title: Supra-spinal FAAH is required for the analgesic action of paracetamol in an inflammatory context.
abstract: Paracetamol (acetaminophen) is the most commonly used analgesic in the world. Recently, a new view of its action has emerged: that paracetamol would be a pro-drug that should be metabolized by the FAAH enzyme into AM404, its active metabolite. However, this hypothesis has been demonstrated only in naive animals, a far cry from the clinical pathologic context of paracetamol use. Moreover, FAAH is a ubiquitous enzyme expressed both in the central nervous system and in the periphery. Thus, we explored: (i) the involvement of FAAH in the analgesic action of paracetamol in a mouse model of inflammatory pain; and (ii) the contributions of central versus peripheral FAAH in this action. The analgesic effect of paracetamol was evaluated in thermal hyperalgesia, mechanical allodynia and hyperalgesia induced by an intra-plantar injection of carrageenan (3%) in FAAH knock-out mice or their littermates. Moreover, the contribution of the central and peripheral enzymes was explored by comparing the effect of a global FAAH inhibitor (URB597) to that of a peripherally restricted FAAH inhibitor (URB937) on paracetamol action. Here, we show that in a model of inflammatory pain submitted to different stimuli, the analgesic action of paracetamol was abolished when FAAH was genetically or pharmacologically inhibited. Whereas a global FAAH inhibitor, URB597 (0.3 mg/kg), reduced the anti-hyperalgesic action of paracetamol, a brain-impermeant FAAH inhibitor, URB937 (0.3 mg/kg), had no influence. However, administered intracerebroventricularly, URB937 (5 μg/mouse) reduced the action of paracetamol. These results demonstrate that the supra-spinally-located FAAH enzyme is necessary for the analgesic action of paracetamol.
authors.affiliation: Clermont Université, Université d'Auvergne, Pharmacologie Fondamentale et Clinique de la Douleur, BP 10448, F-63000 Clermont-Ferrand, France; Inserm, U 1107, Neuro-Dol, F-63000 Clermont-Ferrand, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Dalmann
authors.affiliation: Clermont Université, Université d'Auvergne, Pharmacologie Fondamentale et Clinique de la Douleur, BP 10448, F-63000 Clermont-Ferrand, France; Inserm, U 1107, Neuro-Dol, F-63000 Clermont-Ferrand, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Daulhac
authors.affiliation: Inserm, U 1107, Neuro-Dol, F-63000 Clermont-Ferrand, France; Clermont Université, Université d'Auvergne, Douleur Trigéminale et Migraine, BP 10448, F-63000 Clermont-Ferrand, France.
authors.forename: Myriam
authors.initials: M
authors.lastname: Antri
authors.affiliation: Clermont Université, Université d'Auvergne, Pharmacologie Fondamentale et Clinique de la Douleur, BP 10448, F-63000 Clermont-Ferrand, France; Inserm, U 1107, Neuro-Dol, F-63000 Clermont-Ferrand, France; CHU Clermont-Ferrand, Service de Pharmacologie, F-63003 Clermont-Ferrand, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Eschalier
authors.affiliation: Clermont Université, Université d'Auvergne, Pharmacologie Fondamentale et Clinique de la Douleur, BP 10448, F-63000 Clermont-Ferrand, France; Inserm, U 1107, Neuro-Dol, F-63000 Clermont-Ferrand, France. Electronic address: Christophe.Mallet@udamail.fr.
authors.forename: Christophe
authors.initials: C
authors.lastname: Mallet
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage*; D000581:Amidohydrolases / Q000235:genetics / Q000502:physiology*; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage*; D000818:Animals; D001921:Brain / Q000201:enzymology*; D002351:Carrageenan; D006930:Hyperalgesia / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy / Q000201:enzymology*; D007249:Inflammation / Q000150:complications / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010146:Pain / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy / Q000201:enzymology*; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000082:Acetaminophen; D000581:Amidohydrolases; D018712:Analgesics, Non-Narcotic; D002351:Carrageenan; D000099252:Fatty Acid Amide Hydrolases
keywords: Analgesia; Brain; FAAH; Paracetamol