The Cannabinoids Δ8THC, CBD, and HU-308 Act via Distinct Receptors to Reduce Corneal Pain and Inflammation

Mary Ann Liebert, Inc. publishers

“Corneal injury can result in dysfunction of corneal nociceptive signaling and corneal sensitization.

Activation of the endocannabinoid system has been reported to be analgesic and anti-inflammatory.

The purpose of this research was to investigate the antinociceptive and anti-inflammatory effects of cannabinoids with reported actions at cannabinoid 1 (CB1R) and cannabinoid 2 (CB2R) receptors and/or noncannabinoid receptors in an experimental model of corneal hyperalgesia.

Topical cannabinoids reduce corneal hyperalgesia and inflammation.

The antinociceptive and anti-inflammatory effects of Δ8THC are mediated primarily via CB1R, whereas that of the cannabinoids CBD and HU-308, involve activation of 5-HT1A receptors and CB2Rs, respectively.

Cannabinoids could be a novel clinical therapy for corneal pain and inflammation resulting from ocular surface injury.”

https://www.ncbi.nlm.nih.gov/pubmed/29450258

http://online.liebertpub.com/doi/abs/10.1089/can.2017.0041

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Role of the endocannabinoid system in the formation and development of depression.

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“Two types of cannabinoid (CB) receptors have been described in the human body: CB1 and CB2 receptors. CB1 receptor distribution may be related to the cannabinoid functions of memory and cognition regulation as well as motor control.

In addition, the endocannabinoid system (ECS) related to CB1 receptors may be involved in human emotion regulation, especially depression occurrence. Indeed, CB1 receptors are all distributed in depression associated neuroanatomical structures and neural circuits.

Both animal experiments and clinical studies have demonstrated that impairment of the ECS pathway is present in depression models and patients, and application of both CB1 receptor agonists and anandamide (cannabinoid-like substance) degradation inhibitors produce similar biochemical and behavioral effects as antidepressants.

These findings provide a solid basis for understanding the ECS role in the formation and development of depression. Therefore, it can be inferred that the ECS may have an important function in both depression treatment and the effects of antidepressants.”

https://www.ncbi.nlm.nih.gov/pubmed/29441900

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Chronic High Doses of Cannabinoids Promote Hippocampal Neurogenesis

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“Hippocampal neurogenesis is suppressed following chronic administration of the major drugs of abuse (including opiates, alcohol, nicotine, and cocaine). However, CB1-knockout mice display significantly decreased hippocampal neurogenesis, suggesting that CB1 receptors activated by endogenous, plant-derived, or synthetic cannabinoids may promote hippocampal neurogenesis.

Cannabinoids can regulate the proliferation of hippocampal NS/PCs by acting on CB1 receptors. They found that both the synthetic cannabinoid HU210 and the endocannabinoid anandamide profoundly promote embryonic hippocampal NS/PC proliferation. Chronic, but not acute, HU210 significantly increases the number of newborn hippocampal neurons in adult rats by promoting NS/PC proliferation.

A significant increase was observed in the hipoppocampal newborn neurons of mice following twice-daily HU210 injection for 10 days.

This suggests that cannabinoids are the only illicit drug that can promote adult hippocampal neurogenesis following chronic  administration.”

Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects.” https://www.jci.org/articles/view/25509

http://www.science20.com/science_why_not/blog/chronic_high_doses_cannabinoids_promote_hippocampal_neurogenesis

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Involvement of spinal cannabinoid receptors in the antipruritic effects of WIN 55,212-2, a cannabinoid receptor agonist.

Clinical and Experimental Dermatology

“Cannabinoids have been used for their analgesic and euphoric effects for millennia, but recently the antipruritic effects of cannabis have been discovered.

Considering the similarities between pain and itch sensations, we hypothesized that cannabinoid receptors may play a role in the antipruritic effects of cannabinoids.

Our findings support prior researches indicating that cannabinoids exert antipruritic effects. Moreover, our results show that the antipruritic effects of cannabinoids are partially mediated by spinal CB1 receptors.”

https://www.ncbi.nlm.nih.gov/pubmed/29424035

http://onlinelibrary.wiley.com/doi/10.1111/ced.13398/abstract

“antipruritic: 1. Preventing or relieving itching. 2. An agent that relieves itching.”   https://medical-dictionary.thefreedictionary.com/antipruritic

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The Endocannabinoid System and Heart Disease: The Role of Cannabinoid Receptor Type 2.

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“Decades of research has provided evidence for the role of the endocannabinoid system in human health and disease. This versatile system, consisting of two receptors (CB1 and CB2), their endogenous ligands (endocannabinoids), and metabolic enzymes has been implicated in a wide variety of disease states, ranging from neurological disorders to cancer.

CB2 has gained much interest for its beneficial immunomodulatory role that can be obtained without eliciting psychotropic effects through CB1. Recent studies have shed light on a protective role of CB2 in cardiovascular disease, an ailment which currently takes more lives each year in Western countries than any other disease or injury.

By use of CB2 knockout mice and CB2-selective ligands, knowledge of how CB2 signaling affects atherosclerosis and ischemia has been acquired, providing a major stepping stone between basic science and translational clinical research.

Here, we summarize the current understanding of the endocannabinoid system in human pathologies and provide a review of the results from preclinical studies examining its function in cardiovascular disease, with a particular emphasis on possible CB2-targeted therapeutic interventions to alleviate atherosclerosis.”

https://www.ncbi.nlm.nih.gov/pubmed/29412125

“Researchers suggest that THC and other cannabinoids, which are active at CB2, the cannabinoid receptor expressed on immune cells, may be valuable in treating atherosclerosis.” https://www.medscape.com/viewarticle/787468

“Cardiovascular disease: New use for cannabinoids”  https://www.nature.com/articles/nrd1733

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The endocannabinoid system in canine Steroid-Responsive Meningitis-Arteritis and Intraspinal Spirocercosis.

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“Endocannabinoids (ECs) are involved in immunomodulation, neuroprotection and control of inflammation in the central nervous system (CNS).

Activation of cannabinoid type 2 receptors (CB2) is known to diminish the release of pro-inflammatory factors and enhance the secretion of anti-inflammatory cytokines.

Furthermore, the endocannabinoid 2-arachidonoyl glycerol (2-AG) has been proved to induce the migration of eosinophils in a CB2 receptor-dependent manner in peripheral blood and activate neutrophils independent of CB activation in humans.

The present study revealed an upregulated endocannabinoid system in dogs with inflammatory CNS diseases, highlighting the endocannabinoid system as a potential target for treatment of inflammatory CNS diseases.”

https://www.ncbi.nlm.nih.gov/pubmed/29408878

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0187197

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Cannabinoid Receptors in Diabetic Kidney Disease.

 Current Diabetes Reports

“The purpose of this review is to examine and summarize studies assessing the relevance of the endocannabinoid system (ECS) in diabetic kidney disease (DKD).

Endocannabinoids and endocannabinoid receptors of type 1 (CB1R) and of type 2 (CB2R) are present in the normal kidney. Expression of CB1R and CB2R is altered in experimental DKD.

Studies in experimental animals and cultured kidney cells show a beneficial effect of peripheral CB1R blockade and CB2R activation in DKD and an even greater efficacy of a combined treatment.

Preclinical studies confirm that both CB1R and CB2R are implicated in the pathogenesis of DKD and may represent novel targets for treatment.”

https://www.ncbi.nlm.nih.gov/pubmed/29399721

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Targeting the endocannabinoid system as a potential anticancer approach.

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“The endocannabinoid system is currently under intense investigation due to the therapeutic potential of cannabinoid-based drugs as treatment options for a broad variety of diseases including cancer.

Besides the canonical endocannabinoid system that includes the cannabinoid receptors CB1 and CB2 and the endocannabinoids N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol, recent investigations suggest that other fatty acid derivatives, receptors, enzymes, and lipid transporters likewise orchestrate this system as components of the endocannabinoid system when defined as an extended signaling network.

As such, fatty acids acting at cannabinoid receptors (e.g. 2-arachidonoyl glyceryl ether [noladin ether], N-arachidonoyldopamine) as well as endocannabinoid-like substances that do not elicit cannabinoid receptor activation (e.g. N-palmitoylethanolamine, N-oleoylethanolamine) have raised interest as anticancerogenic substances.

Furthermore, the endocannabinoid-degrading enzymes fatty acid amide hydrolase and monoacylglycerol lipase, lipid transport proteins of the fatty acid binding protein family, additional cannabinoid-activated G protein-coupled receptors, members of the transient receptor potential family as well as peroxisome proliferator-activated receptors have been considered as targets of antitumoral cannabinoid activity. Therefore, this review focused on the antitumorigenic effects induced upon modulation of this extended endocannabinoid network.” https://www.ncbi.nlm.nih.gov/pubmed/29390896  http://www.tandfonline.com/doi/abs/10.1080/03602532.2018.1428344?journalCode=idmr20

“Anticancer mechanisms of cannabinoids”   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4791144/
“Cannabinoids as Anticancer Drugs.”
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Cannabinoid CB1 and CB2 Receptors, and Monoacylglycerol Lipase Gene Expression Alterations in the Basal Ganglia of Patients with Parkinson’s Disease.

Neurotherapeutics

“Previous studies suggest that the endocannabinoid system plays an important role in the neuropathological basis of Parkinson’s disease (PD).

This study was designed to detect potential alterations in the cannabinoid receptors CB1 (CB1r) and CB2 (A isoform, CB2Ar), and in monoacylglycerol lipase (MAGL) gene expression in the substantia nigra (SN) and putamen (PUT) of patients with PD.

The results of the present study suggest that CB1r, CB2r, and MAGL are closely related to the neuropathological processes of PD.

Therefore, the pharmacological modulation of these targets could represent a new potential therapeutic tool for the management of PD.”

https://www.ncbi.nlm.nih.gov/pubmed/29352424

https://link.springer.com/article/10.1007%2Fs13311-018-0603-x

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The therapeutic potential of targeting the peripheral endocannabinoid/CB1 receptor system.

European Journal of Internal Medicine

“Endocannabinoids (eCBs) are internal lipid mediators recognized by the cannabinoid-1 and -2 receptors (CB1R and CB2R, respectively), which also mediate the different physiological effects of marijuana. The endocannabinoid system, consisting of eCBs, their receptors, and the enzymes involved in their biosynthesis and degradation, is present in a vast number of peripheral organs. In this review we describe the role of the eCB/CB1R system in modulating the metabolism in several peripheral organs. We assess how eCBs, via activating the CB1R, contribute to obesity and regulate food intake. In addition, we describe their roles in modulating liver and kidney functions, as well as bone remodeling and mass. Special importance is given to emphasizing the efficacy of the recently developed peripherally restricted CB1R antagonists, which were pre-clinically tested in the management of energy homeostasis, and in ameliorating both obesity- and diabetes-induced metabolic complications.”

https://www.ncbi.nlm.nih.gov/pubmed/29336868

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