2‐arachidonyl glycerol activates platelets via conversion to arachidonic acid and not by direct activation of cannabinoid receptors

• Published in: British journal of clinical pharmacology Vol. 70; no. 2; pp. 180 - 188
• Main Authors: Keown, Oliver P., Winterburn, Timothy J., Wainwright, Cherry L., Macrury, Sandra M., Neilson, Ilene, Barrett, Fiona, Leslie, Stephen J., Megson, Ian L.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.08.2010; Blackwell; Blackwell Science Inc
• Subjects: 2‐AG; Adolescent; Adult; Aged; AM251; antithrombotic; Arachidonic Acids - pharmacology; Arachidonic Acids - therapeutic use; Aspirin - pharmacology; Biological and medical sciences; Blood Platelets - chemistry; Cannabinoid Receptor Antagonists; Cannabinoid Receptor Modulators - pharmacology; Cannabinoid Receptor Modulators - therapeutic use; Coronary Artery Disease - drug therapy; endocannabinoid system; Endocannabinoids; Glycerides - pharmacology; Glycerides - therapeutic use; Humans; Indoles - pharmacology; Male; Medical sciences; Middle Aged; Pharmacodynamics; Pharmacology. Drug treatments; Piperidines - pharmacology; Platelet Activation - drug effects; Platelet Aggregation - drug effects; Platelet Aggregation Inhibitors - pharmacology; platelets; Pyrazoles - pharmacology; rimonabant; Young Adult; CB1 cannabinoid receptor; Polyunsaturated fatty acid; Lipids; Arachidonic acid; Cannabinoid; Prokinetic agent; Conversion; antithrombotic; platelets; Platelet; n-6 fatty acid; Endogenous; Endocannabinoid; Rimonabant; AM251; Cannabinoid receptor; 2-AG; Antithrombotic agent; Unsaturated fatty acid; endocannabinoid system; Antagonist; Anorectic; 2-arachidonyl glycerol
• ISSN: 0306-5251; 1365-2125; 1365-2125
• DOI: 10.1111/j.1365-2125.2010.03697.x

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • There are conflicting views in the literature as to whether cannabinoids have an impact on platelet activity and to what extent cannabinoid receptors are involved. This is an important issue to resolve because platelet effects of putative therapeutic cannabinoid inhibitors and stimulators will have an impact on their potential benefits and safety. WHAT THIS PAPER ADDS • The data presented in this manuscript clearly show that the endocannabinoid 2‐arrachidonyl glycerol can activate platelet activity, but that the effects are mediated through an aspirin‐sensitive pathway that is not affected by cannabinoid receptor antagonists or FAAH inhibition, but is abolished by MAGL inhibition. The findings question the role of cannabinoid receptors in platelet function and suggest that platelet function is unlikely to be directly affected by cannabinoid receptor antagonists, at least in the acute phase. AIMS Cannabinoid receptor‐1 (CB1) antagonists suppress appetite and induce weight loss. Direct antagonism of CB1 receptors on platelets might be an additional benefit for CB1 antagonists, but the role of CB1 receptors in platelets is controversial. We tested the hypothesis that the endocannabinoid, 2‐arachidonyl glycerol (2‐AG), induces platelet aggregation by a COX‐mediated mechanism rather than through CB1 receptor activation, in blood obtained from healthy volunteers and patients with coronary artery disease receiving low dose aspirin. METHODS Aggregatory responses to the cannabinoids 2‐AG and Δ9‐THC were examined in blood sampled from healthy volunteers (n= 8) and patients (n= 12) with coronary artery disease receiving aspirin using whole blood aggregometry. The effects of CB1 (AM251) and CB2 (AM630) antagonists, as well as fatty acid amide hydrolase (FAAH) and monoacyl glycerol lipase (MAGL) inhibitors and aspirin on 2‐AG‐induced aggregation were also assessed. RESULTS AM251 (100 nm–30 µm) had no effect on platelet aggregation induced by either ADP (P= 0.90) or thrombin (P= 0.86). 2‐AG, but not Δ9‐THC, induced aggregation. 2‐AG‐induced aggregation was unaffected by AM251 and AM630 but was abolished by aspirin (P < 0.001) and by the MAGL inhibitor, URB602 (P < 0.001). Moreover, the aggregatory response to 2‐AG was depressed (by >75%, P < 0.001) in blood from patients with coronary artery disease receiving aspirin compared with that from healthy volunteers. CONCLUSIONS 2‐AG‐mediated activation of platelets is via metabolism to arachidonic acid by MAGL, and not through direct action on CB1 or CB2 receptors, at least in the acute phase.