Cannabinoid-based medicines have therapeutic potential for the treatment of
pain. Augmentation of levels of
endocannabinoids with inhibitors of
fatty acid amide hydrolase (FAAH) is
analgesic in models of acute and inflammatory
pain states. The aim of this study was to determine whether local inhibition of FAAH alters nociceptive responses of spinal neurons in the spinal nerve
ligation model of
neuropathic pain. Electrophysiological studies were performed 14-18 d after spinal nerve
ligation or
sham surgery, and the effects of the FAAH inhibitor cyclohexylcarbamic
acid 3-carbamoyl biphenyl-3-yl
ester (
URB597) on mechanically evoked responses of spinal neurons and levels of
endocannabinoids were determined. Intraplantar
URB597 (25 microg in 50 microl) significantly (p < 0.01) attenuated mechanically evoked responses of spinal neurons in
sham-operated rats. Effects of
URB597 were blocked by the
cannabinoid 1
receptor (CB1) antagonist
AM251 [N-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-
pyrazole-3-carboxamide] (30 microg in 50 microl) and the
opioid receptor antagonist naloxone.
URB597 treatment increased levels of
anandamide, 2-arachidonyl
glycerol, and oleoyl ethanolamide in the ipsilateral hindpaw of
sham-operated rats. Intraplantar
URB597 (25 microg in 50 microl) did not, however, alter mechanically evoked responses of spinal neurons in spinal nerve ligated (SNL) rats or hindpaw levels of
endocannabinoids. Intraplantar injection of a higher dose of
URB597 (100 microg in 50 microl) significantly (p < 0.05) attenuated evoked responses of spinal neurons in SNL rats but did not alter hindpaw levels of
endocannabinoids. Spinal administration of
URB597 attenuated evoked responses of spinal neurons and elevated levels of
endocannabinoids in
sham-operated and SNL rats. These data suggest that peripheral FAAH activity may be altered or that alternative pathways of metabolism have greater importance in SNL rats.