Determination of the Endocannabinoids Anandamide and 2-Arachidonoyl Glycerol with Gas Chromatography-Mass Spectrometry: Analytical and Preanalytical Challenges and Pitfalls

Lanz, Christian; Mattsson, Johan; Stickel, Felix; Dufour, Jean‐François; Brenneisen, Rudolf

doi:10.1159/000489032

Cited by 14 publications

(10 citation statements)

References 50 publications

(56 reference statements)

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“…2‐AG‐mediated endocannabinoid signaling in the NAc is known to influence behavior related to drugs of abuse and natural rewards 7 . As the direct measurement and manipulation of 2‐AG in vivo can be challenging and often not feasible, 53 targeting the enzymes that regulate 2‐AG levels is a suitable alternative. Our findings are consistent with previous studies showing dysregulation of MAGL and DAGL levels in multiple brain regions after cocaine exposure 51,54,55 .…”

Section: Discussionmentioning

confidence: 99%

A role for the endocannabinoid enzymes monoacylglycerol and diacylglycerol lipases in cue‐induced cocaine craving following prolonged abstinence

et al. 2021

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Following exposure to drugs of abuse, long‐term neuroadaptations underlie persistent risk to relapse. Endocannabinoid signaling has been associated with drug‐induced neuroadaptations, but the role of lipases that mediate endocannabinoid biosynthesis and metabolism in regulating relapse behaviors following prolonged periods of drug abstinence has not been examined. Here, we investigated how pharmacological manipulation of lipases involved in regulating the expression of the endocannabinoid 2‐AG in the nucleus accumbens (NAc) influence cocaine relapse via discrete neuroadaptations. At prolonged abstinence (30 days) from cocaine self‐administration, there is an increase in the NAc levels of diacylglycerol lipase (DAGL), the enzyme responsible for the synthesis of the endocannabinoid 2‐AG, along with decreased levels of monoacylglycerol lipase (MAGL), which hydrolyzes 2‐AG. Since endocannabinoid‐mediated behavioral plasticity involves phosphatase dysregulation, we examined the phosphatase calcineurin after 30 days of abstinence and found decreased expression in the NAc, which we demonstrate is regulated through the transcription factor EGR1. Intra‐NAc pharmacological manipulation of DAGL and MAGL with inhibitors DO‐34 and URB‐602, respectively, bidirectionally regulated cue‐induced cocaine seeking and altered the phosphostatus of translational initiation factor, eIF2α. Finally, we found that cocaine seeking 30 days after abstinence leads to decreased phosphorylation of eIF2α and reduced expression of its downstream target NPAS4, a protein involved in experience‐dependent neuronal plasticity. Together, our findings demonstrate that lipases that regulate 2‐AG expression influence transcriptional and translational changes in the NAc related to drug relapse vulnerability.

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Section: Discussionmentioning

confidence: 99%

A role for the endocannabinoid enzymes monoacylglycerol and diacylglycerol lipases in cue‐induced cocaine craving following prolonged abstinence

et al. 2021

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Section: Discussionmentioning

confidence: 99%

“…Similar behavior occurring only at CB2-mediated β-arrestin1 recruitment was also observed with another endogenous ligand, anandamide. Reported 2-AG and anandamide concentrations in human blood are in the nanomolar range71 , with possibly higher local concentrations around the transmembrane receptors due to their high lipophilicity.Therefore, the range of ligand concentrations used within our study corresponds to the physiological endocannabinoid concentrations. Given the importance of GPCR desensitization via arrestin-dependent internalization, as well as the arrestin-mediated signaling, the observation of endocannabinoids preferentially activating β-arrestins over G proteins at higher ligand concentrations as judged by higher amplitudes of the responses could hold answers to physiological regulation of endocannabinoid system signaling.The two tested CB2 inverse agonists, AM630 and SR144528, evoked stronger inhibition on signaling via Gi proteins than Go proteins and β-arrestins, suggesting that CB2 constitutive activity is composed mostly of Gi protein signaling, or that those inverse agonists are less able to inhibit signaling via other G proteins.…”

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confidence: 99%

Diverse chemotypes drive biased signaling by cannabinoid receptors

Miljuš

Heydenreich

Gazzi

et al. 2020

Preprint

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Cannabinoid CB1 and CB2 receptors are members of the G protein-coupled receptor family, which is the largest class of membrane proteins in the human genome. As part of the endocannabinoid system, they have many regulatory functions in the human body. Their malfunction therefore triggers a diverse set of undesired conditions, such as pain, neuropathy, nephropathy, pruritus, osteoporosis, cachexia and Alzheimer’s disease. Although drugs targeting the system exist, the molecular and functional mechanisms involved are still poorly understood, preventing the development of better therapeutics with fewer undesired effects. One path toward the development of better and safer medicines targeting cannabinoid receptors relies on the ability of some compounds to activate a subset of pathways engaged by the receptor while sparing or even inhibiting the others, a phenomenon known as biased signaling. To take advantage of this phenomenon for drug development, a better profiling of the pathways engaged by the receptors is required. Using a BRET-based signaling detection platform, we systematically analyzed the primary signaling cascades activated by CB1 and CB2 receptors, including 9 G protein and 2 β-arrestin subtypes. Given that biased signaling is driven by ligand-specific distinct active conformations of the receptor, establishing a link between the signaling profiles elicited by different drugs and their chemotypes may help designing compounds that selectively activate beneficial pathways while avoiding those leading to undesired effects. We screened a selection of 35 structurally diverse ligands, including endocannabinoids, phytocannabinoids and synthetic compounds structurally similar or significantly different from natural cannabinoids. Our data show that biased signaling is a prominent feature of the cannabinoid receptor system and that, as predicted, ligands with different chemotypes have distinct signaling profiles. The study therefore allows for better understanding of cannabinoid receptors signaling and provides the information about tool compounds that can now be used to link signaling pathways to biological outcomes, aiding the design of improved therapeutics.

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“…Data was collected and analyzed using SCIEX Analyst v1.7. 2-AG was reported as total AG (consisting of 1-AG and 2-AG) due to isomerization during extraction (21).…”

Section: Endocannabinoid Analysismentioning

confidence: 99%

Circulating Endocannabinoids in Canine Multicentric Lymphoma Patients

et al. 2022

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The endocannabinoid system is increasingly being implicated in the pathogenesis and progression of various human cancers. Specifically, increased levels of 2-arachidonoylglycerol (2-AG) and oleoythanolamide (OEA) have been demonstrated in human diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL) patients, respectively. The objectives of this paper were to compare 2-AG, OEA, N-arachidonoylethanolamine (AEA), and palmitoylethanolamide (PEA) levels between dogs with multicentric lymphoma and healthy control dogs. In addition, evaluate 2-AG, OEA, AEA, and PEA levels as biomarkers for progression free interval (PFI) and overall survival time (OST) in the dogs with lymphoma. The study consisted of 26 dogs with multicentric B cell lymphoma, 14 dogs with multicentric T cell lymphoma, and 12 healthy control dogs. Serum 2-AG, OEA, AEA, and PEA levels were measured using liquid chromatography combined with tandem mass spectrometry (LC—MS/MS) in dogs with lymphoma and in healthy dogs. OEA, AEA, and PEA levels were significantly elevated in dogs with lymphoma compared to healthy controls (p < 0.05). Total AG was significantly higher in healthy control dogs (p = 0.049). There was no significant difference between dogs with B cell and T cell lymphoma for any of the measured endocannabinoids. Elevated PEA was significantly associated with decreased PFI (p = 0.04) in dogs with lymphoma with a hazards ratio of 1.816 [95% Confidence Interval (CI): 1.020–3.232]. Overall, dogs with lymphoma have elevated levels of OEA, AEA, and PEA. PEA levels have the potential to be a prognostic biomarker.

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Determination of the Endocannabinoids Anandamide and 2-Arachidonoyl Glycerol with Gas Chromatography-Mass Spectrometry: Analytical and Preanalytical Challenges and Pitfalls

Cited by 14 publications

References 50 publications

A role for the endocannabinoid enzymes monoacylglycerol and diacylglycerol lipases in cue‐induced cocaine craving following prolonged abstinence

A role for the endocannabinoid enzymes monoacylglycerol and diacylglycerol lipases in cue‐induced cocaine craving following prolonged abstinence

Diverse chemotypes drive biased signaling by cannabinoid receptors

Circulating Endocannabinoids in Canine Multicentric Lymphoma Patients

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