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2‐arachidonyl glycerol activates platelets via conversion to arachidonic acid and not by direct activation of cannabinoid receptors
Author(s) -
Keown Oliver P.,
Winterburn Timothy J.,
Wainwright Cherry L.,
Macrury Sandra M.,
Neilson Ilene,
Barrett Fiona,
Leslie Stephen J.,
Megson Ian L.
Publication year - 2010
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2010.03697.x
Subject(s) - cannabinoid , cannabinoid receptor , pharmacology , endocannabinoid system , platelet , receptor , platelet activation , chemistry , cannabinoid receptor type 2 , aspirin , medicine , agonist , biochemistry
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 (CB 1 ) antagonists suppress appetite and induce weight loss. Direct antagonism of CB 1 receptors on platelets might be an additional benefit for CB 1 antagonists, but the role of CB 1 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 CB 1 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 Δ 9 ‐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 CB 1 (AM251) and CB 2 (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 n m –30 µ m ) had no effect on platelet aggregation induced by either ADP ( P = 0.90) or thrombin ( P = 0.86). 2‐AG, but not Δ 9 ‐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 CB 1 or CB 2 receptors, at least in the acute phase.