Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, Genova, Italy Department of Pharmacology, University of California, Irvine, CA, USA Department of Biological Chemistry, University of California, Irvine, CA, USA Dipartimento di Scienze del Farmaco e della Salute, Università degli Studi di Urbino "Carlo Bo", Urbino, Italy Dipartimento Farmaceutico, Università degli Studi di Parma, Parma, Italy.
Pain. 2013 Mar;154(3):350-360. doi: 10.1016/j.pain.2012.10.018. Epub 2012 Nov 2.
Fatty acid ethanolamides (FAEs), which include palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), are endogenous agonists of peroxisome proliferator-activated receptor-α (PPAR-α) and important regulators of the inflammatory response. They are degraded in macrophages by the lysosomal cysteine amidase, N-acylethanolamine acid amidase (NAAA). Previous studies have shown that pharmacological inhibition of NAAA activity suppresses macrophage activation in vitro and causes marked anti-inflammatory effects in vivo, which is suggestive of a role for NAAA in the control of inflammation. It is still unknown, however, whether NAAA-mediated FAE deactivation might regulate pain signaling. The present study examined the effects of ARN077, a potent and selective NAAA inhibitor recently disclosed by our group, in rodent models of hyperalgesia and allodynia caused by inflammation or nerve damage. Topical administration of ARN077 attenuated, in a dose-dependent manner, heat hyperalgesia and mechanical allodynia elicited in mice by carrageenan injection or sciatic nerve ligation. The antinociceptive effects of ARN077 were prevented by the selective PPAR-α antagonist GW6471 and did not occur in PPAR-α-deficient mice. Furthermore, topical ARN077 reversed the allodynia caused by ultraviolet B radiation in rats, and this effect was blocked by pretreatment with GW6471. Sciatic nerve ligation or application of the proinflammatory phorbol ester 12-O-tetradecanoylphorbol 13-acetate decreased FAE levels in sciatic nerve and skin tissue, respectively. ARN077 reversed these biochemical effects. The results identify ARN077 as a potent inhibitor of intracellular NAAA activity, which is active in vivo by topical administration. The findings further suggest that NAAA regulates peripheral pain initiation by interrupting endogenous FAE signaling at PPAR-α.
脂肪酸乙醇酰胺（FAEs），包括棕榈酰乙醇酰胺（PEA）和油酰乙醇酰胺（OEA），是过氧化物酶体增殖物激活受体-α（PPAR-α）的内源性激动剂，也是炎症反应的重要调节剂。它们在巨噬细胞中被溶酶体半胱氨酸酰胺酶，N-酰基乙醇胺酸酰胺酶（NAAA）降解。先前的研究表明，药理学抑制 NAAA 活性可抑制体外巨噬细胞激活，并在体内引起明显的抗炎作用，这表明 NAAA 在炎症控制中起作用。然而，目前尚不清楚 NAAA 介导的 FAEs 失活是否会调节疼痛信号。本研究检查了我们小组最近披露的一种有效的、选择性的 NAAA 抑制剂 ARN077 在炎症或神经损伤引起的痛觉过敏和感觉异常的啮齿动物模型中的作用。ARN077 的局部给药以剂量依赖性方式减轻了角叉菜胶注射或坐骨神经结扎引起的小鼠的热痛觉过敏和机械性感觉异常。选择性 PPAR-α 拮抗剂 GW6471 可预防 ARN077 的镇痛作用，并且在缺乏 PPAR-α 的小鼠中不会发生。此外，局部 ARN077 逆转了大鼠紫外线 B 辐射引起的感觉异常，并且该作用被 GW6471 预处理阻断。坐骨神经结扎或促炎佛波醇酯 12-O-十四烷酰佛波醇 13-乙酸酯的应用分别降低了坐骨神经和皮肤组织中的 FAEs 水平。ARN077 逆转了这些生化效应。结果表明 ARN077 是一种有效的细胞内 NAAA 活性抑制剂，通过局部给药在体内具有活性。这些发现进一步表明，NAAA 通过中断内源性 FAEs 信号传导在 PPAR-α 处调节外周疼痛的发生。
