Tag Archives: endocannabinoid system

Decreased CB receptor binding and cannabinoid signaling in three brain regions of a rat model of schizophrenia.

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“Schizophrenia is a serious mental health disorder characterized by several behavioral and biochemicel abnormalities.

In a previous study we have shown that mu-opioid (MOP) receptor signaling is impaired in specific brain regions of our three-hit animal model of schizophrenia. Since the cannabinoid system is significantly influenced in schizophrenic patients, in the present work we investigated cannabinoid (CB) receptor binding and G-protein activation in cortical, subcortical and cerebellar regions of control and ‘schizophrenic’ rats.

Taken together, in all three brain areas of model rats both cannabinoid receptor binding and cannabinoid agonist-mediated G-protein activation were regularly decreased.

Our results revealed that besides the opioids, the endocannabinoid – cannabis receptor system also shows impairment in our rat model, increasing its face validity and translational utility.”

https://www.ncbi.nlm.nih.gov/pubmed/27639959

Cannabimimetic phytochemicals in the diet – an evolutionary link to food selection and metabolic stress adaptation?

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“The endocannabinoid system (ECS) is a major lipid signaling network that plays important pro-homeostatic (allostatic) roles not only in the nervous system but in peripheral organs.

Increasing evidence points towards a dietary component in the modulation of the ECS.

Cannabinoid receptors in hominids co-evolved with diet and the ECS constitutes a feedback loop for food selection and energy metabolism.

Here it is postulated that the mismatch of ancient lipid genes of hunter-gatheres and pastoralists with the high carbohydrate diet introduced by agriculture could be compensated via dietary modulation of the ECS.

In addition to the fatty acid precursors of endocannabinoids the potential role of dietary cannabimimetic phytochemicals in agriculturist nutrition is discussed.

Dietary secondary metabolites from vegetables and spices able to enhance the activity of cannabinoid-type 2 (CB2) receptors may provide adaptive metabolic advantages and counteract inflammation.

Food able to modulate the CB1/CB2 receptor activation ratio may thus play a role in the nutrition transition of Western high calorie diets. In this review the interplay between diet and the ECS is highlighted from an evolutionary perspective.

The emerging potential of cannabimimetic food as nutraceutical strategy is critically discussed.”

https://www.ncbi.nlm.nih.gov/pubmed/27891602

The endogenous lipid N-arachidonoyl glycine is hypotensive and nitric oxide-cGMP-dependent vasorelaxant.

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“N-arachidonoyl glycine (NAGLY), is the endogenous lipid that activates the G protein-couple receptor 18 (GPR18) with vasodilatory activity in resistance arteries. This study investigates its hemodynamic effects and mechanisms of vasorelaxation.

NAGLY is an endothelium-dependent vasodilator and hypotensive lipid. The vasorelaxation is predominantly via activation of nitric oxide-cGMP pathway and NCX and probably mediated by the “endothelial anandamide” receptor, while the hypotensive effect of NAGLY appears not to involve the anandamide receptor. NAGLY also potentiates carbachol-induced vasorelaxation, the mechanism of which might involve stimulation of NO release.”

https://www.ncbi.nlm.nih.gov/pubmed/27890711

A novel inhibitor of endocannabinoid catabolic enzymes sheds light on behind the scene interplay between chronic pain, analgesic tolerance, and heroin dependence.

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“From the Aristotelian ancient Greece, pain has been associated with appetites or emotions and is opposite to pleasure. Reward and addiction is also linked to pleasure and compulsive drug seeking reinstates pleasure.

Alleviation of chronic pain can induce a euphoric phase similar to what is found in addiction. Both chronic pain and addiction are recognized as a disease of the central nervous system. They share many characteristics and brain regions/mechanisms.

Evidence points to the usefulness of cannabinoids as a new class of agents to add to the pharmaceutical toolbox in the management of chronic pain.

Wilkerson and colleagues, in this issue, examine SA-57, an inhibitor of two different endocannabinoid catabolic enzymes FAAH and MAGL, demonstrating its analgesic effectiveness and morphine-sparing properties in a chronic pain model, as well as its ability to reduce heroin seeking behavior in a self-administration paradigm in mice.

This timely study emphasizes the need for development of more efficacious chronic pain therapeutics with minimized abuse potential and/or reinforcing properties. It also highlights the need for better understanding of the overlapping circuitry of chronic pain, reward, and addiction.”

https://www.ncbi.nlm.nih.gov/pubmed/27890603

The endocannabinoid hydrolysis inhibitor SA-57: Intrinsic antinociceptive effects, augmented morphine-induced antinociception, and attenuated heroin seeking behavior in mice.

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“Although opioids are highly efficacious analgesics, their abuse potential and other untoward side effects diminish their therapeutic utility. The addition of non-opioid analgesics offers a promising strategy to reduce required antinociceptive opioid doses that concomitantly reduce opioid-related side effects.

Inhibitors of the primary endocannabinoid catabolic enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) show opioid-sparing effects in preclinical models of pain. As simultaneous inhibition of these enzymes elicits enhanced antinociceptive effects compared with single enzyme inhibition, the present study tested whether the dual FAAH-MAGL inhibitor SA-57 [4-[2-(4-chlorophenyl)ethyl]-1-piperidinecarboxylic acid 2-(methylamino)-2-oxoethyl ester] produces morphine-sparing antinociceptive effects, without major side effects associated with either drug class.

Although high doses of SA-57 alone were required to produce antinociception, low doses of this compound, which elevated AEA and did not affect 2-AG brain levels, augmented the antinociceptive effects of morphine, but lacked cannabimimetic side effects.

Because of the high abuse liability of opioids and implication of the endocannabinoid system in the reinforcing effects of opioids, the final experiment tested whether SA-57 would alter heroin seeking behavior. Strikingly, SA-57 reduced heroin-reinforced nose poke behavior and the progressive ratio break point for heroin.

In conclusion, the results of the present study suggest that inhibition of endocannabinoid degradative enzymes represents a promising therapeutic approach to decrease effective doses of opioids needed for clinical pain control, and may also possess therapeutic potential to reduce opioid abuse.”

https://www.ncbi.nlm.nih.gov/pubmed/27890602

The cannabinoid receptor 1 gene (CNR1) and multiple sclerosis: an association study in two case-control groups from Spain.

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“Different studies point to the implication of the endocannabinoid system in multiple sclerosis (MS) and animal models of MS.

The purpose of this study was to evaluate a possible association of MS with polymorphic markers at the CNR1 gene, encoding the cannabinoid 1 (CB(1)) receptor.

We have performed a genetic analysis of an AAT repeat microsatellite localized in the downstream region of the CNR1 gene, in two case-control groups of MS patients and healthy controls (HC) from Spain (Madrid and Bilbao).

MSpatients with primary progressive MS (PPMS) had more commonly long ((AAT) > or = (13)) alleles and genotypes with a significant difference for genotype 7/8 in Madrid (p = 0.043) and in the sum of both groups (p = 0.016); short alleles were less frequently found in PPMS with a significant difference for allele 5 in the analysis of both groups together (p = 0.039).

In patients with relapsing MS, no consistent differences in allele and genotype distribution were found. Disease severity and progression was unrelated to AAT repeat variations.

In conclusion, long (AAT) > or = (13) CNR1 genotypes could behave as risk factors for PPMS.”

 https://www.ncbi.nlm.nih.gov/pubmed/20007426

Plasma endocannabinoid levels in multiple sclerosis.

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“Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS.

Therapies that affect the endocannabinoid (EC) system may have immunomodulatory, symptomatic and neuroprotective effects.

The aim of this study was to determine how levels of EC and related compounds are altered in MS.

CONCLUSION:

The EC system is altered in MS. It may be dynamically modulated depending on the subtype of the disease, but further studies with larger subgroups are needed to confirm this.”

https://www.ncbi.nlm.nih.gov/pubmed/19695579

Cannabinoid receptors and TRPA1 on neuroprotection in a model of retinal ischemia.

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“Retinal ischemia is a pathological event present in several retinopathies such as diabetic retinopathy and glaucoma, leading to partial or full blindness with no effective treatment available.

Since synthetic and endogenous cannabinoids have been studied as modulators of ischemic events in the central nervous system (CNS), the present study aimed to investigate the involvement of cannabinoid system in the cell death induced by ischemia in an avascular (chick) retina.

We observed that chick retinal treatment with a combination of WIN 55212-2 and cannabinoid receptor antagonists (either AM251/O-2050 or AM630) decreased the release of lactate dehydrogenase (LDH) induced by retinal ischemia in an oxygen and glucose deprivation (OGD) model.

Further, the increased availability of endocannabinoids together with cannabinoid receptor antagonists also had a neuroprotective effect.

Surprisingly, retinal exposure to any of these drugs alone did not prevent the release of LDH stimulated by OGD.

Since cannabinoids may also activate transient receptor potential (TRP) channels, we investigated the involvement of TRPA1 receptors (TRPA1) in retinal cell death induced by ischemic events.

We demonstrated the presence of TRPA1 in the chick retina, and observed an increase in TRPA1 content after OGD, both by western blot and immunohistochemistry.

In addition, the selective activation of TRPA1 by mustard oil (MO) did not worsen retinal LDH release induced by OGD, whereas the blockage of TRPA1 completely prevented the extravasation of cellular LDH in ischemic condition.

Hence, these results show that during the ischemic event there is an augment of TRPA1, and activation of this receptor is important in cell death induction.

The data also indicate that metabotropic cannabinoid receptors, both type 1 and 2, are not involved with the cell death found in the early stages of ischemia. Therefore, the study points to a potential role of TRPA1 as a target for neuroprotective approaches in retinal ischemia.”

https://www.ncbi.nlm.nih.gov/pubmed/27876485

Endocannabinoid system in sexual motivational processes: is it a novel therapeutic horizon?

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“The endocannabinoid system (ECS), which is composed of the cannabinoid receptors types 1 and 2 (CB1 and CB2) for marijuana’s psychoactive ingredient Δ9-tetrahydrocannabinol (Δ9-THC), the endogenous ligands (AEA and 2-AG) and the enzymatic systems involved in their biosynthesis and degradation, recently emerged as important modulator of emotional and non-emotional behaviors.

For centuries, in addition to its recreational actions, several contradictory claims regarding the effects of Cannabis use in sexual functioning and behavior (e.g. aphrodisiac vs anti-aphrodisiac) of both sexes have been accumulated. The identification of Δ9-THC and later on, the discovery of the ECS have opened a potential therapeutic target for sexual dysfunctions, given the partial efficacy of current pharmacological treatment.

In agreement with the bidirectional modulation induced by cannabinoids on several behavioral responses, the endogenous cannabinoid AEA elicited biphasic effects on sexual behavior as well. The present article reviews current available knowledge on herbal, synthetic and endogenous cannabinoids with respect to the modulation of several aspects of sexuality in preclinical and human studies, highlighting their therapeutic potential.”

https://www.ncbi.nlm.nih.gov/pubmed/27884725

“Cannabis As An Aphrodisiac? The Evidence Is Mounting”  https://www.civilized.life/articles/aphrodisiac-evidence-is-mounting/

Cannabidiol as a Potential New Type of an Antipsychotic. A Critical Review of the Evidence

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“There is urgent need for the development of mechanistically different and less side-effect prone antipsychotic compounds.

The endocannabinoid system has been suggested to represent a potential new target in this indication.

Although, results from animal studies are inconsistent to a certain extent and seem to depend on behavioral paradigms, treatment duration and experimental conditions applied, cannabidiol has shown antipsychotic properties in both rodents and rhesus monkeys.

After some individual treatment attempts, the first randomized, double-blind controlled clinical trial demonstrated that in acute schizophrenia cannabidiol exerts antipsychotic properties comparable to the antipsychotic drug amisulpride while being accompanied by a superior, placebo-like side effect profile.

As the clinical improvement by cannabidiol was significantly associated with elevated anandamide levels, it appears likely that its antipsychotic action is based on mechanisms associated with increased anandamide concentrations.

The antipsychotic potential of cannabidiol has been investigated in various behavioral paradigms and different animal models of aspects of schizophrenia.

Although the results were partially inconsistent, they indicate that cannabidiol treatment ameliorates impairments of PPI, social interaction behavior and cognition in rodents and rhesus monkeys.

In addition, individual treatment attempts as well as one randomized, double-blind clinical study, demonstrated the antipsychotic potential of cannabidiol and its superior side effect profile compared to conventional antipsychotics. In addition, a recently conducted clinical trial investigating cannabidiol as an add-on medication showed promising results, although these have not yet been published in a peer reviewed process.

Obviously more clinical trials are needed to substantiate the current findings, and in particular to investigate long-term efficacy and safety in larger cohorts.

However, cannabidiol seems to represent a mechanistically different and less side-effect prone antipsychotic compound for the treatment of schizophrenia, even though the underlying pharmacological mechanisms are still under debate.

Nevertheless, the association between increased anandamide levels and reduced psychotic symptoms in schizophrenic patients treated with cannabidiol, points to a potentially new antipsychotic mechanism of action involving anandamide.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5099166/