Ghosh Sudeshna, Kinsey Steven G, Liu Qing-Song, Hruba Lenka, McMahon Lance R, Grim Travis W, Merritt Christina R, Wise Laura E, Abdullah Rehab A, Selley Dana E, Sim-Selley Laura J, Cravatt Benjamin F, Lichtman Aron H
Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, Virginia (S.G., T.W.G., C.R.M., L.E.W., R.A.A., D.E.S., L.J.S.-S., A.H.L.); Department of Psychology, West Virginia University, Morgantown, West Virginia (S.G.K.); Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin (Q.L.); Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas (L.H., L.R.M.); and The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California (B.F.C.).
Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, Virginia (S.G., T.W.G., C.R.M., L.E.W., R.A.A., D.E.S., L.J.S.-S., A.H.L.); Department of Psychology, West Virginia University, Morgantown, West Virginia (S.G.K.); Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin (Q.L.); Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas (L.H., L.R.M.); and The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California (B.F.C.)
J Pharmacol Exp Ther. 2015 Aug;354(2):111-20. doi: 10.1124/jpet.115.222851. Epub 2015 May 21.
Inhibition of fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL), the primary hydrolytic enzymes for the respective endocannabinoids N-arachidonoylethanolamine (AEA) and 2-arachidonylglycerol (2-AG), produces antinociception but with minimal cannabimimetic side effects. Although selective inhibitors of either enzyme often show partial efficacy in various nociceptive models, their combined blockade elicits augmented antinociceptive effects, but side effects emerge. Moreover, complete and prolonged MAGL blockade leads to cannabinoid receptor type 1 (CB1) receptor functional tolerance, which represents another challenge in this potential therapeutic strategy. Therefore, the present study tested whether full FAAH inhibition combined with partial MAGL inhibition would produce sustained antinociceptive effects with minimal cannabimimetic side effects. Accordingly, we tested a high dose of the FAAH inhibitor PF-3845 (N-3-pyridinyl-4-[[3-[[5-(trifluoromethyl)-2-pyridinyl]oxy]phenyl]methyl]-1-piperidinecarboxamide; 10 mg/kg) given in combination with a low dose of the MAGL inhibitor JZL184 [4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate] (4 mg/kg) in mouse models of inflammatory and neuropathic pain. This combination of inhibitors elicited profound increases in brain AEA levels (>10-fold) but only 2- to 3-fold increases in brain 2-AG levels. This combination produced significantly greater antinociceptive effects than single enzyme inhibition and did not elicit common cannabimimetic effects (e.g., catalepsy, hypomotility, hypothermia, and substitution for Δ(9)-tetrahydrocannabinol in the drug-discrimination assay), although these side effects emerged with high-dose JZL184 (i.e., 100 mg/kg). Finally, repeated administration of this combination did not lead to tolerance to its antiallodynic actions in the carrageenan assay or CB1 receptor functional tolerance. Thus, full FAAH inhibition combined with partial MAGL inhibition reduces neuropathic and inflammatory pain states with minimal cannabimimetic effects.
脂肪酸酰胺水解酶（FAAH）或单酰甘油脂肪酶（MAGL）分别是内源性大麻素N-花生四烯酸乙醇胺（AEA）和2-花生四烯酸甘油酯（2-AG）的主要水解酶，抑制这些酶可产生镇痛作用，但大麻样副作用极小。尽管这两种酶的选择性抑制剂在各种伤害性感受模型中通常显示出部分疗效，但联合阻断它们会产生增强的镇痛效果，但副作用也会出现。此外，完全且长时间阻断MAGL会导致1型大麻素受体（CB1）功能耐受，这是这种潜在治疗策略中的另一个挑战。因此，本研究测试了完全抑制FAAH并联合部分抑制MAGL是否会产生持续的镇痛作用，且大麻样副作用最小。相应地，我们在炎症性和神经性疼痛的小鼠模型中测试了高剂量的FAAH抑制剂PF-3845（N-3-吡啶基-4-[[3-[[5-（三氟甲基）-2-吡啶基]氧基]苯基]甲基]-1-哌啶甲酰胺；10 mg/kg）与低剂量的MAGL抑制剂JZL184 [4-硝基苯基4-（二苯并[d][1,3]二氧杂环戊烯-5-基（羟基）甲基）哌啶-1-羧酸酯]（4 mg/kg）联合使用的效果。这种抑制剂组合使大脑AEA水平显著升高（>10倍），但大脑2-AG水平仅升高2至3倍。这种组合产生的镇痛作用比单一酶抑制作用显著更强，并且不会引发常见的大麻样效应（例如僵住、运动减少、体温过低以及在药物辨别试验中替代Δ9-四氢大麻酚），尽管高剂量的JZL184（即100 mg/kg）会出现这些副作用。最后，重复给予这种组合在角叉菜胶试验中不会导致其抗痛觉过敏作用产生耐受，也不会导致CB1受体功能耐受。因此，完全抑制FAAH并联合部分抑制MAGL可减轻神经性和炎症性疼痛状态，且大麻样副作用最小。
