Inhibition of fatty acid amide hydrolase and cyclooxygenase-2 increases levels of endocannabinoid related molecules and produces analgesia via peroxisome proliferator-activated receptor-alpha in a model of inflammatory pain
Inhibition of fatty acid amide hydrolase and cyclooxygenase-2 increases levels of endocannabinoid related molecules and produces analgesia via peroxisome proliferator-activated receptor-alpha in a model of inflammatory pain
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DOI：
10.1016/j.neuropharm.2008.04.018
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发表时间：
2008-07-01
影响因子：
4.7
通讯作者：
Chapman, Victoria
中科院分区：
文献类型：
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作者：
Jhaveri, Maulik D.;Richardson, Denise;Chapman, Victoria
通过抑制脂肪酸酰胺水解酶 (FAAH) 等分解代谢酶，可以增强内源性大麻素 (EC) 的镇痛作用。 ECs 通过其他途径（例如环氧合酶-2 (COX2)）代谢的生理相关性尚不清楚。为了解决这个问题，我们比较了局部抑制 FAAH 与 COX2（分别为 URB597 和尼美舒利）对后爪炎症性痛觉过敏以及内源性大麻素和相关分子水平的影响。足底注射角叉菜胶后测量炎症性痛觉过敏。足底内注射 URB597（25 μg 和 100 μg）或尼美舒利（50 μg）对痛觉过敏和后爪中花生四烯酸乙醇胺 (AEA)、2-花生四烯酰甘油 (2AG) 和 N-棕榈酰乙醇胺 (PEA) 水平的影响进行了测定。尽管两种剂量的 URB597 均增加了角叉菜胶发炎中的 AEA 和 2AG 水平后爪，只有较低剂量的 URB597 可以减轻痛觉过敏（P < 0.05）。尼美舒利可减轻痛觉过敏和后爪水肿（分别为 P < 0.001，P < 0.01），并增加后爪 PEA 水平（P < 0.05）。由于 AEA 和 PEA 都是过氧化物酶体增殖物激活受体-α (PPAR α) 的配体，因此研究了 PPAR α 拮抗剂 GW6471 对尼美舒利和 URB597 介导的作用的影响。 GW6471（而非 PPAR γ 拮抗剂）阻断尼美舒利和 URB597 对痛觉过敏的抑制作用。我们的数据表明 COX2 和 FAAH 在内源性大麻素和相关分子的代谢中发挥作用。 PPAR α 拮抗剂阻断尼美舒利和 URB597 的抑制作用的发现表明，PPAR α 有助于其在炎症性痛觉过敏的角叉菜胶模型中发挥镇痛作用。 (c) 2008 Elsevier Ltd. 保留所有权利。
The antinociceptive effects of the endocannabinoids (ECs) are enhanced by inhibiting catabolic enzymes such as fatty acid amide hydrolase (FAAH). The physiological relevance of the metabolism of ECs by other pathways, such as cyclooxygenase-2 (COX2) is less clear. To address this question we compared the effects of local inhibition of FAAH versus COX2 (URB597 and nimesulide, respectively) on inflammatory hyperalgesia and levels of endocannabinoids and related molecules in the hindpaw.Inflammatory hyperalgesia was measured following intraplantar injection of carrageenan. Effects of intraplantar injection of URB597 (25 mu g and 100 mu g) or nimesulide (50 mu g) on hyperalgesia and hindpaw levels of anandamide (AEA), 2-arachidonoylglycerol (2AG) and N-palmitoylethanolamine (PEA) were determined.Although both doses of URB597 increased levels of AEA and 2AG in the carrageenan inflamed hindpaw, only the lower dose of URB597 attenuated hyperalgesia (P < 0.05). Nimesulide attenuated both hyperalgesia and hindpaw oedema (P < 0.001, P < 0.01, respectively) and increased levels of PEA (P < 0.05) in the hindpaw. Since both AEA and PEA are ligands for peroxisome proliferator-activated receptor-alpha (PPAR alpha), the effects of the PPAR alpha antagonist GW6471 on nimesulide- and URB597-mediated effects were studied. GW6471, but not a PPAR gamma antagonist, blocked the inhibitory effects of nimesulide and URB597 on hyperalgesia.Our data suggest that both COX2 and FAAH play a role in the metabolism of endocannabinoids and related molecules. The finding that PPAR alpha antagonism blocked the inhibitory effects of nimesulide and URB597 suggests that PPAR alpha contributes to their antinociceptive effects in the carrageenan model of inflammatory hyperalgesia. (c) 2008 Elsevier Ltd. All rights reserved.