Chang Leon, Luo Lin, Palmer James A, Sutton Steven, Wilson Sandy J, Barbier Ann J, Breitenbucher James Guy, Chaplan Sandra R, Webb Michael
Johnson & Johnson Pharmaceutical Research & Development, L.L.C., San Diego, CA 92121-1126, USA.
Br J Pharmacol. 2006 May;148(1):102-13. doi: 10.1038/sj.bjp.0706699.
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 found in 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 ED(50) between 6 and 9 mg kg(-1). The plasma concentration at the ED(50) in both models was 0.7 microM (240 ng ml(-1)). 6 In the rat SNL model, coadministration of the selective CB(2) 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 CB(1) 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.
可逆性脂肪酸酰胺水解酶（FAAH）抑制剂OL135可逆转大鼠脊髓神经结扎（SNL）和轻度热损伤（MTI）模型中的机械性异常性疼痛。本研究旨在探讨大麻素和阿片系统在介导这种镇痛作用中的作用。
在腹腔注射20mg/kg的阿南达酰胺前15分钟腹腔注射OL135（20mg/kg）的大鼠脑中，发现阿南达酰胺的脑浓度升高（组织浓度为350pmol/g，而在给予赋形剂的对照中为60pmol/g）。
发现在给予不可逆FAAH抑制剂（URB597：0.3mg/kg心内注射）前30分钟用OL135（2-60mg/kg腹腔注射）预先给药大鼠，可保护脑FAAH免于不可逆失活。酶保护水平与同一脑内的OL135浓度相关。
OL135（100mg/kg腹腔注射）在给药30分钟后可使FAAH（+/+）小鼠中由MTI诱导的机械性异常性疼痛的最大可能效应（MPE）降低50%（用von Frey细丝测量），但对FAAH（-/-）小鼠无效。
腹腔注射OL135可使大鼠MTI和SNL模型中的机械性异常性疼痛产生剂量依赖性逆转，ED（50）在6至9mg/kg之间。两个模型中ED（50）时的血浆浓度均为0.7μM（240ng/ml）。
在大鼠SNL模型中，选择性CB（2）受体拮抗剂SR144528（5mg/kg腹腔注射）与20mg/kg的OL135共同给药可阻断OL135诱导的机械性异常性疼痛逆转，但选择性CB（1）拮抗剂SR141716A（5mg/kg腹腔注射）无效。
在大鼠MTI模型中，SR141716A或SR144528（均为5mg/kg腹腔注射），或两种拮抗剂与OL135（20mg/kg）共同给药，在给药30分钟后评估时均未阻断机械性异常性疼痛的逆转。
在大鼠的MTI模型和SNL模型中，纳洛酮（1mg/kg，在OL135后30分钟腹腔注射）可逆转OL135产生的镇痛作用（在MTI模型中降至对照水平的15%，在SNL模型中降至零）。
