Tag Archives: cannabinoid receptors

The nonpsychotropic cannabinoid cannabidiol modulates and directly activates alpha-1 and alpha-1-Beta glycine receptor function.

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“Loss of inhibitory synaptic transmission within the dorsal horn of the spinal cord plays a key role in the development of chronic pain following inflammation or nerve injury. Inhibitory postsynaptic transmission in the adult spinal cord involves mainly glycine.

Cannabidiol is a nonpsychotropic plant constituent of Cannabis sativa.

As we hypothesized that non-CB receptor mechanisms of cannabidiol might contribute to its anti-inflammatory and neuroprotective effects, we investigated the interaction of cannabidiol with strychnine-sensitive alpha(1 )and alpha(1)beta glycine receptors by using the whole-cell patch clamp technique.

Cannabidiol showed a positive allosteric modulating effect in a low micromolar concentration range (EC(50) values: alpha(1) = 12.3 +/- 3.8 micromol/l and alpha(1)beta = 18.1 +/- 6.2 micromol/l). Direct activation of glycine receptors was observed at higher concentrations above 100 micromol/l (EC(50) values: alpha(1) = 132.4 +/- 12.3 micromol/l and alpha(1)beta = 144.3 +/- 22.7 micromol/l).

These in vitro results suggest that strychnine-sensitive glycine receptors may be a target for cannabidiol mediating some of its anti-inflammatory and neuroprotective properties.”

https://www.ncbi.nlm.nih.gov/pubmed/19204413

https://www.karger.com/Article/Abstract/201556

2-Arachidonoylglycerol: A signaling lipid with manifold actions in the brain.

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“2-Arachidonoylglycerol (2-AG) is a signaling lipid in the central nervous system that is a key regulator of neurotransmitter release. 2-AG is an endocannabinoid that activates the cannabinoid CB1 receptor. It is involved in a wide array of (patho)physiological functions, such as emotion, cognition, energy balance, pain sensation and neuroinflammation. In this review, we describe the biosynthetic and metabolic pathways of 2-AG and how chemical and genetic perturbation of these pathways has led to insight in the biological role of this signaling lipid. Finally, we discuss the potential therapeutic benefits of modulating 2-AG levels in the brain.”

 https://www.ncbi.nlm.nih.gov/pubmed/29751000
https://www.sciencedirect.com/science/article/pii/S0163782717300619

Emerging Role of (Endo)Cannabinoids in Migraine.

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“In this mini-review, we summarize recent discoveries and present new hypotheses on the role of cannabinoids in controlling trigeminal nociceptive system underlying migraine pain.

Individual sections of this review cover key aspects of this topic, such as: (i) the current knowledge on the endocannabinoid system (ECS) with emphasis on expression of its components in migraine related structures; (ii) distinguishing peripheral from central site of action of cannabinoids, (iii) proposed mechanisms of migraine pain and control of nociceptive traffic by cannabinoids at the level of meninges and in brainstem, (iv) therapeutic targeting in migraine of monoacylglycerol lipase and fatty acid amide hydrolase, enzymes which control the level of endocannabinoids; (v) dual (possibly opposing) actions of cannabinoids via anti-nociceptive CB1 and CB2 and pro-nociceptive TRPV1 receptors.

We explore the cannabinoid-mediated mechanisms in the frame of the Clinical Endocannabinoid Deficiency (CECD) hypothesis, which implies reduced tone of endocannabinoids in migraine patients. We further discuss the control of cortical excitability by cannabinoids via inhibition of cortical spreading depression (CSD) underlying the migraine aura.

Finally, we present our view on perspectives of Cannabis-derived (extracted or synthetized marijuana components) or novel endocannabinoid therapeutics in migraine treatment.”

https://www.ncbi.nlm.nih.gov/pubmed/29740328

https://www.frontiersin.org/articles/10.3389/fphar.2018.00420/full

Control of excessive neural circuit excitability and prevention of epileptic seizures by endocannabinoid signaling

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Cellular and Molecular Life Sciences

“Progress in research on endocannabinoid signaling has greatly advanced our understanding of how it controls neural circuit excitability in health and disease.

In general, endocannabinoid signaling at excitatory synapses suppresses seizures by inhibiting glutamate release. In contrast, endocannabinoid signaling promotes seizures by inhibiting GABA release at inhibitory synapses. The physiological distribution of endocannabinoid signaling molecules becomes disrupted with the development of epileptic focus in patients with mesial temporal lobe epilepsy and in animal models of experimentally induced epilepsy.

Augmentation of endocannabinoid signaling can promote the development of epileptic focus at initial stages. However, at later stages, increased endocannabinoid signaling delays it and suppresses spontaneous seizures. Thus, the regulation of endocannabinoid signaling at specific synapses that cause hyperexcitability during particular stages of disease development may be effective for treating epilepsy and epileptogenesis.”

https://link.springer.com/article/10.1007/s00018-018-2834-8

http://www.x-mol.com/paper/661834

Activation of the Cannabinoid Type 2 Receptor by a Novel Indazole Derivative Normalizes the Survival Pattern of Lymphoblasts from Patients with Late-Onset Alzheimer’s Disease.

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CNS Drugs

“Alzheimer’s disease is a multifactorial disorder for which there is no disease-modifying treatment yet.

CB2 receptors have emerged as a promising therapeutic target for Alzheimer’s disease because they are expressed in neuronal and glial cells and their activation has no psychoactive effects.

OBJECTIVE:

The aim of this study was to investigate whether activation of the CB2 receptor would restore the aberrant enhanced proliferative activity characteristic of immortalized lymphocytes from patients with late-onset Alzheimer’s disease. It is assumed that cell-cycle dysfunction occurs in both peripheral cells and neurons in patients with Alzheimer’s disease, contributing to the instigation of the disease.

METHODS:

Lymphoblastoid cell lines from patients with Alzheimer’s disease and age-matched control individuals were treated with a new, in-house-designed dual drug PGN33, which behaves as a CB2 agonist and butyrylcholinesterase inhibitor. We analyzed the effects of this compound on the rate of cell proliferation and levels of key regulatory proteins. In addition, we investigated the potential neuroprotective action of PGN33 in β-amyloid-treated neuronal cells.

RESULTS:

We report here that PGN33 normalized the increased proliferative activity of Alzheimer’s disease lymphoblasts. The compound blunted the calmodulin-dependent overactivation of the PI3K/Akt pathway, by restoring the cyclin-dependent kinase inhibitor p27 levels, which in turn reduced the activity of the cyclin-dependent kinase/pRb cascade. Moreover, this CB2 agonist prevented β-amyloid-induced cell death in neuronal cells.

CONCLUSION:

Our results suggest that the activation of CB2 receptors could be considered a useful therapeutic approach for Alzheimer’s disease.”

https://www.ncbi.nlm.nih.gov/pubmed/29736745

https://link.springer.com/article/10.1007%2Fs40263-018-0515-7

LH-21, A Peripheral Cannabinoid Receptor 1 Antagonist, Exerts Favorable Metabolic Modulation Including Antihypertensive Effect in KKAy Mice by Regulating Inflammatory Cytokines and Adipokines on Adipose Tissue.

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“Patients with obesity are susceptible to hypertension and diabetes. Over-activation of cannabinoid receptor 1 (CB1R) in adipose tissue is proposed in the pathophysiology of metabolic disorders, which led to the metabolic dysfunction of adipose tissue and deregulated production and secretion of adipokines.

In the current study, we determined the impact of LH-21, a representative peripheral CB1R antagonist, on the obesity-accompanied hypertension and explored the modulatory action of LH-21 on the adipose tissue in genetically obese and diabetic KKAy mice.

3-week LH-21 treatment significantly decreased blood pressure with a concomitant reduction in body weight, white adipose tissue (WAT) mass, and a slight loss on food intake in KKAy mice. Meanwhile, glucose handling and dyslipidemia were also markedly ameliorated after treatment. Gene expression of pro-inflammatory cytokines in WAT and the aortae were both attenuated apparently by LH-21, as well the mRNA expression of adipokines (lipocalin-2, leptin) in WAT. Concomitant amelioration on the accumulation of lipocalin-2 was observed in both WAT and aortae. In corresponding with this, serum inflammatory related cytokines (tumor necrosis factor α, IL-6, and CXCL1), and lipocalin-2 and leptin were lowered notably.

Thus according to current results, it can be concluded that the peripheral CB1R antagonist LH-21 is effective in managing the obesity-accompanied hypertension in KKAy mice. These metabolic benefits are closely associated with the regulation on the production and secretion of inflammatory cytokines and adipokines in the WAT, particularly alleviated circulating lipocalin-2 and its accumulation in aortae.”

https://www.ncbi.nlm.nih.gov/pubmed/29731737

https://www.frontiersin.org/articles/10.3389/fendo.2018.00167/full

Effects of cannabinoid type 2 receptor agonist AM1241 on morphine-induced antinociception, acute and chronic tolerance, and dependence in mice.

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“Morphine is a potent opioid analgesic used to alleviate moderate or severe pain but the development of drug tolerance and dependence limits its use in pain management.

Previous studies showed that cannabinoid type 2 (CB2) receptor ligands may modulate opioid effects. However, there is no report of the effect of CB2 receptor agonist on acute morphine tolerance and physical dependence. We therefore investigated the effect of a CB2 receptor agonist (AM1241) on morphine-induced morphine tolerance and physical dependence in mice.

Our findings suggest that coadministration of the CB2 receptor agonist and morphine could increase morphine antinociception and reduce morphine tolerance and physical dependence in mice.

PERSPECTIVE:

Combination of a CB2 agonist and morphine may provide a new strategy for better treatment of acute and chronic pain, and prevention of opioid tolerance and dependence. This may also provide a clue for the treatment of opioid tolerance and dependence in clinic.”

https://www.ncbi.nlm.nih.gov/pubmed/29729431

https://www.sciencedirect.com/science/article/pii/S1526590018301597

“Antinociceptive Synergy between 9 -Tetrahydrocannabinol and Opioids after Oral Administration” http://jpet.aspetjournals.org/content/jpet/304/3/1010.full.pdf

Molecular and cellular basis of cannabinoid and opioid interactions.

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 Pharmacology Biochemistry and Behavior

“Cannabinoids and opioids have been shown to possess several similar pharmacological effects, including analgesia and stimulation of brain circuitry that are believed to underlie drug addiction and reward. In recent years, these phenomena have supported the possible existence of functional links in the mechanisms of action of both types of drugs.

The present review addresses the recent advances in the study of biochemical and molecular mechanisms underlying opioid and cannabinoid interaction. Several hypothesis have been formulated to explain this cross-modulation including the release of opioid peptides by cannabinoids or endocannabinoids by opioids and interaction at the level of receptor and/or their signal transduction mechanisms.

Moreover it is important to consider that the nature of cannabinoid and opioid interaction might differ in the brain circuits mediating reward and in those mediating other pharmacological properties, such as antinociception.

Further studies are needed since a better knowledge of the opioid-cannabinoid interaction may lead to exciting therapeutic possibilities.”

https://www.ncbi.nlm.nih.gov/pubmed/15927245

https://www.sciencedirect.com/science/article/pii/S0091305705001450?via%3Dihub

Synergistic interactions between cannabinoid and opioid analgesics.

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Life Sciences

“Cannabinoids and opioids both produce analgesia through a G-protein-coupled mechanism that blocks the release of pain-propagating neurotransmitters in the brain and spinal cord. However, high doses of these drugs, which may be required to treat chronic, severe pain, are accompanied by undesirable side effects.

Thus, a search for a better analgesic strategy led to the discovery that delta 9-tetrahydrocannabinol (THC), the major psychoactive constituent of marijuana, enhances the potency of opioids such as morphine in animal models.

In addition, studies have determined that the analgesic effect of THC is, at least in part, mediated through delta and kappa opioid receptors, indicating an intimate connection between cannabinoid and opioid signaling pathways in the modulation of pain perception.

A host of behavioral and molecular experiments have been performed to elucidate the role of opioid receptors in cannabinoid-induced analgesia. The aim of such studies is to develop a novel analgesic regimen using low dose combinations of cannabinoids and opioids to effectively treat acute and chronic pain, especially pain that may be resistant to opioids alone.”

 https://www.ncbi.nlm.nih.gov/pubmed/14706563
https://www.sciencedirect.com/science/article/pii/S0024320503010129?via%3Dihub

The role of cannabinoid signaling in acute and chronic kidney diseases.

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 Image result for Kidney Int. “The endogenous cannabinoids anandamide and 2-arachidonoylglycerol bind to the cannabinoid receptors of type 1 and 2. These receptors are also the binding sites for exogenous, both natural and synthetic, cannabinoids that are used for recreation purposes.

Until recently, cannabinoids and cannabinoid receptors have attracted little interest among nephrologists; however, a full endocannabinoid system (ECS) is present in the kidney and it has recently emerged as an important player in the pathogenesis of diabetic nephropathy, drug nephrotoxicity, and progressive chronic kidney disease.

This newly established role of the ECS in the kidney might have therapeutic relevance, as pharmacological modulation of the ECS has renoprotective effects in experimental animals, raising hope for future potential applications in humans.

In addition, over the last years, there has been a number of reported cases of acute kidney injury (AKI) associated with the use of synthetic cannabinoids that appear to have higher potency and rate of toxicity than natural Cannabis. This poorly recognized cause of renal injury should be considered in the differential diagnosis of AKI, particularly in young people.

In this review we provide an overview of preclinical evidence indicating a role of the ECS in renal disease and discuss potential future therapeutic applications.”

https://www.ncbi.nlm.nih.gov/pubmed/29706358