Category Archives: Endocannabinoid System

Cannabinoid modulation of prefrontal-limbic activation during fear extinction learning and recall in humans.

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“Pre-extinction administration of Δ9-tetrahydrocannibinol (THC) facilitates recall of extinction in healthy humans, and evidence from animal studies suggest that this likely involves via enhancement of the cannabinoid system within the ventromedial prefrontal cortex (vmPFC) and hippocampus (HIPP), brain structures critical to fear extinction…

 This study provides the first evidence that pre-extinction administration of THC modulates prefrontal-limbic circuits during fear extinction in humans and prompts future investigation to test if cannabinoid agonists can rescue or correct the impaired behavioral and neural function during extinction recall in patients with PTSD.

 Ultimately, the cannabinoid system may serve as a promising target for innovative intervention strategies (e.g. pharmacological enhancement of exposure-based therapy) in PTSD and other fear learning-related disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/24055595

Cannabinoid facilitation of fear extinction memory recall in humans.

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“Animal studies have shown that activation of the cannabinoid system during extinction learning enhances fear extinction and its retention. Specifically, CB1 receptor agonists, such as Δ9-tetrahydrocannibinol (THC), can facilitate extinction recall by preventing recovery of extinguished fear…

 We conducted a study using a randomized, double-blind, placebo-controlled, between-subjects design, coupling a standard Pavlovian fear extinction paradigm and simultaneous skin conductance response (SCR) recording with an acute pharmacological challenge with oral dronabinol (synthetic THC) or placebo (PBO) 2 h prior to extinction learning in 29 healthy adult volunteers (THC = 14; PBO = 15) and tested extinction retention 24 h after extinction learning.

Compared to subjects that received PBO, subjects that received THC showed low SCR to a previously extinguished CS when extinction memory recall was tested 24 h after extinction learning, suggesting that THC prevented the recovery of fear.

These results provide the first evidence that pharmacological enhancement of extinction learning is feasible in humans using cannabinoid system modulators, which may thus warrant further development and clinical testing. This article is part of a Special Issue entitled ‘Cognitive Enhancers’.”

http://www.ncbi.nlm.nih.gov/pubmed/22796109

Selective Activation of Cannabinoid Receptor 2 in Leukocytes Suppresses Their Engagement of the Brain Endothelium and Protects the Blood-Brain Barrier.

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“Cannabinoid receptor 2 (CB2) is highly expressed in immune cells and stimulation decreases inflammatory responses. We tested the idea that selective CB2 activation in human monocytes suppresses their ability to engage the brain endothelium and migrate across the blood-brain barrier (BBB), preventing consequent injury…

These results indicate that selective CB2 activation in leukocytes decreases key steps in monocyte-BBB engagement, thus suppressing inflammatory leukocyte responses and preventing neuroinflammation.”

http://www.ncbi.nlm.nih.gov/pubmed/24055259

The role of androgen receptor in transcriptional modulation of cannabinoid receptor type 1 gene in rat trigeminal ganglia.

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“We have previously shown that anti-hyperalgesic effects of cannabinoid agonists under inflammatory condition are much greater in male than female, and that inflammatory cytokines upregulate cannabinoid receptor type 1 (CB1) expression in male, but not female, trigeminal ganglia (TG) in a testosterone-dependent manner. In this study, we investigated the mechanisms underlying the testosterone-mediated regulation of peripheral CB1 expression…

These experiments provided compelling evidence that testosterone regulates CB1 gene transcription in TG through AR following cytokine stimulation.

These results should provide mechanistic bases for understanding cytokine-hormone-neuron interactions in peripheral cannabinoid systems, and have important clinical implications for pain patients in whom testosterone level is naturally low, gradually declining or pharmacologically compromised.”

http://www.ncbi.nlm.nih.gov/pubmed/24055403

Critical appraisal of the potential use of cannabinoids in cancer management

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“Cannabinoids have been attracting a great deal of interest as potential anticancer agents. Originally derived from the plant Cannabis sativa, there are now a number of endo-, phyto- and synthetic cannabinoids available. This review summarizes the key literature to date around the actions, antitumor activity, and mechanisms of action for this broad range of compounds…

Two therapeutic avenues exist for the development of cannabinoids as anticancer agents. As antiemetic and analgesic compounds, this class of compounds has been explored in terms of palliative care. More recently, cannabinoid agonists and antagonists have been screened for potential direct antitumorigenic properties.

… results suggest that overall the cannabinoids affect multiple cellular signaling pathways, which means they have the potential to decrease cancer development, growth, and metastasis.

Overall, the cannabinoids may show future promise in the treatment of cancer, but there are many significant hurdles to be overcome. There is much still to be learned about the action of the cannabinoids and the endocannabinoid system.

It is a distinct possibility that the cannabinoids may have a place in the future treatment of cancer.”

Full Text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3770515/

Therapeutic Potential of a Novel Cannabinoid Agent CB52 in the Mouse Model ofExperimental Autoimmune Encephalomyelitis.

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“The endocannabinoid system has recently emerged as a promising therapeutic target for MS. The protective mechanisms of cannabinoids are thought to be mediated by activation of cannabinoid receptor 1 (CB1) and 2 (CB2)…

activation of CB1 receptors contributes significantly to the anti-inflammatory and neuroprotective effects of cannabinoids on MS.”

http://www.ncbi.nlm.nih.gov/pubmed/24036373

Cannabinoid receptors expression in bone marrow trephine biopsy of chronic lymphocytic leukaemia patients treated with purine analogues.

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“Cannabinoid receptors CB1 and CB2 are part the endocannabinoid system that plays an important role in the process of proliferation and apoptosis of different neoplastic cells. B-cell chronic lymphocytic leukaemia is one of the diseases in which these processes are altered… The aim of our study was the assessment of cannabinoid receptor expression on the B-lymphocytes in bone marrow trephine biopsy from leukaemic patients at diagnosis and after purine analogue treatment….

CONCLUSION:

The study provides original evidence for the existence of cannabinoid receptors on B-lymphocytes in chronic lymphocytic leukaemia patients. The receptors are thought to be a new structure that can modify the course of the disease and may be considered as a new target in leukaemia treatment.”

http://www.ncbi.nlm.nih.gov/pubmed/18004250

Anticancer activity of anandamide in human cutaneous melanoma cells.

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“Cannabinoids are implicated in the control of cell proliferation, but little is known about the role of the endocannabinoid system in human malignant melanoma. This study was aimed at characterizing the in vitro antitumor activity of anandamide (AEA) in A375 melanoma cells…

 Overall, these findings demonstrate that AEA induces cytotoxicity against human melanoma cells in the micromolar range of concentrations through a complex mechanism, which involve COX-2 and LOX-derived product synthesis and CB1 activation. Lipid raft modulation, probably linked to GPR55 activation, might also have a role.”

http://www.ncbi.nlm.nih.gov/pubmed/24041928

Therapeutic potential of cannabinoid medicines.

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Drug Testing and Analysis

“Cannabis was extensively used as a medicine throughout the developed world in the nineteenth century but went into decline early in the twentieth century ahead of its emergence as the most widely used illicit recreational drug later that century. Recent advances in cannabinoid pharmacology alongside the discovery of the endocannabinoid system (ECS) have re-ignited interest in cannabis-based medicines.

The ECS has emerged as an important physiological system and plausible target for new medicines. Its receptors and endogenous ligands play a vital modulatory role in diverse functions including immune response, food intake, cognition, emotion, perception, behavioural reinforcement, motor co-ordination, body temperature, wake/sleep cycle, bone formation and resorption, and various aspects of hormonal control. In disease it may act as part of the physiological response or as a component of the underlying pathology.

In the forefront of clinical research are the cannabinoids delta-9-tetrahydrocannabinol and cannabidiol, and their contrasting pharmacology will be briefly outlined. The therapeutic potential and possible risks of drugs that inhibit the ECS will also be considered. This paper will then go on to review clinical research exploring the potential of cannabinoid medicines in the following indications: symptomatic relief in multiple sclerosis, chronic neuropathic pain, intractable nausea and vomiting, loss of appetite and weight in the context of cancer or AIDS, psychosis, epilepsy, addiction, and metabolic disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/24006213

http://onlinelibrary.wiley.com/doi/10.1002/dta.1529/abstract

Small animal PET imaging of the type 1 cannabinoid receptor in a rodent model for anorexia nervosa.

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“Several lines of evidence strongly implicate a dysfunctional endocannabinoid system (ECS) in eating disorders…

CONCLUSION:

These data point to a widespread transient disturbance of the endocannabinoid transmission, specifically for CB1 receptors in the ABA model. Our data also suggest (1) gender effects on regional CB1 receptor binding in the hippocampus and (2) add further proof to the validity of the ABA model to mimic aspects of human disease.”

http://www.ncbi.nlm.nih.gov/pubmed/24006151