Abstract
The endocannabinoids anandamide and 2-arachidonoylglycerol are predominantly regulated
by the respective catabolic enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol
lipase (MAGL). Inhibition of these enzymes elevates endocannabinoid levels and attenuates
neuropathic pain. In the present study, CB1 and CB2 receptor-deficient mice were subjected to chronic constriction injury (CCI) of the
sciatic nerve to examine the relative contribution of each receptor for the anti-allodynic
effects of the FAAH inhibitor, PF-3845, and the MAGL inhibitor, JZL184. CCI caused
marked hypersensitivity to mechanical and cold stimuli, which was not altered by deletion
of either the CB1 or CB2 receptor, but was attenuated by gabapentin, as well as by each enzyme inhibitor.
Whereas PF-3845 lacked anti-allodynic efficacy in both knockout lines, JZL184 did
not produce anti-allodynic effects in CB1 (-/-) mice, but retained its anti-allodynic effects in CB2 (-/-) mice. These data indicate that FAAH and MAGL inhibitors reduce nerve injury-related
hyperalgesic states through distinct cannabinoid receptor mechanisms of action. In
conclusion, although endogenous cannabinoids do not appear to play a tonic role in
long-term expression of neuropathic pain states, both FAAH and MAGL represent potential
therapeutic targets for the development of pharmacological agents to treat chronic
pain resulting from nerve injury.
Perspective
This article presents data addressing the cannabinoid receptor mechanisms underlying
the anti-allodynic actions of endocannabinoid catabolic enzyme inhibitors in the mouse
sciatic nerve ligation model. Fatty acid amide hydrolase and monoacylglycerol lipase
inhibitors reduced allodynia through distinct cannabinoid receptor mechanisms. These
enzymes offer potential targets to treat neuropathic pain.
Key words
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Article info
Publication history
Published online: June 17, 2010
Accepted:
April 6,
2010
Received in revised form:
February 17,
2010
Received:
December 10,
2009
Footnotes
Supported by the National Institute on Drug Abuse (grants T32DA007027, P01DA009789, P01DA017259, P50DA005274, and R01DA015197).
Identification
Copyright
© 2010 American Pain Society. Published by Elsevier Inc. All rights reserved.
