Inhibition of fatty acid amide hydrolase produces analgesia by multiple mechanisms
Inhibition of fatty acid amide hydrolase produces analgesia by multiple mechanisms
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DOI：
10.1038/sj.bjp.0706699
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发表时间：
2006-05-01
影响因子：
7.3
通讯作者：
Webb, Michael
中科院分区：
文献类型：
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作者：
Chang, Leon;Luo, Lin;Webb, Michael
1可逆性脂肪酸酰胺水解酶（FAAH）抑制剂OL 135可逆转大鼠脊神经结扎（SNL）和轻度热损伤（MTI）模型的机械性痛觉超敏。本研究的目的是研究大麻素和阿片系统在介导这种镇痛作用中的作用。（350 pmol g（-1）组织vs 60 pmol g（-1）溶剂处理对照组）（20 mg kg（-1））i. p. 15 min前腹腔注射20 mg kg（-1）anandamide。在给药前30分钟给予不可逆FAAH抑制剂（URB 597：心内0.3 mg/kg），发现可保护脑FAAH免于不可逆失活。酶保护水平与相同脑中的OL 135浓度相关。4 OL 135（100 mg kg（-1）i. p.）在给药后30分钟，在FAAH（+/+）小鼠中（von Frey细丝测量），由MTI诱导的机械性异常性疼痛降低了50%的最大可能功效（MPE），但在FAAH（-/-）小鼠中没有效果。5在大鼠的MTI和SNL模型中，腹膜内给予OL 135导致机械性异常性疼痛的剂量响应性逆转，ED 50在6和9 mg kg（-1）之间。在两种模型中，ED 50时的血浆浓度均为0.7 μ M（240 ng/ml）。6在大鼠SNL模型中，同时给予选择性CB 2受体拮抗剂SR 144528（5 mg/kg），20 mg kg（-1）OL 135可阻断OL 135诱导的机械性异常性疼痛的逆转，但选择性CB 1拮抗剂SR 141716 A（5 mg kg（-1）i. p.）7在大鼠MTI模型中，SR 141716 A或SR 144528（均为5 mg/kg i. p.），或两种拮抗剂的组合与OL 135（20 mg kg（-1））联合给药阻断了给药后30分钟评估的机械性异常性疼痛的逆转。8在大鼠的MTI模型和SNL模型中，纳洛酮（1 mg kg（-1），OL 135后30分钟腹腔注射）逆转了OL 135产生的镇痛作用（在MTI模型中为对照水平的15%，在SNL中为零）。
1 The reversible fatty acid amide hydrolase (FAAH) inhibitor OL135 reverses mechanical allodynia in the spinal nerve ligation (SNL) and mild thermal injury (MTI) models in the rat. The purpose of this study was to investigate the role of the cannabinoid and opioid systems in mediating this analgesic effect.2 Elevated brain concentrations of anandamide (350 pmol g(-1) of tissue vs 60 pmol g(-1) in vehicle treated controls) were founding brains of rats given OL135 (20 mg kg(-1)) i.p. 15 min prior to 20 mg kg(-1) i.p. anandamide.3 Predosing rats with OL135 (2-60 mg kg(-1) i.p.) 30 min before administration of an irreversible FAAH inhibitor (URB597: 0.3 mg kg(-1) intracardiac) was found to protect brain FAAH from irreversible inactivation. The level of enzyme protection was correlated with the OL135 concentrations in the same brains.4 OL135 (100 mg kg(-1) i.p.) reduced by 50% of the maximum possible efficacy (MPE) mechanical allodynia induced by MTI in FAAH(+/+)mice (von Frey filament measurement) 30 min after dosing, but was without effect in FAAH(-/-) mice.5 OL135 given i.p. resulted in a dose-responsive reversal of mechanical allodynia in both MTI and SNL models in the rat with an ED50 between 6 and 9 mg kg(-1). The plasma concentration at the ED50 in both models was 0.7 mu M (240 ng ml(-1)).6 In the rat SNL model, coadministration of the selective CB2 receptor antagonist SR144528 (5 mg kg(-1) i.p.), with 20 mg kg(-1) OL135 blocked the OL135-induced reversal of mechanical allodynia, but the selective CB1 antagonist SR141716A (5 mg kg(-1) i.p.) was without effect.7 In the rat MTI model neither SR141716A or SR144528 (both at 5 mg kg(-1) i.p.), or a combination of both antagonists coadministered with OL135 (20 mg kg(-1)) blocked reversal of mechanical allodynia assessed 30 min after dosing.8 In both the MTI model and SNL models in rats, naloxone (1 mg kg(-1), i.p. 30 min after OL135) reversed the analgesia (to 15% of control levels in the MTI model, to zero in the SNL) produced by OL135.