Cellular Distribution of Canonical and Putative Cannabinoid Receptors in Canine Cervical Dorsal Root Ganglia.

Image result for frontiers in veterinary science“Growing evidence indicates cannabinoid receptors as potential therapeutic targets for chronic pain.

Consequently, there is an increasing interest in developing cannabinoid receptor agonists for treating human and veterinary pain.

The present study may represent a morphological substrate to consider in order to develop therapeutic strategies against chronic pain.”

https://www.ncbi.nlm.nih.gov/pubmed/31608295

“The anti-nociceptive potential of the endocannabinoid system has prompted the development of therapeutic cannabinoid receptors agonists or medical marjiuana to be used in pets in order to treat chronic pain.”

https://www.frontiersin.org/articles/10.3389/fvets.2019.00313/full

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Effects of cannabidiol (CBD) in neuropsychiatric disorders: A review of pre-clinical and clinical findings.

Progress in Molecular Biology and Translational Science“Cannabis sativa (cannabis) is one of the oldest plants cultivated by men. Cannabidiol (CBD) is the major non-psychomimetic compound derived from cannabis. It has been proposed to have a therapeutic potential over a wide range of neuropsychiatric disorders.

In this narrative review, we have summarized a selected number of pre-clinical and clinical studies, examining the effects of CBD in neuropsychiatric disorders. In some pre-clinical studies, CBD was demonstrated to potentially exhibit anti-epileptic, anti-oxidant, anti-inflammatory anti-psychotic, anxiolytic and anti-depressant properties. Moreover, CBD was shown to reduce addictive effects of some drugs of abuse.

In clinical studies, CBD was shown to be safe, well-tolerated and efficacious in mitigating the symptoms associated with several types of seizure disorders and childhood epilepsies.

Given that treatment with CBD alone was insufficient at managing choreic movements in patients with Huntington’s disease, other cannabis-derived treatments are currently being investigated. Patients with Parkinson’s disease (PD) have reported improvements in sleep and better quality of life with CBD; however, to fully elucidate the therapeutic potential of CBD on the symptoms of PD-associated movement disorders, larger scale, randomized, placebo-controlled studies still need to be conducted in the future.

Currently, there are no human studies that investigated the effects of CBD in either Alzheimer’s disease or unipolar depression, warranting further investigation in this area, considering that CBD was shown to have effects in pre-clinical studies.

Although, anxiolytic properties of CBD were reported in the Social Anxiety Disorder, antipsychotic effects in schizophrenia and anti-addictive qualities in alcohol and drug addictions, here too, larger, randomized, placebo-controlled trials are needed to evaluate the therapeutic potential of CBD.”

https://www.ncbi.nlm.nih.gov/pubmed/31601406

https://www.sciencedirect.com/science/article/pii/S187711731930095X?via%3Dihub

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Cannabinoid Receptor Type 1 and Its Role as an Analgesic: An Opioid Alternative?

 Publication Cover“Understanding how the body regulates pain is fundamental to develop rational strategies to combat the growing prevalence of chronic pain states, opioid dependency, and the increased financial burden to the medical care system.

Pain is the most prominent reason why Americans seek medical attention and extensive literature has identified the importance of the endocannabinoid pathway in controlling pain. Modulation of the endocannabinoid system offers new therapeutic opportunities for the selective control of excessive neuronal activity in several pain conditions (acute, inflammatory, chronic, and neuropathic).

Cannabinoids have a long history of medicinal use and their analgesic properties are well documented; however, there are major impediments to understanding cannabinoid pain modulation.

One major issue is the presence of psychotropic side effects associated with D9-tetrahydrocannabinol (THC) or synthetic derivatives, which puts an emphatic brake on their use. This dose-limiting effect prevents the appropriate degree of analgesia .

Animal studies have shown that the psychotropic effects are mediated via brain cannabinoid type 1 (CB1) receptors, while analgesic activity in chronic pain states may be mediated via CB1R action in the spinal cord, brainstem, peripheral sensory neurons, or immune cells.

The development of appropriate therapies is incumbent on our understanding of the role of peripheral versus central endocannabinoid-driven analgesia. Recent physiological, pharmacological, and anatomical studies provide evidence that one of the main roles of the endocannabinoid system is the regulation of gamma-aminobutyric acid (GABA) and/or glutamate release.

This article will review this evidence in the context of its implications for pain. We first provide a brief overview of CB1R’s role in the regulation of nociception, followed by a review of the evidence that the peripheral endocannabinoid system modulates nociception.

We then look in detail at regulation of central-mediated analgesia, followed up with evidence that cannabinoid mediated modulation of pain involves modulation of GABAergic and glutamatergic neurotransmission in key brain regions. Finally, we discuss cannabinoid action on non-neuronal cells in the context of inflammation and direct modulation of neurons.

This work stands to reveal long-standing controversies in the cannabinoid analgesia area that have had an impact on failed clinical trials and implementation of therapeutics targeting this system.”

https://www.ncbi.nlm.nih.gov/pubmed/31596190

https://www.tandfonline.com/doi/abs/10.1080/15504263.2019.1668100?journalCode=wjdd20

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Cannabinoid receptor 1 knockout alleviates hepatic steatosis by downregulating perilipin 2.

Image result for LI laboratory investigations journal“The endocannabinoid (EC) system has been implicated in the pathogenesis of several metabolic diseases, including nonalcoholic fatty liver disease (NAFLD).

With the current study we aimed to verify the modulatory effect of endocannabinoid receptor 1 (CB1)-signaling on perilipin 2 (PLIN2)-mediated lipophagy.

In conclusion, these results suggest that loss of CB1 signaling leads to reduced PLIN2 abundance, which triggers lipophagy. Our new findings about the association between CB1 signaling and PLIN2 may stimulate translational studies analyzing new diagnostic and therapeutic options for NAFLD.”

https://www.ncbi.nlm.nih.gov/pubmed/31570772

“In conclusion, we demonstrated that the CB1 receptor knockout in vivo and pharmacologic antagonization of CB1 in cell culture decreased PLIN2 expression, which might be an essential step in lipid breakdown. Thus, pharmacologic modulation of the CB1-PLIN2 axis might represent a novel therapeutic approach for the treatment of steatosis.”

https://www.nature.com/articles/s41374-019-0327-5

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Absence of Entourage: Terpenoids Commonly Found in Cannabis sativa Do Not Modulate the Functional Activity of Δ9-THC at Human CB1 and CB2 Receptors.

 View details for Cannabis and Cannabinoid Research cover image“Compounds present in Cannabis sativa such as phytocannabinoids and terpenoids may act in concert to elicit therapeutic effects. Cannabinoids such as Δ9-tetrahydrocannabinol (Δ9-THC) directly activate cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2); however, it is not known if terpenoids present in Cannabis also affect cannabinoid receptor signaling. Therefore, we examined six common terpenoids alone, and in combination with cannabinoid receptor agonists, on CB1 and CB2 signaling in vitro.

Results: α-Pinene, β-pinene, β-caryophyllene, linalool, limonene, and β-myrcene (up to 30-100 μM) did not change membrane potential in AtT20 cells expressing CB1 or CB2, or affect the response to a maximally effective concentration of the synthetic cannabinoid CP55,940. The presence of individual or a combination of terpenoids did not affect the hyperpolarization produced by Δ9-THC (10 μM): (CB1: control, 59%±7%; with terpenoids (10 μM each) 55%±4%; CB2: Δ9-THC 16%±5%, with terpenoids (10 μM each) 17%±4%). To investigate possible effect on desensitization of CB1 responses, all six terpenoids were added together with Δ9-THC and signaling measured continuously over 30 min. Terpenoids did not affect desensitization, after 30 min the control hyperpolarization recovered by 63%±6% in the presence of the terpenoids recovery was 61%±5%.

Discussion: None of the six of the most common terpenoids in Cannabis directly activated CB1 or CB2, or modulated the signaling of the phytocannabinoid agonist Δ9-THC. These results suggest that if a phytocannabinoid-terpenoid entourage effect exists, it is not at the CB1 or CB2 receptor level. It remains possible that terpenoids activate CB1 and CB2 signaling pathways that do not involve potassium channels; however, it seems more likely that they may act at different molecular target(s) in the neuronal circuits important for the behavioral effect of Cannabis.”

https://www.ncbi.nlm.nih.gov/pubmed/31559333

https://www.liebertpub.com/doi/10.1089/can.2019.0016

“Terpenoids and Phytocannabinoids Co-Produced in Cannabis Sativa Strains Show Specific Interaction for Cell Cytotoxic Activity. We found that in “high THC” or “high CBD” strains, phytocannabinoids are produced alongside certain sets of terpenoids. Only co-related terpenoids enhanced the cytotoxic activity of phytocannabinoids on MDA-MB-231 and HCT-116 cell lines. This was found to be most effective in natural ratios found in extracts of cannabis inflorescence.”  https://www.ncbi.nlm.nih.gov/pubmed/31438532

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Preclinical and Clinical Evidence Supporting Use of Cannabidiol in Psychiatry.

Image result for hindawi “Cannabidiol (CBD) is a major chemical compound present in Cannabis sativa.

CBD is a nonpsychotomimetic substance, and it is considered one of the most promising candidates for the treatment of psychiatric disorders.

The aim of this review is to illustrate the state of art about scientific research and the evidence of effectiveness of CBD in psychiatric patients.

RESULTS:

Preclinical and clinical studies on potential role of CBD in psychiatry were collected and further discussed. We found four clinical studies describing the effects of CBD in psychiatric patients: two studies about schizophrenic patients and the other two studies carried out on CBD effects in patients affected by generalized social anxiety disorder (SAD).

CONCLUSION:

Results from these studies are promising and suggest that CBD may have a role in the development of new therapeutic strategies in mental diseases, and they justify an in-depth commitment in this field. However, clinical evidence we show for CBD in psychiatric patients is instead still poor and limited to schizophrenia and anxiety, and it needs to be implemented with further studies carried out on psychiatric patients.”

https://www.ncbi.nlm.nih.gov/pubmed/31558911

“Results of our research, enriched in assessment of methodological quality of the studies, confirm the view of this cannabinoid as a promising molecule especially in particular sectors of psychiatry such as schizophrenia, anxiety, depression, and autism. CBD is considered a safe substance and is one of the most promising candidates for the treatment of psychiatric disorders”.

https://www.hindawi.com/journals/ecam/2019/2509129/

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Potential of Cannabinoid Receptor Ligands as Treatment for Substance Use Disorders.

 “Substance use disorder (SUD) is a major public health crisis worldwide, and effective treatment options are limited.

During the past 2 decades, researchers have investigated the impact of a variety of pharmacological approaches to treat SUD, one of which is the use of medical cannabis or cannabinoids.

Significant progress was made with the discovery of rimonabant, a selective CB1 receptor (CB1R) antagonist (also an inverse agonist), as a promising therapeutic for SUDs and obesity. However, serious adverse effects such as depression and suicidality led to the withdrawal of rimonabant (and almost all other CB1R antagonists/inverse agonists) from clinical trials worldwide in 2008.

Since then, much research interest has shifted to other cannabinoid-based strategies, such as peripheral CB1R antagonists/inverse agonists, neutral CB1R antagonists, allosteric CB1R modulators, CB2R agonists, fatty acid amide hydrolase (FAAH) inhibitors, monoacylglycerol lipase (MAGL) inhibitors, fatty acid binding protein (FABP) inhibitors, or nonaddictive phytocannabinoids with CB1R or CB2R-binding profiles, as new therapeutics for SUDs.

In this article, we first review recent progress in research regarding the endocannabinoid systems, cannabis reward versus aversion, and the underlying receptor mechanisms. We then review recent progress in cannabinoid-based medication development for the treatment of SUDs.

As evidence continues to accumulate, neutral CB1R antagonists (such as AM4113), CB2R agonists (JWH133, Xie2-64), and nonselective phytocannabinoids (cannabidiol, β-caryophyllene, ∆9-tetrahydrocannabivarin) have shown great therapeutic potential for SUDs, as shown in experimental animals.

Several cannabinoid-based medications (e.g., dronabinol, nabilone, PF-04457845) that entered clinical trials have shown promising results in reducing withdrawal symptoms in cannabis and opioid users.”

https://www.ncbi.nlm.nih.gov/pubmed/31549358

https://link.springer.com/article/10.1007%2Fs40263-019-00664-w

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Selective Cannabinoid 2 Receptor Agonists as Potential Therapeutic Drugs for the Treatment of Endotoxin-Induced Uveitis.

molecules-logo“The cannabinoid 2 receptor (CB2R) is a promising anti-inflammatory drug target and development of selective CB2R ligands may be useful for treating sight-threatening ocular inflammation. This study examined the pharmacology of three novel chemically-diverse selective CB2R ligands. These unique ligands are potent and selective for CB2R and have good immunomodulating actions in the eye. The data generated with these three structurally-diverse and highly-selective CB2R agonists support selective targeting of CB2R for treating ocular inflammatory diseases.”
https://www.ncbi.nlm.nih.gov/pubmed/31540271
https://www.mdpi.com/1420-3049/24/18/3338

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Druggable Targets of the Endocannabinoid System: Implications for the Treatment of HIV-Associated Neurocognitive Disorder.

Brain Research“HIV-associated neurocognitive disorder (HAND) affects nearly half of all HIV-infected individuals. Synaptodendritic damage correlates with neurocognitive decline in HAND, and many studies have demonstrated that HIV-induced neuronal injury results from excitotoxic and inflammatory mechanisms.

The endocannabinoid (eCB) system provides on-demand protection against excitotoxicity and neuroinflammation.

Here, we discuss evidence of the neuroprotective and anti-inflammatory properties of the eCB system from in vitro and in vivo studies. We examine the pharmacology of the eCB system and evaluate the therapeutic potential of drugs that modulate eCB signaling to treat HAND.

Finally, we provide perspective on the need for additional studies to clarify the role of the eCB system in HIV neurotoxicity and speculate that strategies that enhance eCB signaling might slow cognitive decline in HAND.”

https://www.ncbi.nlm.nih.gov/pubmed/31539547

https://www.sciencedirect.com/science/article/abs/pii/S0006899319305219?via%3Dihub

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Medical cannabis for chronic pain: can it make a difference in pain management?

 “Globally, chronic pain is a major therapeutic challenge and affects more than 15% of the population. As patients with painful terminal diseases may face unbearable pain, there is a need for more potent analgesics.

Although opioid-based therapeutic agents received attention to manage severe pain, their adverse drug effects and mortality rate associated with opioids overdose are the major concerns.

Evidences from clinical trials showed therapeutic benefits of cannabis, especially delta-9-tetrahydrocannabinol and cannabinoids reduced neuropathic pain intensity in various conditions. Also, there are reports on using combination cannabinoid therapies for chronic pain management.

The association of cannabis dependence and addiction has been discussed much and the reports mentioned that it can be comparatively lower than other substances such as nicotine and alcohol.

More countries have decided to legalise the medicinal use of cannabis and marijuana.

Healthcare professionals should keep themselves updated with the changing state of medical cannabis and its applications.”

https://www.ncbi.nlm.nih.gov/pubmed/31535218

https://link.springer.com/article/10.1007%2Fs00540-019-02680-y

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