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Inhibition of fatty acid amide hydrolase produces PPAR‐α‐mediated analgesia in a rat model of inflammatory pain
Author(s) -
Sagar D R,
Kendall D A,
Chapman V
Publication year - 2008
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/bjp.2008.335
Subject(s) - fatty acid amide hydrolase , chemistry , am251 , pharmacology , cannabinoid , endocannabinoid system , antagonist , receptor antagonist , palmitoylethanolamide , endocrinology , receptor , medicine , cannabinoid receptor , biochemistry , biology
Background and purpose: 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. Experimental approach: Extracellular single‐unit recordings of dorsal horn neurons were made in anaesthetized rats with hind paw inflammation induced by λ‐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‐1 H ‐pyrazole‐3‐carboxamide) and the peroxisome proliferator‐
activated receptor (PPAR)‐α antagonist GW6471 ([(2 S )‐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. Key results: URB597 (25 μg in 50 μL) pretreatment significantly inhibited carrageenan‐evoked receptive field expansion and this was significantly reversed by co‐administration of the PPAR‐α antagonist but not the CB 1 antagonist. Pretreatment with the PPAR‐α 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 μg in 50 μL) had no significant effect on mechanically evoked responses of spinal neurons. Conclusions and implications: 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‐α 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‐α activation due to enhanced EC levels. British Journal of Pharmacology (2008) 155 , 1297–1306; doi: 10.1038/bjp.2008.335 ; published online 25 August 2008