The central cannabinoid receptor type-2 (CB2) and chronic pain.

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“Cannabinoid receptor type-2 (CB2, CB2 Receptor, or CB2-R) mediates analgesia, via two mechanisms. CB2 receptors contained in peripheral immune tissue mediates analgesia by altering cytokine profiles, and thus has little adverse effects on central nervous systems. CB2 is also expressed in the neurons and glial cells of the Central Nervous System (CNS). This neuronal expression may also contribute to pain attenuation. The CB2 receptor has been proposed as a potential target in treating chronic pain of several etiologies.”

https://www.ncbi.nlm.nih.gov/pubmed/27842450

Survey of herbal cannabis (marijuana) use in rheumatology clinic attenders with a rheumatologist confirmed diagnosis.

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“Cannabinoids may hold potential for the management of rheumatic pain.

Arthritis, often self-reported, is commonly cited as the reason for the use of medicinal herbal cannabis (marijuana). We have examined the prevalence of marijuana use among 1000 consecutive rheumatology patients with a rheumatologist-confirmed diagnosis and compared in an exploratory manner the clinical characteristics of medicinal users and nonusers.

Current marijuana use, medicinal or recreational, was reported by 38 patients (3.8%; 95% CI: 2.8-5.2). Ever use of marijuana for medical purposes was reported by 4.3% (95% CI: 3.2-5.7), with 28 (2.8%; 95% CI: 1.9-4.0) reporting current medicinal use. Current medicinal users had a spectrum of rheumatic conditions, with over half diagnosed with osteoarthritis. Medicinal users were younger, more likely unemployed or disabled, and reported poorer global health. Pain report and opioid use was greater for users, but they had similar physician global assessment of disease status compared with nonusers.

Medicinal users were more likely previous recreational users, with approximately 40% reporting concurrent recreational use. Therefore, less than 3% of rheumatology patients reported current use of medicinal marijuana. This low rate of use in patients with a rheumatologist-confirmed diagnosis is in stark contrast to the high rates of severe arthritis frequently reported by medicinal marijuana users, especially in Canada. Familiarity with marijuana as a recreational product may explain use for some as disease status was similar for both groups.”

https://www.ncbi.nlm.nih.gov/pubmed/27842047

The combination of β-caryophyllene, baicalin and catechin synergistically suppresses the proliferation and promotes the death of RAW267.4 macrophages in vitro.

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“β-caryophyllene, which is a constituent of many essential oils, has been known to be a selective agonist of the cannabinoid receptor type-2 and to exert cannabimimetic anti-inflammatory effects in animals.

On the whole, this study demonstrates that the combination of β-caryophyllene, baicalin and (+)-catechin exerts synergistic suppressive effects on macrophages in vitro.

This composition may be a useful as an anti-inflammatory treatment strategy.”

https://www.ncbi.nlm.nih.gov/pubmed/27840942

Antagonism of cannabinoid receptor 1 attenuates the anti-inflammatory effects of electroacupuncture in a rodent model of migraine.

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“The anti-nociceptive effects of electroacupuncture (EA) in migraine have been documented in multiple randomised controlled trials.

Neurogenic inflammation plays a key role in migraine attacks, and the anti-inflammatory effects of acupuncture have been associated with the type 1 cannabinoid (CB1) receptor.

CB1 receptors appear to mediate anti-inflammatory effects of EA in a rat model of migraine.”

https://www.ncbi.nlm.nih.gov/pubmed/27834685

Cannabinoid receptor ligand bias: implications in the central nervous system.

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“The G protein-coupled cannabinoid receptors CB1, CB2, GPR18, and GPR55 regulate neurotransmission, pain, and inflammation and have been intensively investigated as potential drug targets. Each of these GPCRs is coupled to multiple effector proteins mediating divergent cellular signals. The ligand bias of cannabinoid-targeted compounds is only beginning to be quantified. Research into cannabinoid bias is now revealing correlations between bias in cell culture and functional outcomes in vivo. We present an example study of cannabinoid bias in the context of Huntington disease. In future, an understanding of cannabinoid receptor structure and quantification of ligand bias will optimize drug selection matched to patient population and disease.”

https://www.ncbi.nlm.nih.gov/pubmed/27835801

PTSD: from neurobiology to pharmacological treatments.

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“Posttraumatic stress disorder (PTSD) is a chronic debilitating psychiatric disorder characterized by symptoms of re-experience, avoidance, and hyperarousal that can arise immediately or many years after exposure to a traumatic event and injury. Although extensive research has been done over the past 30 years, the etiology of PTSD remains largely unknown. Several neurobiological systems have been implicated in the pathophysiology and vulnerability for developing PTSD; however, first-line pharmacotherapies are limited. Less than 30% achieve full remission, and even then, approved pharmacological treatments often take weeks for therapeutic effect. This article aims to review the pathophysiology of PTSD within multiple neurobiological systems and how these mechanisms are used as pharmacologic targets of treatment, as well as their potential for future targets of intervention.”

 https://www.ncbi.nlm.nih.gov/pubmed/27837583

Novel indole-based compounds that differentiate alkylindole-sensitive receptors from cannabinoid receptors and microtubules: Characterization of their activity on glioma cell migration.

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“Indole-based compounds, such as the alkyl-indole (AI) compound WIN55212-2, activate the cannabinoid receptors, CB1 and CB2, two well-characterized G protein-coupled receptors (GPCR). Reports indicate that several indole-based cannabinoid agonists, including WIN55212-2, lack selectivity and interact with at least two additional targets: AI-sensitive GPCRs and microtubules. Studying how indole-based compounds modulate the activity of these 4 targets has been difficult as selective chemical tools were not available. Here we report the pharmacological characterization of six newly-developed indole-based compounds (ST-11, ST-23, ST-25, ST-29, ST-47 and ST-48) that exhibit distinct binding affinities at AI-sensitive receptors, cannabinoid CB1 and CB2 receptors and the colchicine site of tubulin. Several compounds exhibit some level of selectivity for AI-sensitive receptors, including ST-11 that binds AI-sensitive receptors with a Kd of 52nM and appears to have a weaker affinity for the colchicine site of tubulin (Kd=3.2μM) and does not bind CB1/CB2 receptors. Leveraging these characteristics, we show that activation of AI-sensitive receptors with ST-11 inhibits both the basal and stimulated migration of the Delayed Brain Tumor (DBT) mouse glioma cell line. Our study describes a new series of indole-based compounds that enable the pharmacological and functional differentiation of alkylindole-sensitive receptors from cannabinoidreceptors and microtubules.”

https://www.ncbi.nlm.nih.gov/pubmed/27832960

A cannabinoid link between mitochondria and memory.

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“Cellular activity in the brain depends on the high energetic support provided by mitochondria, the cell organelles which use energy sources to generate ATP. Acute cannabinoid intoxication induces amnesia in humans and animals, and the activation of type-1cannabinoid receptors present at brain mitochondria membranes (mtCB1) can directly alter mitochondrial energetic activity. Although the pathological impact of chronic mitochondrial dysfunctions in the brain is well established, the involvement of acute modulation of mitochondrial activity in high brain functions, including learning and memory, is unknown. Here, we show that acute cannabinoid-induced memory impairment in mice requires activation of hippocampal mtCB1 receptors. Genetic exclusion of CB1 receptors from hippocampal mitochondria prevents cannabinoid-induced reduction of mitochondrial mobility, synaptic transmission and memory formation. mtCB1 receptors signal through intra-mitochondrial Gαi protein activation and consequent inhibition of soluble-adenylyl cyclase (sAC). The resulting inhibition of protein kinase A (PKA)-dependent phosphorylation of specific subunits of the mitochondrial electron transport system eventually leads to decreased cellular respiration. Hippocampal inhibition of sAC activity or manipulation of intra-mitochondrial PKA signalling or phosphorylation of the Complex I subunit NDUFS2 inhibit bioenergetic and amnesic effects ofcannabinoids. Thus, the G protein-coupled mtCB1 receptors regulate memory processes via modulation of mitochondrial energy metabolism. By directly linking mitochondrial activity to memory formation, these data reveal that bioenergetic processes are primary acute regulators of cognitive functions.”

https://www.ncbi.nlm.nih.gov/pubmed/27828947

Cannabinoid CB1 Receptors Are Localized in Striated Muscle Mitochondria and Regulate Mitochondrial Respiration.

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“The cannabinoid type 1 (CB1) receptor is widely distributed in the brain and peripheral organs where it regulates cellular functions and metabolism. In the brain, CB1 is mainly localized on presynaptic axon terminals but is also found on mitochondria (mtCB1), where it regulates cellular respiration and energy production. Likewise, CB1 is localized on muscle mitochondria, but very little is known about it. The aim of this study was to further investigate in detail the distribution and functional role of mtCB1 in three different striated muscles.

Immunoelectron microscopy for CB1 was used in skeletal muscles (gastrocnemius and rectus abdominis) and myocardium from wild-type and CB1 -KO mice. Functional assessments were performed in mitochondria purified from the heart of the mice and the mitochondrial oxygen consumption upon application of different acute delta-9-tetrahydrocannabinol (Δ9-THC) concentrations (100 nM or 200 nM) was monitored. About 26% of the mitochondrial profiles in gastrocnemius, 22% in the rectus abdominis and 17% in the myocardium expressed CB1. Furthermore, the proportion of mtCB1 versus total CB1 immunoparticles was about 60% in the gastrocnemius, 55% in the rectus abdominis and 78% in the myocardium. Importantly, the CB1 immunolabeling pattern disappeared in muscles of CB1 -KO mice.

Functionally, acute 100 nM or 200 nM THC treatment specifically decreased mitochondria coupled respiration between 12 and 15% in wild-type isolated mitochondria of myocardial muscles but no significant difference was noticed between THC treated and vehicle in mitochondria isolated from CB1 -KO heart. Furthermore, gene expression of key enzymes involved in pyruvate synthesis, tricarboxylic acid (TCA) cycle and mitochondrial respiratory chain was evaluated in the striated muscle of CB1 -WT and CB1 -KO. CB1 -KO showed an increase in the gene expression of Eno3, Pkm2, and Pdha1, suggesting an increased production of pyruvate. In contrast, no significant difference was observed in the Sdha and Cox4i1 expression, between CB1 -WT andCB1 -KO.

In conclusion, CB1 receptors in skeletal and myocardial muscles are predominantly localized in mitochondria. The activation of mtCB1 receptors may participate in the mitochondrial regulation of the oxidative activity probably through the relevant enzymes implicated in the pyruvate metabolism, a main substrate for TCA activity.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5078489/

Tetrahydrocannabinol:Cannabidiol Oromucosal Spray for Multiple Sclerosis-Related Resistant Spasticity in Daily Practice.

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“Tetrahydrocannabinol:cannabidiol (THC:CBD) oromucosal spray (Sativex®) is an add-on therapy for moderate-to-severe multiple sclerosis (MS)-related drug-resistant spasticity (MSS).

In everyday clinical practice, THC:CBD oromucosal spray provided symptomatic relief of MSS and related troublesome symptoms.”

https://www.ncbi.nlm.nih.gov/pubmed/27732980