Blockade of Endocannabinoid-Degrading Enzymes Attenuates Neuropathic Pain
Blockade of Endocannabinoid-Degrading Enzymes Attenuates Neuropathic Pain
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DOI：
10.1124/jpet.109.155465
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发表时间：
2009-09-01
影响因子：
3.5
通讯作者：
Lichtman, A. H.
中科院分区：
文献类型：
--
作者：
Kinsey, S. G.;Long, J. Z.;Lichtman, A. H.
众所周知，直接作用的大麻素受体激动剂可以减少神经损伤后的痛觉过敏反应和异常性疼痛，尽管它们的精神活性副作用抑制了对其治疗开发的热情。或者，抑制脂肪酸酰胺水解酶（FAAH）和单酰基甘油脂肪酶（MAGL）（负责降解相应内源性大麻素、大麻素酰胺（AEA）和2-花生四烯酸甘油（2-AG）的主要酶）在多种伤害感受测定中降低伤害感受，而没有或具有最小的行为影响。在本研究中，我们测试是否抑制这些酶减弱机械异常性疼痛，丙酮诱导的冷异常性疼痛的小鼠坐骨神经慢性压迫损伤。急性给药不可逆FAAH抑制剂环己基氨基甲酸3 '-氨基甲酰基联苯-3-基酯（URB 597）或可逆FAAH抑制剂1-氧代-1-[5-（2-吡啶基）-2-基]-7-苯基庚烷（OL-135）可降低两种试验中的异常性疼痛。这种衰减被CB 1或CB 2受体拮抗剂预处理完全阻断，但不能被TRPV 1受体拮抗剂辣椒平或阿片受体拮抗剂纳洛酮阻断。新型MAGL抑制剂4-硝基苯基4-（二苯并[d][1，3]间二氧杂环戊烯-5基（羟基）甲基）哌啶-1-甲酸酯（JZL 184）也通过CB 1而不是CB 2受体作用机制减轻机械性和冷异常性疼痛。URB 597在FAAH（-/-）小鼠中没有引起抗异常性疼痛作用，而JZL 184的作用是FAAH非依赖性的。最后，URB 597增加了脑和脊髓AEA水平，而JZL 184增加了这些组织中的2-AG水平，但在神经损伤和对照小鼠之间没有发现任何内源性大麻素的差异。这些数据表明，FAAH和MAGL的抑制通过不同的受体作用机制减少神经性疼痛，并为镇痛治疗剂的开发提供了可行的靶点。
Direct-acting cannabinoid receptor agonists are well known to reduce hyperalgesic responses and allodynia after nerve injury, although their psychoactive side effects have damped enthusiasm for their therapeutic development. Alternatively, inhibiting fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), the principal enzymes responsible for the degradation of the respective endogenous cannabinoids, anandamide (AEA) and 2-arachydonylglycerol (2-AG), reduce nociception in a variety of nociceptive assays, with no or minimal behavioral effects. In the present study we tested whether inhibition of these enzymes attenuates mechanical allodynia, and acetone-induced cold allodynia in mice subjected to chronic constriction injury of the sciatic nerve. Acute administration of the irreversible FAAH inhibitor, cyclohexylcarbamic acid 3'-carbamoylbiphenyl-3-yl ester (URB597), or the reversible FAAH inhibitor, 1-oxo-1-[5-(2-pyridyl)-2-yl]-7-phenylheptane (OL-135), decreased allodynia in both tests. This attenuation was completely blocked by pretreatment with either CB1 or CB2 receptor antagonists, but not by the TRPV1 receptor antagonist, capsazepine, or the opioid receptor antagonist, naltrexone. The novel MAGL inhibitor, 4-nitrophenyl 4-(dibenzo[d][1,3] dioxol-5yl(hydroxy) methyl)piperidine-1-carboxylate (JZL184) also attenuated mechanical and cold allodynia via a CB 1, but not a CB2, receptor mechanism of action. Whereas URB597 did not elicit antiallodynic effects in FAAH(-/-) mice, the effects of JZL184 were FAAH-independent. Finally, URB597 increased brain and spinal cord AEA levels, whereas JZL184 increased 2-AG levels in these tissues, but no differences in either endo-cannabinoid were found between nerve-injured and control mice. These data indicate that inhibition of FAAH and MAGL reduces neuropathic pain through distinct receptor mechanisms of action and present viable targets for the development of analgesic therapeutics.