabinoid pharmacology has proven nettlesome with issues of promiscuity a common theme among both agonists and antagonists.

One recourse is to develop allosteric ligands to modulate cannabinoid receptor signaling.

Cannabinoids have come late to the allosteric table…

In summary, three of the allosteric modulators evaluated function in a manner consistent with allosterism in a neuronal 2-AG-based model of endogenous cannabinoid signaling.”

http://www.ncbi.nlm.nih.gov/pubmed/26211948

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