Wise Laura E, Cannavacciulo Roberta, Cravatt Benjamin F, Martin Billy F, Lichtman Aron H
Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 North 12th Street, PO Box 980613, Richmond, VA 23298, USA.
Neuropharmacology. 2008 Jan;54(1):181-8. doi: 10.1016/j.neuropharm.2007.06.003. Epub 2007 Jun 22.
While it has long been recognized that Delta(9)-tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis, and other cannabinoid receptor agonists possess anti-inflammatory properties, their well known CNS effects have dampened enthusiasm for therapeutic development. On the other hand, genetic deletion of fatty acid amide hydrolase (FAAH), the enzyme responsible for degradation of fatty acid amides, including endogenous cannabinoid N-arachidonoyl ethanolamine (anandamide; AEA), N-palmitoyl ethanolamine (PEA), N-oleoyl ethanolamine (OEA), and oleamide, also elicits anti-edema, but does not produce any apparent cannabinoid effects. The purpose of the present study was to investigate whether exogenous administration of FAAs would augment the anti-inflammatory phenotype of FAAH (-/-) mice in the carrageenan model. Thus, we evaluated the effects of the FAAs AEA, PEA, OEA, and oleamide in wild-type and FAAH (-/-) mice. For comparison, we evaluated the anti-edema effects of THC, dexamethasone (DEX), a synthetic glucocorticoid, diclofenac (DIC), a nonselective cyclooxygenase (COX) inhibitor, in both genotypes. A final study determined if tolerance to the anti-edema effects of PEA occurs after repeated dosing. PEA, THC, DEX, DIC elicited significant decreases in carrageenan-induced paw edema in wild-type mice. In contrast OEA produced a less reliable anti-edema effect than these other drugs, and AEA and oleamide failed to produce any significant decreases in paw edema. Moreover, none of the agents evaluated augmented the anti-edema phenotype of FAAH (-/-) mice, suggesting that maximal anti-edema effects had already been established. PEA was the most effective FAA in preventing paw edema and its effects did not undergo tolerance. While the present findings do not support a role for AEA in preventing carrageenan-induced edema, PEA administration and FAAH blockade elicited anti-edema effects of an equivalent magnitude as produced by THC, DEX, and DIC in this assay.
长期以来，人们一直认识到大麻的主要精神活性成分Δ⁹-四氢大麻酚（THC）和其他大麻素受体激动剂具有抗炎特性，但其众所周知的中枢神经系统作用减弱了人们对其治疗开发的热情。另一方面，脂肪酸酰胺水解酶（FAAH）的基因缺失，该酶负责降解脂肪酸酰胺，包括内源性大麻素N-花生四烯酰乙醇胺（花生四烯酸乙醇胺；AEA）、N-棕榈酰乙醇胺（PEA）、N-油酰乙醇胺（OEA）和油酰胺，也能引发抗水肿作用，但不会产生任何明显的大麻素效应。本研究的目的是调查外源性给予脂肪酸酰胺是否会增强FAAH基因敲除（-/-）小鼠在角叉菜胶模型中的抗炎表型。因此，我们评估了脂肪酸酰胺AEA、PEA、OEA和油酰胺对野生型和FAAH（-/-）小鼠的影响。为了进行比较，我们评估了THC、地塞米松（DEX）（一种合成糖皮质激素）、双氯芬酸（DIC）（一种非选择性环氧化酶（COX）抑制剂）对两种基因型小鼠的抗水肿作用。最后一项研究确定了重复给药后是否会产生对PEA抗水肿作用的耐受性。PEA、THC、DEX、DIC在野生型小鼠中显著减轻了角叉菜胶诱导的爪肿胀。相比之下，OEA产生的抗水肿作用不如其他药物可靠，AEA和油酰胺未能使爪肿胀有任何显著减轻。此外，所评估的药物均未增强FAAH（-/-）小鼠的抗水肿表型，这表明最大抗水肿作用已经确立。PEA是预防爪肿胀最有效的脂肪酸酰胺，其作用不会产生耐受性。虽然目前的研究结果不支持AEA在预防角叉菜胶诱导的水肿中发挥作用，但在该试验中，给予PEA和阻断FAAH所产生的抗水肿作用与THC、DEX和DIC产生的作用强度相当。
