title: Lack of effect of chronic pre-treatment with the FAAH inhibitor URB597 on inflammatory pain behaviour: evidence for plastic changes in the endocannabinoid system.
abstract: OBJECTIVE
  Elevating levels of endocannabinoids with inhibitors of fatty acid amide hydrolase (FAAH) is a major focus of pain research, purported to be a safer approach devoid of cannabinoid receptor-mediated side effects. Here, we have determined the effects of sustained pharmacological inhibition of FAAH on inflammatory pain behaviour and if pharmacological inhibition of FAAH was as effective as genetic deletion of FAAH on pain behaviour.
  
  
  METHODS
  Effects of pre-treatment with a single dose, versus 4 day repeated dosing with the selective FAAH inhibitor, URB597 (i.p. 0.3 mg·kg⁻¹), on carrageenan-induced inflammatory pain behaviour and spinal pro-inflammatory gene induction were determined in rats. Effects of pain induction and of the drug treatments on levels of arachidonoyl ethanolamide (AEA), palmitoyl ethanolamide (PEA) and oleolyl ethanolamide (OEA) in the spinal cord were determined.
  
  
  RESULTS
  Single, but not repeated, URB597 treatment significantly attenuated the development of inflammatory hyperalgesia (P < 0.001, vs. vehicle-treated animals). Neither mode of URB597 treatment altered levels of AEA, PEA and OEA in the hind paw, or carrageenan-induced paw oedema. Single URB597 treatment produced larger increases in AEA, PEA and OEA in the spinal cord, compared with those after repeated administration. Single and repeated URB597 treatment decreased levels of immunoreactive N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD) in the spinal cord and attenuated carrageenan-induced spinal pro-inflammatory gene induction.
  
  
  CONCLUSIONS
  Changes in the endocannabinoid system may contribute to the loss of analgesic effects following repeated administration of low dose URB597 in this model of inflammatory pain.
authors.affiliation: School of Biomedical Sciences, University of Nottingham, Queen's Medical Centre, UK.
authors.forename: Bright N
authors.initials: BN
authors.lastname: Okine
authors.forename: Leonie M
authors.initials: LM
authors.lastname: Norris
authors.forename: Stephen
authors.initials: S
authors.lastname: Woodhams
authors.forename: James
authors.initials: J
authors.lastname: Burston
authors.forename: Annie
authors.initials: A
authors.lastname: Patel
authors.forename: Stephen P H
authors.initials: SP
authors.lastname: Alexander
authors.forename: David A
authors.initials: DA
authors.lastname: Barrett
authors.forename: David A
authors.initials: DA
authors.lastname: Kendall
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Bennett
authors.forename: Victoria
authors.initials: V
authors.lastname: Chapman
mesh_terms: D000577:Amides; D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology*; D002219:Carbamates / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D063388:Endocannabinoids / Q000378:metabolism*; D004983:Ethanolamines / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy / Q000503:physiopathology; D008297:Male; D009829:Oleic Acids / Q000378:metabolism; D010146:Pain / Q000188:drug therapy* / Q000209:etiology; D010169:Palmitic Acids / Q000378:metabolism; D053284:Polyunsaturated Alkamides / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000577:Amides; D000581:Amidohydrolases; D001095:Arachidonic Acids; D001549:Benzamides; D002219:Carbamates; D063388:Endocannabinoids; D004983:Ethanolamines; D009829:Oleic Acids; D010169:Palmitic Acids; D053284:Polyunsaturated Alkamides; D000099252:Fatty Acid Amide Hydrolases; C440229:Oleylethanolamide; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; C005958:palmidrol; C078814:anandamide