Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298-0613, USA.
Neuropsychopharmacology. 2013 May;38(6):1039-49. doi: 10.1038/npp.2012.269. Epub 2013 Jan 3.
Inhibition of the endocannabinoid catabolic enzymes, monoacylglycerol lipase (MAGL) or fatty acid amide hydrolase (FAAH) attenuates naloxone-precipitated opioid withdrawal signs in mice via activation of CB1 receptors. Complete FAAH inhibition blocks only a subset of withdrawal signs, whereas complete MAGL inhibition elicits enhanced antiwithdrawal efficacy, but is accompanied with some cannabimimetic side effects. Thus, the primary objective of the present study was to determine whether combined, full FAAH inhibition and partial MAGL represents an optimal strategy to reduce opioid withdrawal. To test this hypothesis, we examined whether combined administration of high-dose of the FAAH inhibitor PF-3845 and low-dose of the MAGL inhibitor JZL184, as well as the novel dual FAAH-MAGL inhibitor SA-57, which is 100-fold more potent in inhibiting FAAH than MAGL, would prevent spontaneous withdrawal in morphine-dependent mice, a model with greater face validity than precipitating withdrawal with μ-opioid receptor antagonists. Strikingly, a combination of low-dose JZL184 and high-dose PF-3845 as well as the dual inhibitor SA-57 reduced all abrupt withdrawal signs (ie, platform jumping, paw flutters, head shakes, diarrhea, and total body weight loss), but did not elicit any cannabimimetic side effects. In addition, JZL184 or PF-3845 blocked naloxone-precipitated hypersecretion in morphine-dependent small intestinal tissue. Collectively, these results are the first to show that endocannabinoid catabolic enzyme inhibitors reduce abrupt withdrawal in morpine-dependent mice and are effective in a novel in vitro model of opioid withdrawal. More generally, these findings support the idea that joint MAGL and FAAH inhibition represents a promising approach for the treatment of opioid dependence.
抑制内源性大麻素代谢酶，单酰基甘油脂肪酶（MAGL）或脂肪酸酰胺水解酶（FAAH），通过激活 CB1 受体，可减轻小鼠纳洛酮诱发的阿片类药物戒断症状。完全抑制 FAAH 只能阻断部分戒断症状，而完全抑制 MAGL 则会增强抗戒断作用，但伴有一些大麻样副作用。因此，本研究的主要目的是确定联合使用完全 FAAH 抑制和部分 MAGL 是否是减少阿片类药物戒断的最佳策略。为了验证这一假设，我们研究了高剂量 FAAH 抑制剂 PF-3845 和低剂量 MAGL 抑制剂 JZL184 的联合给药，以及新型双重 FAAH-MAGL 抑制剂 SA-57 是否会预防吗啡依赖小鼠的自发性戒断，与用 μ-阿片受体拮抗剂诱发戒断相比，该模型具有更高的表面效度。令人惊讶的是，低剂量 JZL184 和高剂量 PF-3845 的组合以及双重抑制剂 SA-57 可减轻所有突然戒断症状（即平台跳跃、爪子颤抖、摇头、腹泻和体重减轻），但不会引起任何大麻样副作用。此外，JZL184 或 PF-3845 阻断了吗啡依赖小肠组织中纳洛酮诱发的过度分泌。总的来说，这些结果首次表明，内源性大麻素代谢酶抑制剂可减轻吗啡依赖小鼠的突然戒断，并在新型阿片类药物戒断体外模型中有效。更普遍地说，这些发现支持联合使用 MAGL 和 FAAH 抑制是治疗阿片类药物依赖的一种有前途的方法的观点。
