n−3 polyunsaturated N-acylethanolamines are CB2 cannabinoid receptor-preferring endocannabinoids

Alharthi, Nahed; Christensen, Peter; Hourani, Wafa; Ortori, Catherine; Barrett, David A.; Bennett, Andrew J.; Chapman, Victoria; Alexander, Stephen P.H.

Abstract

Anandamide, the first identified endogenous cannabinoid and TRPV1 agonist, is one of a series of endogenous N-acylethanolamines, NAEs. We have generated novel assays to quantify the levels of multiple NAEs in biological tissues and their rates of hydrolysis through fatty acid amide hydrolase. This range of NAEs was also tested in rapid response assays of CB1, CB2 cannabinoid and TRPV1 receptors. The data indicate that PEA, SEA and OEA are not endocannabinoids or endovanilloids, and that the higher endogenous levels of these metabolites compared to polyunsaturated analogues are a correlate of their slow rates of hydrolysis. The n-6 NAEs (AEA, docosatetraenoyl and docosapentaenoyl derivatives) activated both CB1 and CB2 receptors, as well as TRPV1 channels, suggesting them to be ‘genuine’ endocannabinoids and ‘endovanilloids’. The n-3 NAEs (eicosapentaenoyl, docosapentaenoyl and docosahexaenoyl derivatives) activated CB2 receptors and some n-3 NAEs (docosapentaenoyl and docosahexaenoyl derivatives) also activated TRPV1 channels, but failed to activate the CB1 receptor. We hypothesise that the preferential activation of CB2 receptors by n-3 PUFA NAEs contributes, at least in some part, to their broad anti-inflammatory profile.

Citation

Alharthi, N., Christensen, P., Hourani, W., Ortori, C., Barrett, D. A., Bennett, A. J., Chapman, V., & Alexander, S. P. (2018). n−3 polyunsaturated N-acylethanolamines are CB2 cannabinoid receptor-preferring endocannabinoids. Biochimica et Biophysica Acta Molecular and Cell Biology of Lipids, 1863(11), 1433-1440. https://doi.org/10.1016/j.bbalip.2018.08.003

• Journal Article Type: Article
• Acceptance Date: Aug 4, 2018
• Online Publication Date: Aug 7, 2018
• Publication Date: 2018-11
• Deposit Date: Oct 22, 2018
• Publicly Available Date: Aug 8, 2019
• Journal: Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
• Print ISSN: 1388-1981
• Electronic ISSN: 1879-2618
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 1863
• Issue: 11
• Pages: 1433-1440
• DOI: https://doi.org/10.1016/j.bbalip.2018.08.003
• Keywords: Anandamide; Endocannabinoids; Cannabinoid receptors; Vanilloid receptors; Fatty acid amide hydrolase; Polyunsaturated fatty acids
• Public URL: https://nottingham-repository.worktribe.com/output/1132975
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S1388198118302026
• Additional Information: This article is maintained by: Elsevier; Article Title: n−3 polyunsaturated N-acylethanolamines are CB2 cannabinoid receptor-preferring endocannabinoids; Journal Title: Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.bbalip.2018.08.003; Content Type: article; Copyright: © 2018 Published by Elsevier B.V.
• Contract Date: Oct 23, 2018