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.