Department of Diabetes & Cardiovascular Science, UHI Millennium Institute, The Centre for Health Science, Old Perth Road, Inverness IV2 3JH, UK.
Br J Clin Pharmacol. 2010 Aug;70(2):180-8. doi: 10.1111/j.1365-2125.2010.03697.x.
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.
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.
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.
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.
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.
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.
关于大麻素是否对血小板活性有影响，以及大麻素受体在多大程度上参与其中，文献中有相互矛盾的观点。这是一个需要解决的重要问题，因为潜在治疗性大麻素抑制剂和刺激剂的血小板作用将影响其潜在益处和安全性。
本文提供的数据清楚地表明，内源性大麻素 2-花生四烯酰甘油可以激活血小板活性，但作用是通过阿司匹林敏感途径介导的，该途径不受大麻素受体拮抗剂或 FAAH 抑制的影响，但被 MAGL 抑制所消除。这些发现质疑了大麻素受体在血小板功能中的作用，并表明血小板功能不太可能直接受到大麻素受体拮抗剂的影响，至少在急性期是如此。
大麻素受体 1（CB1）拮抗剂可抑制食欲并减轻体重。血小板上 CB1 受体的直接拮抗作用可能是 CB1 拮抗剂的另一个益处，但 CB1 受体在血小板中的作用存在争议。我们测试了以下假设，即内源性大麻素 2-花生四烯酰甘油（2-AG）通过 COX 介导的机制而不是通过 CB1 受体激活诱导血小板聚集，这是在从接受低剂量阿司匹林的健康志愿者和患有冠状动脉疾病的患者中获得的血液中进行的。
使用全血聚集仪检查了取自健康志愿者（n=8）和接受阿司匹林治疗的患有冠状动脉疾病的患者（n=12）的血液中 2-AG 和 Delta9-THC 对大麻素的聚集反应。还评估了 CB1（AM251）和 CB2（AM630）拮抗剂以及脂肪酸酰胺水解酶（FAAH）和单酰甘油脂肪酶（MAGL）抑制剂以及阿司匹林对 2-AG 诱导的聚集的影响。
AM251（100nm-30μm）对 ADP（P=0.90）或凝血酶（P=0.86）诱导的血小板聚集无影响。2-AG 但不是 Delta9-THC 诱导聚集。2-AG 诱导的聚集不受 AM251 和 AM630 的影响，但被阿司匹林（P<0.001）和 MAGL 抑制剂 URB602（P<0.001）消除。此外，与健康志愿者相比，接受阿司匹林治疗的冠状动脉疾病患者的血液中 2-AG 诱导的聚集反应被抑制（>75%，P<0.001）。
至少在急性期，2-AG 介导的血小板激活是通过 MAGL 代谢为花生四烯酸，而不是通过直接作用于 CB1 或 CB2 受体。
