The Role of the Brain’s Endocannabinoid System in Pain and Its Modulation by Stress.

Posted on December 8, 2015 by David

“Stress has a complex, bidirectional modulatory influence on pain. Stress may either reduce (stress-induced analgesia) or exacerbate (stress-induced hyperalgesia) pain depending on the nature, duration, and intensity of the stressor.

The endogenous cannabinoid (endocannabinoid) system is present throughout the neuroanatomical pathways that mediate and modulate responses to painful stimuli.

The specific role of the endocannabinoid system in the brain in pain and the modulation of pain by stress is reviewed herein.

We first provide a brief overview of the endocannabinoid system, followed by a review of the evidence that the brain’s endocannabinoid system modulates pain.

We provide a comprehensive evaluation of the role of the endocannabinoid system supraspinally, and particularly in the rostral ventromedial medulla, periaqueductal gray, amygdala, and prefrontal cortex, in pain, stress-induced analgesia, and stress-induced hyperalgesia.

Increased understanding of endocannabinoid-mediated regulation of pain and its modulation by stress will inform the development of novel therapeutic approaches for pain and its comorbidity with stress-related disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/26638768

Inhibitors of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase: New Targets for Future Antidepressants.

Posted on December 8, 2015 by David

“Cannabis and analogs of Δ9-tetrahydrocannabinol have been used for therapeutic purposes…

Endogenous cannabinoids have been discovered, and dysregulation of endocannabinoid signaling is implicated in the pathophysiology of major depressive disorder (MDD).

Recently, endocannabinoid hydrolytic enzymes such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) have become new therapeutic targets in the treatment of MDD.

Several FAAH or MAGL inhibitors are reported to have no cannabimimetic side effects and, therefore, are new potential therapeutic options for patients with MDD who are resistant to first-line antidepressants (selective serotonin and serotonin-norepinephrine reuptake inhibitors).

In this review, we focus on the possible relationships between MDD and the endocannabinoid system as well as the inhibitors’ therapeutic potential.

MAGL inhibitors may reduce inflammatory responses through activation of cannabinoid receptor type 2.

In the hypothalamic-pituitary-adrenal axis, repeated FAAH inhibitor administration may be beneficial for reducing circulating glucocorticoid levels. Both FAAH and MAGL inhibitors may contribute to dopaminergic system regulation. Recently, several new inhibitors have been developed with strong potency and selectivity. FAAH inhibitor, MAGL inhibitor, or dual blocker use would be promising new treatments for MDD. Further pre-clinical studies and clinical trials using these inhibitors are warranted.”

http://www.ncbi.nlm.nih.gov/pubmed/26630956

Computational Prediction and Biochemical Analyses of New Inverse Agonists for the CB1 Receptor.

Posted on December 4, 2015 by David

“Human cannabinoid type 1 (CB1) G-protein coupled receptor is a potential therapeutic target for obesity.

The previously predicted and experimentally validated ensemble of ligand-free conformations of CB1 are used here to predict the binding sites for known CB1-selective inverse agonists including rimonabant and its seven known derivatives.

This binding pocket, which differs significantly from previously published models, is used to identify 16 novel compounds expected to be CB1 inverse agonists by exploiting potential new interactions.

We show experimentally that two of these compounds exhibit inverse agonist properties including inhibition of basal and agonist-induced G-protein coupling activity, as well as an enhanced level of CB1 cell surface localization.

This demonstrates the utility of using the predicted binding sites for an ensemble of CB1 receptor structures for designing new CB1 inverse agonists.”

http://www.ncbi.nlm.nih.gov/pubmed/26633590

Potentiation of the antitumor activity of adriamycin against osteosarcoma by cannabinoid WIN-55,212-2

Posted on December 3, 2015 by David

“Osteosarcoma is the most frequent primary malignant bone tumor that occurs in children and adolescents. Osteosarcoma is a bone malignancy that predominantly affects children and adolescents, and exhibits high invasion and metastasis rates.

Although adriamycin (ADM) is an effective benchmark agent for the management of osteosarcoma, it also results in harmful side-effects including toxicity and chemoresistance that substantially affect the quality of life of patients. Therefore, novel therapeutic approaches and drugs must be sought for the treatment of osteosarcoma.

Natural products which have potential antitumor activities have become a focus of attention for study in previous years. Cannabinoids, the active components naturally derived from the marijuana plant Cannabis sativa L., have been reported as potential antitumor drugs based on their ability to limit inflammation, cell proliferation and cell survival.

To date, several cannabinoids have been identified and characterized, including Δ(9)-tetrahydrocannabinol (THC), cannabidiol, cannabinol (CBN) and anandamide, as well as synthetic cannabinoids, including WIN-55,212-2, JWH-133 and (R)-methanandamide.

In the early 1970s, THC and CBN were shown to inhibit tumor growth in Lewis lung carcinoma. Subsequently, cannabinoids were found to induce apoptosis and inhibit the proliferation of various cancer cells, including those of glioma and lymphoma, and prostate, breast, skin and pancreatic cancer…

In conclusion, the present study indicated that cannabinoid WIN-55,212-2 is antiproliferative, antimetastatic and antiangiogenic against MG-63 cells in vitro, and presented evidence that cannabinoid WIN-55,212-2 may result in synergistic antitumor action in combination with ADM against osteosarcoma.

These findings may offer a novel strategy for the treatment of osteosarcoma.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4580018/

A Sativex(®) -like combination of phytocannabinoids as a disease-modifying therapy in a viral model of multiple sclerosis.

Posted on November 23, 2015 by David

“Sativex(®) is an oromucosal spray, containing equivalent amounts of Δ(9) -tetrahydrocannabinol (Δ(9) -THC) and cannabidiol (CBD)-botanical drug substance (BDS), which has been approved for the treatment of spasticity and pain associated to multiple sclerosis (MS).

In this study, we investigated whether Sativex may also serve as a disease-modifying agent in the Theiler’s murine encephalomyelitis virus-induced demyelinating disease model of MS.

The data support the therapeutic potential of Sativex to slow MS progression and its relevance in CNS repair.”

http://www.ncbi.nlm.nih.gov/pubmed/25857324

The endocannabinoid system in guarding against fear, anxiety and stress.

Posted on November 21, 2015 by David

“The endocannabinoid (eCB) system has emerged as a central integrator linking the perception of external and internal stimuli to distinct neurophysiological and behavioural outcomes (such as fear reaction, anxiety and stress-coping), thus allowing an organism to adapt to its changing environment.

eCB signalling seems to determine the value of fear-evoking stimuli and to tune appropriate behavioural responses, which are essential for the organism’s long-term viability, homeostasis and stress resilience; and dysregulation of eCB signalling can lead to psychiatric disorders.

An understanding of the underlying neural cell populations and cellular processes enables the development of therapeutic strategies to mitigate behavioural maladaptation.”

http://www.ncbi.nlm.nih.gov/pubmed/26585799

Controlled release tablet formulation containing natural δ9 tetrahydrocannabinol.

Posted on November 21, 2015 by David

“Cannabinoids are increasingly being used in the treatment of chemotherapy induced nausea and vomiting (CINV) because of their action on the cannabinoid receptors, CB1 and CB2.

The currently marketed capsule formulations (sesame oil based and crystalline powder) are required to be administered frequently to maintain therapeutic levels, which leads to non-compliance.

In the present study, oral controlled release tablet formulations of Δ9- tetrahydrocannabinol (THC) were prepared using the lipids Precirol® and Compritrol®. Release profiles using THC-lipid matrices and/or with the lipids in the external phase (blend) were evaluated…

The overall results demonstrate the feasibility of preparing oral THC tablets for once a day administration which can improve CINV management.”

http://www.ncbi.nlm.nih.gov/pubmed/26585693

Pharmacological benefits of selective modulation of cannabinoid receptor type 2 (CB2) in experimental Alzheimer’s disease.

Posted on November 19, 2015 by David

“Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that pervasively affects the population across the world.

Currently, there is no effective treatment available for this and existing drugs merely slow the progression of cognitive function decline. Thus, massive effort is required to find an intended therapeutic target to overcome this condition.

The present study has been framed to investigate the ameliorative role of selective modulator of cannabinoid receptor type 2 (CB2), 1-phenylisatin in experimental AD condition…

Hence, this study concludes that CB2 receptor modulation can be a potential therapeutic target for the management of AD.”

http://www.ncbi.nlm.nih.gov/pubmed/26577751

Cannabidiol as potential treatment in refractory pediatric epilepsy.

Posted on November 17, 2015 by David

“In recent years there has been great scientific and public interest focused on the therapeutic potential of compounds derived from cannabis for the treatment of refractory epilepsy in children.

From in vitro and in vivo studies on animal models, cannabidiol (CBD) appears to be a promising anticonvulsant drug with a favorable side-effect profile.

In humans, CBD efficacy and safety is not supported by well designed trials and its use has been described by anecdotal reports.

It will be necessary to investigate CBD safety, pharmacokinetics and interaction with other antiepileptic drugs alongside performing double-blinded placebo-controlled trials in order to obtain conclusive data on its efficacy and safety in children.”

http://www.ncbi.nlm.nih.gov/pubmed/26567560

http://www.thctotalhealthcare.com/category/epilepsy-2/

Seeing over the horizon – targeting the endocannabinoid system for the treatment of ocular disease.

Posted on November 14, 2015 by David

“The observation that marijuana reduces intraocular pressure was made by Hepler and Frank in the 1970s. Since then, there has been a significant body of work investigating cannabinoids for their potential use as therapeutics.

To date, no endocannabinoid system (ECS)-modulating drug has been approved for clinical use in the eye; however, recent advances in our understanding of the ECS, as well as new pharmacological tools, has renewed interest in the development of ocular ECS-based therapeutics.

This review summarizes the current state-of-affairs for the use of ECS-modulating drugs for the treatment of glaucoma and ocular inflammatory and ischemic disease.”

http://www.ncbi.nlm.nih.gov/pubmed/26565550