Although
cannabinoids are efficacious in laboratory animal models of inflammatory
pain, their established cannabimimetic actions diminish enthusiasm for their therapeutic development. Conversely,
fatty acid amide hydrolase (FAAH), the chief catabolic
enzyme regulating the endogenous
cannabinoid N-arachidonoylethanolamine (
anandamide), has emerged as an attractive target for treating
pain and other conditions. Here, we tested
WIN 55212-2 [(R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de)-1,4-benzoxazin-6-yl]-1-napthalenylmethanone], a
cannabinoid receptor agonist, and genetic deletion or pharmacological inhibition of FAAH in the
lipopolysaccharide (LPS) mouse model of inflammatory
pain.
WIN 55212-2 significantly reduced
edema and hot-plate
hyperalgesia caused by LPS infusion into the hind paws, although the mice also displayed
analgesia and other central nervous system effects. FAAH(-/-) mice exhibited reduced paw
edema and
hyperalgesia in this model without apparent cannabimimetic effects. Transgenic mice expressing FAAH exclusively on neurons continued to display the antiedematous, but not the antihyperalgesic, phenotype. The CB(2)
cannabinoid receptor (CB(2)) antagonist
SR144528 [N-[(1S)-endo-1,3,3-trimethyl bicyclo [2.2.1] heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-
pyrazole-3-carboxamide] blocked this non-neuronal, anti-inflammatory phenotype, and the CB(1)
cannabinoid receptor (CB(1)) antagonist
rimonabant [
SR141716, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-
pyrazole-3-carboxamide] blocked the antihyperalgesic phenotype. The FAAH inhibitor
URB597 [cyclohexylcarbamic
acid 3'-carbamoylbiphenyl-3-yl
ester] attenuated the development of LPS-induced paw
edema and reversed LPS-induced
hyperalgesia through the respective CB(2) and CB(1) mechanisms of action. However, the transient receptor potential vanilloid type 1 antagonist
capsazepine did not affect either the antihyperalgesic or antiedematous effects of
URB597. Finally,
URB597 attenuated levels of the proinflammatory
cytokines interleukin-1beta and
tumor necrosis factor alpha in LPS-treated paws. These findings demonstrate that simultaneous elevations in non-neuronal and neuronal
endocannabinoid signaling are possible through inhibition of a single enzymatic target, thereby offering a potentially powerful strategy for treating chronic inflammatory
pain syndromes that operate at multiple levels of anatomical integration.