Brain activity of anandamide: a rewarding bliss?

 

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“Anandamide is a lipid mediator that acts as an endogenous ligand of CB1 receptors. These receptors are also the primary molecular target responsible for the pharmacological effects of Δ9-tetrahydrocannabinol, the psychoactive ingredient in Cannabis sativa.

Several studies demonstrate that anandamide exerts an overall modulatory effect on the brain reward circuitry. Several reports suggest its involvement in the addiction-producing actions of other abused drugs, and it can also act as a behavioral reinforcer in animal models of drug abuse.

Importantly, all these effects of anandamide appear to be potentiated by pharmacological inhibition of its metabolic degradation. Enhanced brain levels of anandamide after treatment with inhibitors of fatty acid amide hydrolase, the main enzyme responsible for its degradation, seem to affect the rewarding and reinforcing actions of many drugs of abuse.

In this review, we will provide an overview from a preclinical perspective of the current state of knowledge regarding the behavioral pharmacology of anandamide, with a particular emphasis on its motivational/reinforcing properties. We will also discuss how modulation of anandamide levels through inhibition of enzymatic metabolic pathways could provide a basis for developing new pharmaco-therapeutic tools for the treatment of substance use disorders.”

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Modulation of the Oxidative Stress and Lipid Peroxidation by Endocannabinoids and Their Lipid Analogues.

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“Growing evidence supports the pivotal role played by oxidative stress in tissue injury development, thus resulting in several pathologies including cardiovascular, renal, neuropsychiatric, and neurodegenerative disorders, all characterized by an altered oxidative status. Reactive oxygen and nitrogen species and lipid peroxidation-derived reactive aldehydes including acrolein, malondialdehyde, and 4-hydroxy-2-nonenal, among others, are the main responsible for cellular and tissue damages occurring in redox-dependent processes.

In this scenario, a link between the endocannabinoid system (ECS) and redox homeostasis impairment appears to be crucial. Anandamide and 2-arachidonoylglycerol, the best characterized endocannabinoids, are able to modulate the activity of several antioxidant enzymes through targeting the cannabinoid receptors type 1 and 2 as well as additional receptors such as the transient receptor potential vanilloid 1, the peroxisome proliferator-activated receptor alpha, and the orphan G protein-coupled receptors 18 and 55.

Moreover, the endocannabinoids lipid analogues N-acylethanolamines showed to protect cell damage and death from reactive aldehydes-induced oxidative stress by restoring the intracellular oxidants-antioxidants balance. In this review, we will provide a better understanding of the main mechanisms triggered by the cross-talk between the oxidative stress and the ECS, focusing also on the enzymatic and non-enzymatic antioxidants as scavengers of reactive aldehydes and their toxic bioactive adducts.”

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Role of the Endocannabinoid System in the Pathophysiology of Schizophrenia: Implications for Pharmacological Intervention.

 

“The term schizophrenia describes a group of multifaceted psychiatric conditions causing significant impairment of the quality of life of affected patients. Although multiple pharmacological treatment options exist, e.g. first- or second-generation antipsychotics, these therapeutics often cause disturbing side effects, such as extrapyramidal symptoms, prolactin increase, sexual dysfunction and/or metabolic syndrome. Furthermore, cognitive impairments and negative symptoms, two factors significantly influencing the course and outcome, are not sufficiently addressed by the available antipsychotics.

Since its discovery, multiple clinical and preclinical studies have linked the endocannabinoid system to schizophrenia.

Both the endocannabinoid anandamide and the cannabinoid CB1 receptor are deeply linked to underlying disease processes. Based hereon, clinical trials in schizophrenia have explored cannabidiol, a primary component of Cannabis sativa, and rimonabant, a partial antagonist to the CB1 receptor.

While the latter did not reveal positive results, cannabidiol significantly ameliorated psychotic symptoms, which was associated with an increase in anandamide serum levels. However, the exact mechanisms of the antipsychotic effects of cannabidiol are not fully understood, and, furthermore, only a limited number of clinical trials in humans have been concluded to date.

Thus, the level of proof of safety and efficacy required to approve the therapeutic use of cannabidiol in schizophrenia is currently lacking. However, cannabidiol is a promising candidate as an effective and mechanistically different antipsychotic treatment with a favourable side-effect profile. We therefore conclude that further studies are urgently needed to clarify the antipsychotic effects and safety profile of cannabidiol, and to fully explore its potential antipsychotic mechanism.”

https://www.ncbi.nlm.nih.gov/pubmed/30022465

https://link.springer.com/article/10.1007%2Fs40263-018-0539-z

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Ischemia/Reperfusion Model Impairs Endocannabinoid Signaling and Na+/K+ ATPase Expression and Activity in Kidney Proximal Tubule Cells.

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“LLC-PK1 cells, an immortalized epithelial cell line derived from pig renal proximal tubules, express all the major players of the endocannabinoid system (ECS) such as CB1, CB2 and TRPV1 receptor, as well as the main enzymes involved in the biosynthesis and degradation of the major endocannabinoids named 2-arachidonoylglycerol, 2-AG and anandamide, AEA.

Here we investigated whether the damages caused by ischemic insult either in vitro using LLC-PK1 cells exposed to antimycin A (an inductor of ATP-depletion) or in vivo using Wistar rats in a classic renal ischemia and reperfusion (IR) protocol, lead to changes in AEA and 2-AG levels, as well as altered expression of genes from the main enzymes involved in the regulation of the ECS.

Our data show that the mRNA levels of CB1 receptor gene were downregulated, while the transcript levels of monoacylglycerol lipase (MAGL), the main 2-AG degradative enzyme, are upregulated in LLC-PK1 cells after IR model. Accordingly, IR was accompanied by a significant reduction in the levels of 2-AG and AEA, as well as of the two endocannabinoid related molecules, oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) in LLC-PK1 cells. In kidney cortex homogenates, the AEA levels were selectively significantly decreased. In addition, we found that both the in vitro and in vivo model of IR caused a reduction in the expression and activity of the Na+/K+ATPase. These changes were reversed by the CB1/CB2 agonist WIN55,212, in a CB1-receptor dependent manner on LLC-PK1 IR model.

In conclusion, the ECS and Na+/K+ ATPase are down-regulated following IR model in LLC-PK1 cells and rat kidney. We suggest that CB1 agonists might represent a potential strategy to reverse the consequences of IR injury in kidney tissues.”

https://www.ncbi.nlm.nih.gov/pubmed/29890144

https://www.sciencedirect.com/science/article/pii/S0006295218302132

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The Pharmacological Inhibition of Fatty Acid Amide Hydrolase Prevents Excitotoxic Damage in the Rat Striatum: Possible Involvement of CB1 Receptors Regulation.

Molecular Neurobiology

“The endocannabinoid system (ECS) actively participates in several physiological processes within the central nervous system.

Among such, its involvement in the downregulation of the N-methyl-D-aspartate receptor (NMDAr) through a modulatory input at the cannabinoid receptors (CBr) has been established. After its production via the kynurenine pathway (KP), quinolinic acid (QUIN) can act as an excitotoxin through the selective overactivation of NMDAr, thus participating in the onset and development of neurological disorders.

In this work, we evaluated whether the pharmacological inhibition of fatty acid amide hydrolase (FAAH) by URB597, and the consequent increase in the endogenous levels of anandamide, can prevent the excitotoxic damage induced by QUIN. URB597 (0.3 mg/kg/day × 7 days, administered before, during and after the striatal lesion) exerted protective effects on the QUIN-induced motor (asymmetric behavior) and biochemical (lipid peroxidation and protein carbonylation) alterations in rats.

URB597 also preserved the structural integrity of the striatum and prevented the neuronal loss (assessed as microtubule-associated protein-2 and glutamate decarboxylase localization) induced by QUIN (1 μL intrastriatal, 240 nmol/μL), while modified the early localization patterns of CBr1 (CB1) and NMDAr subunit 1 (NR1).

Altogether, these findings support the concept that the pharmacological manipulation of the endocannabinoid system plays a neuroprotective role against excitotoxic insults in the central nervous system.”

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Endocannabinoid system and pathophysiology of adipogenesis: current management of obesity.

“The endocannabinoids are now known as novel and important regulators of energy metabolism and homeostasis.

The endocrine functions of white adipose are chiefly involved in the control of whole-body metabolism, insulin sensitivity and food intake. Adipocytes produce hormones, such as leptin and adiponectin, that can improve insulin resistance or peptides, such as TNF-α, that elicit insulin resistance. Adipocytes express specific receptors, such as peroxisome proliferator-activated receptor (PPAR)-γ, which serve as adipocyte targets for insulin sensitizers such as thiazolidinediones.

Recently, endocannabinoids and related compounds were identified in human fat cells.

The endocannabinoid system consists primarily of two receptors, cannabinoid (CB)1 and CB2, their endogenous ligands termed endocannabinoids and the enzymes responsible for ligand biosynthesis and degradation.

The endocannabinoids 2-arachidonylglycerol and anandamide or N-arachidonoylethanolamine increase food intake and promote weight gain in animals. Rimonabant, a selective CB1 blocker, reduces food intake and body weight in animals and humans.”

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Anandamide Revisited: How Cholesterol and Ceramides Control Receptor-Dependent and Receptor-Independent Signal Transmission Pathways of a Lipid Neurotransmitter.

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“Anandamide is a lipid neurotransmitter derived from arachidonic acid, a polyunsaturated fatty acid.

The chemical differences between anandamide and arachidonic acid result in a slightly enhanced solubility in water and absence of an ionisable group for the neurotransmitter compared with the fatty acid. In this review, we first analyze the conformational flexibility of anandamide in aqueous and membrane phases. We next study the interaction of the neurotransmitter with membrane lipids and discuss the molecular basis of the unexpected selectivity of anandamide for cholesterol and ceramide from among other membrane lipids.

We show that cholesterol behaves as a binding partner for anandamide, and that following an initial interaction mediated by the establishment of a hydrogen bond, anandamide is attracted towards the membrane interior, where it forms a molecular complex with cholesterol after a functional conformation adaptation to the apolar membrane milieu.

The complex is then directed to the anandamide cannabinoid receptor (CB1) which displays a high affinity binding pocket for anandamide. We propose that cholesterol may regulate the entry and exit of anandamide in and out of CB1 by interacting with low affinity cholesterol recognition sites (CARC and CRAC) located in transmembrane helices.

The mirror topology of cholesterol binding sites in the seventh transmembrane domain is consistent with the delivery, extraction and flip-flop of anandamide through a coordinated cholesterol-dependent mechanism. The binding of anandamide to ceramide illustrates another key function of membrane lipids which may occur independently of protein receptors.

Interestingly, ceramide forms a tight complex with anandamide which blocks the degradation pathway of both lipids and could be exploited for anti-cancer therapies.”

“The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC20983/

“The endogenous cannabinoid, anandamide, induces cell death in colorectal carcinoma cells: a possible role for cyclooxygenase 2”  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1774787/

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Anandamide and endocannabinoid system: an attractive therapeutic approach for cardiovascular disease.

SAGE Journals

“Cardiovascular disease is currently not adequately managed and has become one of the main causes of morbidity and mortality worldwide. Current therapies are inadequate in terms of preventing its progression. There are several limitations, such as poor oral bioavailability, side effects, low adherence to treatment, and high dosage frequency of formulations due to the short half-life of the active ingredients used, among others.

This review aims to highlight the most relevant aspects of the relationship between the cardiovascular system and the endocannabinoid system, with special attention to the possible translational effect of the use of anandamide in cardiovascular health. The deep and detailed knowledge of this interaction, not always beneficial, and that for years has gone unnoticed, is essential for the development of new therapies.

We discuss the most recent and representative results obtained in the field of basic research, referring to the aforementioned subject, emphasizing fundamentally the main role of nitric oxide, renal physiology and its deregulation in pathological processes.”

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Possible mechanisms of cannabinoid-induced antinociception in the spinal cord.

European Journal of Pharmacology

“Anandamide is an endogenous ligand at both the inhibitory cannabinoid CB(1) receptor and the excitatory vanilloid receptor 1 (VR1). The CB(1) receptor and vanilloid VR1 receptor are expressed in about 50% and 40% of dorsal root ganglion neurons, respectively. While all vanilloid VR1 receptor-expressing cells belong to the calcitonin gene-related peptide-containing and isolectin B4-binding sub-populations of nociceptive primary sensory neurons, about 80% of the cannabinoid CB(1) receptor-expressing cells belong to those sub-populations. Furthermore, all vanilloid VR1 receptor-expressing cells co-express the cannabinoid CB(1) receptor.

In agreement with these findings, neonatal capsaicin treatment that induces degeneration of capsaicin-sensitive, vanilloid VR1 receptor-expressing, thin, unmyelinated, nociceptive primary afferent fibres significantly reduced the cannabinoid CB(1) receptor immunostaining in the superficial spinal dorsal horn.

Synthetic cannabinoid CB(1) receptor agonists, which do not have affinity at the vanilloid VR1 receptor, and low concentrations of anandamide both reduce the frequency of miniature excitatory postsynaptic currents and electrical stimulation-evoked or capsaicin-induced excitatory postsynaptic currents in substantia gelatinosa cells in the spinal cord without any effect on their amplitude. These effects are blocked by selective cannabinoid CB(1) receptor antagonists. Furthermore, the paired-pulse ratio is increased while the postsynaptic response of substantia gelatinosa neurons induced by alpha-amino-3-hydroxy-5-methylisoxasole-propionic acid (AMPA) in the presence of tetrodotoxin is unchanged following cannabinoid CB(1) receptor activation.

These results strongly suggest that the cannabinoid CB(1) receptor is expressed presynaptically and that the activation of these receptors by synthetic cannabinoid CB(1) receptor agonists or low concentration of anandamide results in inhibition of transmitter release from nociceptive primary sensory neurons. High concentrations of anandamide, on the other hand, increase the frequency of miniature excitatory postsynaptic currents recorded from substantia gelatinosa neurons. This increase is blocked by ruthenium red, suggesting that this effect is mediated through the vanilloid VR1 receptor.

Thus, anandamide at high concentrations can activate the VR1 and produce an opposite, excitatory effect to its inhibitory action produced at low concentrations through cannabinoid CB(1) receptor activation. This “dual”, concentration-dependent effect of anandamide could be an important presynaptic modulatory mechanism in the spinal nociceptive system.”

https://www.ncbi.nlm.nih.gov/pubmed/11698030

https://www.sciencedirect.com/science/article/pii/S0014299901013097?via%3Dihub

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Synergistic interactions of endogenous opioids and cannabinoid systems.

 Brain Research

“Cannabinoids and opioids are distinct drug classes historically used in combination to treat pain. Delta(9)-THC, an active constituent in marijuana, releases endogenous dynorphin A and leucine enkephalin in the production of analgesia.

The endocannabinoid, anandamide (AEA), fails to release dynorphin A. The synthetic cannabinoid, CP55,940, releases dynorphin B. Neither AEA nor CP55,940 enhances morphine analgesia. The CB1 antagonist, SR141716A, differentially blocks Delta(9)-THC versus AEA. Tolerance to Delta(9)-THC, but not AEA, involves a decrease in the release of dynorphin A.

Our preclinical studies indicate that Delta(9)-THC and morphine can be useful in low dose combination as an analgesic. Such is not observed with AEA or CP55,940.

We hypothesize the existence of a new CB receptor differentially linked to endogenous opioid systems based upon data showing the stereoselectivity of endogenous opioid release. Such a receptor, due to the release of endogenous opioids, may have significant impact upon the clinical development of cannabinoid/opioid combinations for the treatment of a variety of types of pain in humans.”

https://www.ncbi.nlm.nih.gov/pubmed/10612710

https://www.sciencedirect.com/science/article/pii/S0006899399019083?via%3Dihub

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