Inflammation and CB2 signaling drive novel changes in the ocular lipidome and regulate immune cell activity in the eye.

Prostaglandins & Other Lipid Mediators

“Uveitis is inflammation of the uvea which consists of the iris, ciliary body and the choroid of the eye. Uveitis can lead to impaired vision and is responsible for 10% of all cases of blindness globally.

Using an endotoxin-induced uveitis (EIU) rodent model, our previous data implicated the endogenous cannabinoid system (ECS) in the amelioration of many of the components of the inflammatory response.

Here, we test the hypothesis that the reduction in inflammatory mediators in the EIU model by the CB2 agonist, HU308, is associated with changes in ECS endogenous ligands as well as related lipids, prostaglandins (PGs), 2-acyl glycerols, and lipoamines.

These data implicate ocular CB2 as a key component of lipid signaling in the eye and part of the regulatory processes of inflammation.”

https://www.ncbi.nlm.nih.gov/pubmed/30232034

https://www.sciencedirect.com/science/article/pii/S109888231830025X?via%3Dihub

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Effect of cannabidiolic acid and ∆9-tetrahydrocannabinol on carrageenan-induced hyperalgesia and edema in a rodent model of inflammatory pain.

“Cannabidiol (CBD), a non-intoxicating component of cannabis, or the psychoactive Δ9-tetrahydrocannabiol (THC), shows anti-hyperalgesia and anti-inflammatory properties.

OBJECTIVES:

The present study evaluates the anti-inflammatory and anti-hyperalgesia effects of CBD’s potent acidic precursor, cannabidiolic acid (CBDA), in a rodent model of carrageenan-induced acute inflammation in the rat hind paw, when administered systemically (intraperitoneal, i.p.) or orally before and/or after carrageenan. In addition, we assess the effects of oral administration of THC or CBDA, their mechanism of action, and the efficacy of combined ineffective doses of THC and CBDA in this model. Finally, we compare the efficacy of CBD and CBDA.

RESULTS:

CBDA given i.p. 60 min prior to carrageenan (but not 60 min after carrageenan) produced dose-dependent anti-hyperalgesia and anti-inflammatory effects. In addition, THC or CBDA given by oral gavage 60 min prior to carrageenan produced anti-hyperalgesia effects, and THC reduced inflammation. The anti-hyperalgesia effects of THC were blocked by SR141716 (a cannabinoid 1 receptor antagonist), while CBDA’s effects were blocked by AMG9810 (a transient receptor potential cation channel subfamily V member 1 antagonist). In comparison to CBDA, an equivalent low dose of CBD did not reduce hyperalgesia, suggesting that CBDA is more potent than CBD for this indication. Interestingly, when ineffective doses of CBDA or THC alone were combined, this combination produced an anti-hyperalgesia effect and reduced inflammation.

CONCLUSION:

CBDA or THC alone, as well as very low doses of combined CBDA and THC, has anti-inflammatory and anti-hyperalgesia effects in this animal model of acute inflammation.”

https://www.ncbi.nlm.nih.gov/pubmed/30225659

https://link.springer.com/article/10.1007%2Fs00213-018-5034-1

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Endocannabinoids in the treatment of gasytrointestinal inflammation and symptoms.

 Current Opinion in Pharmacology

“The evolving policies regarding the use of therapeutic Cannabis have steadily increased the public interest in its use as a complementary and alternative medicine in several disorders, including inflammatory bowel disease.

Endocannabinoids represent both an appealing therapeutic strategy and a captivating scientific dilemma.

Results from clinical trials have to be carefully interpreted owing to possible reporting-biases related to cannabinoids psychotropic effects. Moreover, discriminating between symptomatic improvement and the real gain on the underlying inflammatory process is often challenging.

This review summarizes the advances and latest discovery in this ever-changing field of investigation, highlighting the main limitations in the current use of these drugs in clinical practice and the possible future perspectives to overcome these flaws.”

https://www.ncbi.nlm.nih.gov/pubmed/30218940

https://www.sciencedirect.com/science/article/pii/S1471489218300183?via%3Dihub

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Cannabidiol prevents haloperidol-induced vacuos chewing movements and inflammatory changes in mice via PPARγ receptors.

Brain, Behavior, and Immunity

“The chronic use of drugs that reduce the dopaminergic neurotransmission can cause a hyperkinetic movement disorder called tardive dyskinesia (TD). The pathophysiology of this disorder is not entirely understood but could involve oxidative and neuroinflammatory mechanisms.

Cannabidiol (CBD), the major non-psychotomimetic compound present in Cannabis sativa plant, could be a possible therapeutic alternative for TD. This phytocannabinoid shows antioxidant, anti-inflammatory and antipsychotic properties and decreases the acute motor effects of classical antipsychotics.

The present study investigated if CBD would attenuate orofacial dyskinesia, oxidative stress and inflammatory changes induced by chronic administration of haloperidol in mice. Furthermore, we verified in vivo and in vitro (in primary microglial culture) whether these effects would be mediated by PPARγ receptors.

The results showed that the male Swiss mice treated daily for 21 days with haloperidol develop orofacial dyskinesia. Daily CBD administration before each haloperidol injection prevented this effect.

Mice treated with haloperidol showed an increase in microglial activation and inflammatory mediators in the striatum. These changes were also reduced by CBD. On the other hand, the levels of the anti-inflammatory cytokine IL-10 increased in the striatum of animals that received CBD and haloperidol.

Regarding oxidative stress, haloperidol induced lipid peroxidation and reduced catalase activity. This latter effect was attenuated by CBD. The combination of CBD and haloperidol also increased PGC-1α mRNA expression, a co-activator of PPARγ receptors. Pretreatment with the PPARγ antagonist, GW9662, blocked the behavioural effect of CBD in our TD model. CBD also prevented LPS-stimulated microglial activation, an effect that was also antagonized by GW9662.

In conclusion, our results suggest that CBD could prevent haloperidol-induced orofacial dyskinesia by activating PPARγ receptors and attenuating neuroinflammatory changes in the striatum.”

“Haloperidol, marketed under the trade name Haldol among others, is a typical antipsychotic medication. Haloperidol is used in the treatment of schizophrenia, tics in Tourette syndromemania in bipolar disorder, nausea and vomiting, delirium, agitation, acute psychosis, and hallucinations in alcohol withdrawal”  https://en.wikipedia.org/wiki/Haloperidol
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Understanding the endocannabinoid system as a modulator of the trigeminal pain response to concussion.

“Post-traumatic headache is the most common symptom of postconcussion syndrome and becomes a chronic neurological disorder in a substantial proportion of patients.

This review provides a brief overview of the epidemiology of postconcussion headache, research models used to study this disorder, as well as the proposed mechanisms.

An objective of this review is to enhance the understanding of how the endogenous cannabinoid system is essential for maintaining the balance of the CNS and regulating inflammation after injury, and in turn making the endocannabinoid system a potential modulator of the trigeminal response to concussion.

The review describes the role of endocannabinoid modulation of pain and the potential for use of phytocannabinoids to treat pain, migraine and concussion.”

https://www.ncbi.nlm.nih.gov/pubmed/30202590

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ANTINOCICEPTIVE TOLERANCE TO NSAIDS PARTIALLY MEDIATED VIA ENDOCANNABINOIDS IN ANTERIOR CINGULATE CORTEX OF RATS.

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“Pain is characterized as a complex experience, dependent not only on the regulation of nociceptive sensory systems but also on the activation of mechanisms that control emotional processes in limbic brain areas.

Non-opioid, non-steroidal anti-inflammatory drugs (NSAIDs) are the most widely used analgesics in the treatment of not-severe pain. We have recently shown that repeated doses result in tolerance to these drugs like opioids.

Here we investigated the central brain mechanisms of non-opioid induced antinociception in the non-acute pain models of rats, such as the ‘formalin test’ and a relation between administration of NSAIDs in the limbic brain area, – the anterior cingulated cortex (ACC), – and the endocannabinoid system.

The present data support the notion that endocannabinoids’ CB1 receptor contributes in part to antinociceptive effects of NSAIDs and probably involved in activation of the descending opioid modulatory system of pain.”

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Cellular localization and regulation of receptors and enzymes of the endocannabinoid system in intestinal and systemic inflammation.

“Surveys suggest that Cannabis provides benefit for people with inflammatory bowel disease.

However, mechanisms underlying beneficial effects are not clear. We performed in situ hybridization RNAscope® combined with immunohistochemistry to show cell-specific distribution and regulation of cannabinoid receptor 1 and 2 (CB1, CB2), G protein-coupled receptor 55 (GPR55), and monoacylglycerol lipase (MGL) mRNA in immune cells using murine models of intestinal and systemic inflammation.

In summary, our study reveals changes in gene expression of members of the endocannabinoid system in situ attesting particularly GPR55 and MGL a distinct cellular role in the regulation of the immune response to intestinal and systemic inflammation.”

https://www.ncbi.nlm.nih.gov/pubmed/30196316

https://link.springer.com/article/10.1007%2Fs00418-018-1719-0

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Gut microbiota, cannabinoid system and neuroimmune interactions: New perspectives in multiple sclerosis.

Biochemical Pharmacology

“The gut microbiota plays a fundamental role on the education and function of the host immune system.

Immunological dysregulation is the cause of numerous human disorders such as autoimmune diseases and metabolic disorders frequently associated with inflammatory processes therefore is critical to explore novel mechanisms involved in maintaining the immune system homeostasis.

The cannabinoid system and related bioactive lipids participate in multiple central and peripheral physiological processes that affect metabolic, gastrointestinal and neuroimmune regulatory mechanisms displaying a modulatory role and contributing to the maintenance of the organism’s homeostasis.

In this review, we gather the knowledge on the gut microbiota-endocannabinoids interactions and their impact on autoimmune disorders such as inflammatory bowel disease, rheumatoid arthritis and particularly, multiple sclerosis (MS) as the best example of a CNS autoimmune disorder.

Furthermore, we contribute to this field with new data on changes in many elements of the cannabinoid system in a viral model of MS after gut microbiota manipulation by both antibiotics and probiotics.

Finally, we highlight new therapeutic opportunities, under an integrative view, targeting the eCBS and the commensal microbiota in the context of neuroinflammation and MS.”

https://www.ncbi.nlm.nih.gov/pubmed/30171835

https://www.sciencedirect.com/science/article/abs/pii/S0006295218303630

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Cannabis in liver disorders: a friend or a foe?

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“The recent legalization of recreational marijuana use in some parts of the world, the discovery of new indications for the clinical application of cannabis, and the acceptance of the use of cannabis in practice has been paralleled by extensive research on the active components of cannabis and the endocannabinoid system within the human body.

In this review, we evaluate the available evidence on cannabis and its constituents and the application of this evidence in clinical practice, focusing particularly on the liver and liver diseases.

Constituents of cannabis, such as cannabidiol and Δ-tetrahydrocannabinol, have shown anti-inflammatory, antioxidant, and hepatoprotective effects both in in vitro and clinical studies, and appear to have potential in the symptom management and treatment of various liver diseases that were previously considered difficult to manage conservatively.

In addition, the manipulation of the inherent endocannabinoid response system has found favor in many clinical fields and has generated considerable research and clinical interest. Moreover, evidence with regard to the adverse effects of marijuana use in liver diseases is weak, which has led to raise a question on the prior rules, with regard to a denial of liver transplantation to marijuana users.

All in all, the recent trends in research, clinical experiences, as well as the legislature, has opened up new avenues towards the widespread clinical application of cannabis and its derivatives as well as modifiers of the components of the endocannabinoid system. More research is required to fully exploit these new evidences.”

https://www.ncbi.nlm.nih.gov/pubmed/30169449

https://insights.ovid.com/crossref?an=00042737-900000000-97980

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Medicinal Properties of Cannabinoids, Terpenes, and Flavonoids in Cannabis, and Benefits in Migraine, Headache, and Pain: An Update on Current Evidence and Cannabis Science.

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“Comprehensive literature reviews of historical perspectives and evidence supporting cannabis/cannabinoids in the treatment of pain, including migraine and headache, with associated neurobiological mechanisms of pain modulation have been well described.

Most of the existing literature reports on the cannabinoids Δ9 -tetrahydrocannabinol (THC) and cannabidiol (CBD), or cannabis in general. There are many cannabis strains that vary widely in the composition of cannabinoids, terpenes, flavonoids, and other compounds. These components work synergistically to produce wide variations in benefits, side effects, and strain characteristics. Knowledge of the individual medicinal properties of the cannabinoids, terpenes, and flavonoids is necessary to cross-breed strains to obtain optimal standardized synergistic compositions. This will enable targeting individual symptoms and/or diseases, including migraine, headache, and pain.

OBJECTIVE:

Review the medical literature for the use of cannabis/cannabinoids in the treatment of migraine, headache, facial pain, and other chronic pain syndromes, and for supporting evidence of a potential role in combatting the opioid epidemic. Review the medical literature involving major and minor cannabinoids, primary and secondary terpenes, and flavonoids that underlie the synergistic entourage effects of cannabis. Summarize the individual medicinal benefits of these substances, including analgesic and anti-inflammatory properties.

CONCLUSION:

There is accumulating evidence for various therapeutic benefits of cannabis/cannabinoids, especially in the treatment of pain, which may also apply to the treatment of migraine and headache. There is also supporting evidence that cannabis may assist in opioid detoxification and weaning, thus making it a potential weapon in battling the opioid epidemic. Cannabis science is a rapidly evolving medical sector and industry with increasingly regulated production standards. Further research is anticipated to optimize breeding of strain-specific synergistic ratios of cannabinoids, terpenes, and other phytochemicals for predictable user effects, characteristics, and improved symptom and disease-targeted therapies.”

https://www.ncbi.nlm.nih.gov/pubmed/30152161

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