Treatment with tetrahydrocannabinol (THC) prevents infertility in male cystic fibrosis mice.

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“Cystic fibrosis (CF) is a hereditary disease caused by mutations of the gene encoding a channel protein CFTR, conducting Cl- and HCO3 – ions. The disease is characterized by disturbances in most physiological systems, and more than 95% of men are infertile. The mechanism underlying the etiology of CF is associated with an imbalance of fatty acids.

It has been suggested that the function of the endocannabinoid system is also disturbed in CF, because endocannabinoids are derivatives of fatty acids. We assumed, therefore, that endocannabinoid activity, which plays an important role in fertility, is disrupted in CF and could be one of the causes of infertility.

The aim of the present study was to test the hypothesis that stimulation of endocannabinoid receptors in infancy would normalize their function and prevent infertility in adulthood.

Knockout male mice (cftr-/-) were treated with tetrahydrocannabinol (THC), endocannabinoid receptors agonist, in infancy from days 7 until 28, daily.

CF males treated with THC were fully fertile, producing offspring comparable by the number of litters and the number of pups with wild-type mice. CF males that were not treated with THC were completely infertile.

The present study shows that (i) endocannabinoid function is impaired in CF mice, as evidenced by the regenerating effect of its stimulation on the fertility of otherwise infertile males, (ii) endocannabinoid system dysfunction is apparently the determining factor causing infertility in CF, and (iii) mild stimulation of the endocannabinoid system in infancy and adolescence appears to normalize many reproductive processes and thereby prevent infertility in CF males.”

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Behavioral alterations in cystic fibrosis mice are prevented by cannabinoid treatment in infancy.

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“Substantial data have been accumulated regarding the molecular basis of cystic fibrosis (CF) pathogenesis, whereas the influence of biochemical impairments on brain processes has been the focus of much less attention. We have studied some behavioral parameters, such as motor activity and anxiety level, in a mice model of CF.

We have assumed that functioning of the endocannabinoid system could be impaired in CF (endocannabinoids are fatty acid derivatives, and fatty acid deficiency is considered a major factor in CF etiology). We have suggested that chronic treatment with cannabinoid receptors agonist during infancy would balance cannabinoid levels and prevent CF-related behavioral alterations.

Motor activity and anxiety level were studied in naïve adult CF mice (cftr-deficient mice) and compared with wild-type mice and to CF mice treated chronically with Δ9-tetrahydrocannabinol (Δ9-THC; endocannabinoid receptor agonist) during infancy (from days 7 to 28). Motor activity was tested in the tetrad, and level of anxiety in the plus maze, a month after cessation of treatment.

Motor activity decrease and elevated anxiety level were found in adult naïve CF mice compared with wild-type mice. CF mice treated with THC in infancy showed normal motor activity and anxiety levels in adulthood. Motor function alteration and elevated anxiety levels in CF can result from lack of CFTR-channel in neurons and disturbed activity of various brain areas, as well as being secondary and mediated by fatty acids deficiency, altered levels of endocannabinoids and their receptors.

It can be suggested that chronic treatment during infancy restores endocannabinoid function and thus prevents behavioral alterations.”

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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.”

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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.”

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Target regulation of PI3K/Akt/mTOR pathway by cannabidiol in treatment of experimental multiple sclerosis.

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“This study was aimed to investigate whether treatment with purified cannabidiol (CBD) may counteract the development of experimental multiple sclerosis (MS), by targeting the PI3K/Akt/mTOR pathway.

Our results showed a clear downregulation of the PI3K/Akt/mTOR pathway following EAE induction. CBD treatment was able to restore it, increasing significantly the phosphorylation of PI3K, Akt and mTOR. Also, an increased level of BNDF in CBD-treated mice seems to be involved in the activation of PI3K/Akt/mTOR pathway.

In addition, our data demonstrated that therapeutic efficacy of CBD treatment is due to reduction of pro-inflammatory cytokines, like IFN-γ and IL-17 together with an up-regulation of PPARγ. Finally, CBD was found to promote neuronal survival by inhibiting JNK and p38 MAP kinases.

These results provide an interesting discovery about the regulation of the PI3K/Akt/mTOR pathway by cannabidiol administration, that could be a new potential therapeutic target for MS management.”

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Evidence for a GPR18 Role in Diurnal Regulation of Intraocular Pressure.


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“The diurnal cycling of intraocular pressure (IOP) was first described in humans more than a century ago. This cycling is preserved in other species. The physiologic underpinning of this diurnal variation in IOP remains a mystery, even though elevated pressure is indicated in most forms of glaucoma, a common cause of blindness. Once identified, the system that underlies diurnal variation would represent a natural target for therapeutic intervention.

We now report that NAPE-PLD and FAAH mice do not exhibit a diurnal cycling of IOP. These enzymes produce and break down acylethanolamines, including the endogenous cannabinoid anandamide. The diurnal lipid profile in mice shows that levels of most N-acyl ethanolamines and, intriguingly, N-arachidonoyl glycine (NAGly), decline at night: NAGly is a metabolite of arachidonoyl ethanolamine and a potent agonist at GPR18 that lowers intraocular pressure. The GPR18 blocker O1918 raises IOP during the day when pressure is low, but not at night. Quantitative PCR analysis shows that FAAH mRNA levels rise with pressure, suggesting that FAAH mediates the changes in pressure.



Our results support FAAH-dependent NAGly action at GPR18 as the physiologic basis of the diurnal variation of intraocular pressure in mice.”

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Functional selectivity at G-protein coupled receptors: Advancing cannabinoid receptors as drug targets.


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“The phenomenon of functional selectivity, whereby a ligand preferentially directs the information output of a G-protein coupled receptor (GPCR) along (a) particular effector pathway(s) and away from others, has redefined traditional GPCR signaling paradigms to provide a new approach to structure-based drug design.

The two principal cannabinoid receptors (CBRs) 1 and 2 belong to the class-A GPCR subfamily and are considered tenable therapeutic targets for several indications. Yet conventional orthosteric ligands (agonists, antagonists/inverse agonists) for these receptors have had very limited clinical utility due to their propensity to incite on-target adverse events. Chemically distinct classes of cannabinergic ligands exhibit signaling bias at CBRs toward individual subsets of signal transduction pathways.

In this review, we discuss the known signaling pathways regulated by CBRs and examine the current evidence for functional selectivity at CBRs in response to endogenous and exogenous cannabinergic ligands as biased agonists. We further discuss the receptor and ligand structural features allowing for selective activation of CBR-dependent functional responses. The design and development of biased ligands may offer a pathway to therapeutic success for novel CBR-targeted drugs.”

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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.”

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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.”

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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.”

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