title: Endocannabinoid and serotonergic systems are needed for acetaminophen-induced analgesia.
abstract: Acetaminophen is the most used analgesic/antipyretic drug. Its unclear mechanism of action could rely on cyclooxygenase inhibition, NO synthesis blockade or reinforcement of the serotonergic system. Here we show that in thermal, mechanical and chemical pain tests, AM-251, a specific CB(1) receptor antagonist, abolished the analgesic action of acetaminophen, which was also lost in CB(1) receptor knockout mice. Moreover, acetaminophen was shown unable to bind to CB(1) receptors demonstrating an indirect involvement of these receptors in the analgesic effect of this compound. Accordingly with these results, we also demonstrated that the inhibition of FAAH, an enzyme involved in the cerebral metabolism of acetaminophen into AM404, known to reinforce the activity of the endocannabinoid system, suppressed the antinociceptive effect of acetaminophen. In addition, similarly to the interaction of acetaminophen with bulbospinal serotonergic pathways and spinal serotonin receptors, we observed that the antinociceptive activity of ACEA, a CB(1) receptor agonist, was inhibited by lesion of bulbospinal serotonergic pathways and antagonists of spinal 5-HT receptors. We therefore propose that acetaminophen-induced analgesia could involve the following sequence: (1) FAAH-dependent metabolism of acetaminophen into AM404; (2) indirect involvement of CB(1) receptors by this metabolite; (3) endocannabinoid-dependent reinforcement of the serotonergic bulbospinal pathways, and (4) involvement of spinal pain-suppressing serotonergic receptors.
authors.affiliation: INSERM E9904, U766, Facultés de Médecine et de Pharmacie, 28, Place Henri Dunant, B.P. 38, F-63001 Clermont-Ferrand Cedex 01, France Clermont Université, Université d'Auvergne, Faculté de Médecine, Laboratoire de Pharmacologie Médicale, F-63001 Clermont-Ferrand, France Clermont Université, Université d'Auvergne, Faculté de Pharmacie, Laboratoire de Pharmacologie, F-63001 Clermont-Ferrand, France IRIBHM, Université Libre de Bruxelles, B-1070 Bruxelles, Belgium CHU Clermont-Ferrand, Service de Pharmacologie, Hôpital G. Montpied, F-63003 Clermont-Ferrand, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Mallet
authors.forename: Laurence
authors.initials: L
authors.lastname: Daulhac
authors.forename: Jérôme
authors.initials: J
authors.lastname: Bonnefont
authors.forename: Catherine
authors.initials: C
authors.lastname: Ledent
authors.forename: Monique
authors.initials: M
authors.lastname: Etienne
authors.forename: Eric
authors.initials: E
authors.lastname: Chapuy
authors.forename: Frédéric
authors.initials: F
authors.lastname: Libert
authors.forename: Alain
authors.initials: A
authors.lastname: Eschalier
mesh_terms: D000082:Acetaminophen / Q000494:pharmacology / Q000627:therapeutic use*; D000698:Analgesia / Q000379:methods*; D000818:Animals; D063385:Cannabinoid Receptor Modulators / Q000037:antagonists & inhibitors / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010146:Pain / Q000188:drug therapy / Q000378:metabolism; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D011985:Receptors, Serotonin / Q000502:physiology; D012701:Serotonin / Q000378:metabolism / Q000502:physiology*
chemical_list: D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D011985:Receptors, Serotonin; D012701:Serotonin; D000082:Acetaminophen; C103505:AM 251