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 CB(1) or CB(2) 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-5-yl(hydroxy)methyl)
piperidine-1-carboxylate (
JZL184) also attenuated mechanical and cold
allodynia via a CB(1), but not a CB(2), 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.