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


CONCLUSIONS
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.


OBJECTIVE
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 Delta(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 nm-30 microm) had no effect on platelet aggregation induced by either ADP (P= 0.90) or thrombin (P= 0.86). 2-AG, but not Delta(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.
Keown
Oliver P
OP
Department of Diabetes & Cardiovascular Science, UHI Millennium Institute, The Centre for Health Science, Old Perth Road, Inverness IV2 3JH, UK.
Winterburn
Timothy J
TJ
Wainwright
Cherry L
CL
Macrury
Sandra M
SM
Neilson
Ilene
I
Barrett
Fiona
F
Leslie
Stephen J
SJ
Megson
Ian L
IL
D000293:Adolescent; D000328:Adult; D000368:Aged; D001095:Arachidonic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D001241:Aspirin / Q000494:pharmacology; D001792:Blood Platelets / Q000737:chemistry; D063387:Cannabinoid Receptor Antagonists; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology* / Q000627:therapeutic use; D003324:Coronary Artery Disease / Q000188:drug therapy*; D063388:Endocannabinoids; D005989:Glycerides / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D010880:Piperidines / Q000494:pharmacology; D015539:Platelet Activation / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D055815:Young Adult
D001095:Arachidonic Acids; D063387:Cannabinoid Receptor Antagonists; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D005989:Glycerides; D007211:Indoles; D010880:Piperidines; D010975:Platelet Aggregation Inhibitors; D011720:Pyrazoles; C103505:AM 251; C094503:glyceryl 2-arachidonate; D001241:Aspirin; C094023:iodopravadoline