Inhibition of fatty acid amide hydrolase produces PPAR‐α‐mediated analgesia in a rat model of inflammatory pain

Abstract

We have previously demonstrated antinociceptive effects of fatty acid amide hydrolase (FAAH) inhibition that were accompanied by increases in the levels of endocannabinoids (ECs) in the hind paw. Here, the effects of the FAAH inhibitor URB597 (3'-carbamoyl-biphenyl-3-yl-cyclohexylcarbamate) on responses of spinal neurons were studied. Extracellular single-unit recordings of dorsal horn neurons were made in anaesthetized rats with hind paw inflammation induced by lambda-carrageenan. Effects of intraplantar pre-administration of URB597, or vehicle, on carrageenan-evoked expansion of peripheral receptive fields of spinal neurons and mechanically evoked responses of neurons were studied. The cannabinoid receptor type 1 (CB(1)) antagonist AM251 (N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide) and the peroxisome proliferator-activated receptor (PPAR)-alpha antagonist GW6471 ([(2S)-2-[[(1Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl]amino]-3-[4-[2-(5-methyl-2-phenyl-4-oxa zolyl)ethoxy]phenyl]propyl]-carbamic acid ethyl ester) were used to investigate the roles of these receptors in mediating the effects of URB597. URB597 (25 microg in 50 microL) pretreatment significantly inhibited carrageenan-evoked receptive field expansion and this was significantly reversed by co-administration of the PPAR-alpha antagonist but not the CB(1) antagonist. Pretreatment with the PPAR-alpha receptor agonist WY14643 ([[4-chloro-6-[(2,3-dimethylphenyl)amino]-2-pyrimidinyl]thio]acetic acid) also significantly inhibited receptive field expansion. URB597 (25 or 100 microg in 50 microL) had no significant effect on mechanically evoked responses of spinal neurons. URB597 inhibited receptive field expansions but not mechanically evoked responses of spinal neurons in rats with hind paw inflammation. These effects were blocked by PPAR-alpha receptor antagonism. These data support the contention that URB597 exerts its antinociceptive effects by indirect inhibition of sensitization of neuronal responses at least partly through PPAR-alpha activation due to enhanced EC levels.