title: Differential involvement of opioidergic and serotonergic systems in the antinociceptive activity of N-arachidonoyl-phenolamine (AM404) in the rat: comparison with paracetamol.
abstract: It is recognized that paracetamol undergoes a metabolic transformation to N-arachydonylphenolamine (AM404), a CB(1) receptor ligand and anandamide uptake inhibitor. Using hot-plate and paw pressure tests, we decided to establish whether AM404 may act through opioidergic and serotonergic mechanisms. Thus, we pretreated rats with opioid mu(1) (naloxonazine) and kappa (MR2266) or 5-HT(1A) (NAN-190), 5-HT(2) (ketanserin), and 5-HT(3) (ondansetron) receptor antagonists. We investigated the possible changes in 5-hydroxyindoleacetic acid/serotonin ratio in the frontal cortex and pons. The antinociceptive effect of AM404 (10 mg/kg, intraperitoneally) or paracetamol (400 mg/kg, intraperitoneally) in either test was abolished by naloxonazine or MR2266. Ondansetron prevented AM404 activity; NAN-190 and ketanserin were ineffective. Ketanserin antagonized paracetamol activity; NAN-190 and ondansetron were inactive. AM404 did not change serotonergic activity, while paracetamol decreased serotonin turnover. The diverse antinociceptive potency of the compounds might be explained by the different influence on the serotonergic system, despite a similar involvement of opioidergic one.
authors.affiliation: Sect. of Pharmacology, Department of Biomedical Sciences, University of Modena and Reggio Emilia, Via G.Campi 287, 41100 Modena, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Ruggieri
authors.forename: Giovanni
authors.initials: G
authors.lastname: Vitale
authors.forename: Luigi Alberto
authors.initials: LA
authors.lastname: Pini
authors.forename: Maurizio
authors.initials: M
authors.lastname: Sandrini
mesh_terms: D000082:Acetaminophen / Q000494:pharmacology*; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D010146:Pain / Q000188:drug therapy*; D010147:Pain Measurement; D011149:Pons / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000187:drug effects / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000187:drug effects / Q000378:metabolism; D044348:Receptors, Serotonin, 5-HT2 / Q000187:drug effects / Q000378:metabolism; D044406:Receptors, Serotonin, 5-HT3 / Q000187:drug effects / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism
chemical_list: D018712:Analgesics, Non-Narcotic; D001095:Arachidonic Acids; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D044348:Receptors, Serotonin, 5-HT2; D044406:Receptors, Serotonin, 5-HT3; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; D000082:Acetaminophen; D006897:Hydroxyindoleacetic Acid; C107594:N-(4-hydroxyphenyl)arachidonylamide