Human platelets bind and degrade 2‐arachidonoylglycerol, which activates these cells through a cannabinoid receptor

The endocannabinoid 2‐arachidonoylglycerol (2‐Δ 4 Ach‐Gro) activates human platelets in platelet‐rich plasma at physiological concentrations. The activation was inhibited by selective antagonists of CB 1 and CB 2 cannabinoid receptors, but not by acetylsalicylic acid. Human platelets can metabolize 2‐Δ 4 Ach‐Gro by internalization through a high affinity transporter ( K m  = 300 ± 30 n m , V max  = 10 ± 1 pmol·min −1 ·mg protein −1 ), followed by hydrolysis by a fatty acid amide hydrolase ( K m  = 8 ± 1 µ m , V max  = 400 ± 50 pmol·min −1 ·mg protein −1 ). The anandamide transport inhibitor AM404, and anandamide itself, were ineffective on 2‐Δ 4 Ach‐Gro uptake by platelets, whereas anandamide competitively inhibited 2‐Δ 4 Ach‐Gro hydrolysis (inhibition constant = 10 ± 1 µ m ). Platelet activation by 2‐Δ 4 Ach‐Gro was paralleled by an increase of intracellular calcium and inositol‐1,4,5‐trisphosphate, and by a decrease of cyclic AMP. Moreover, treatment of preloaded platelet‐rich plasma with 2‐Δ 4 Ach‐Gro induced an approximately threefold increase in [ 3 H]2‐Δ 4 Ach‐Gro release, according to a CB receptor‐dependent mechanism. On the other hand, ADP and collagen counteracted the activation of platelets by 2‐Δ 4 Ach‐Gro, whereas 5‐hydroxytryptamine (serotonin) enhanced and extended its effects. Remarkably, ADP and collagen also reduced [ 3 H]2‐Δ 4 Ach‐Gro release from 2‐Δ 4 Ach‐Gro‐activated platelets, whereas 5‐hydroxytryptamine further increased it. These findings suggest a so far unnoticed interplay between the peripheral endocannabinoid system and physiological platelet agonists.