Differential involvement of opioidergic and serotoninergic systems in the antinociceptive activity of N-arachidonoyl-phenolamine (AM404) in the rat: comparison with paracetamol

It is recognized that paracetamol undergoes ametabolic transformation to N-arachydonylphenolamine(AM404), a CB1 receptor ligand and anandamide uptakeinhibitor. Using hot-plate and paw pressure tests, wedecided to establish whether AM404 may act throughopioidergic and serotonergic mechanisms. Thus, we pretreatedrats with opioid μ1 (naloxonazine) and κ (MR2266)or 5-HT1A (NAN-190), 5-HT2 (ketanserin), and 5-HT3(ondansetron) receptor antagonists. We investigated thepossible changes in 5-hydroxyindoleacetic acid/serotoninratio in the frontal cortex and pons. The antinociceptiveeffect of AM404 (10 mg/kg, intrapertoneally) or paracetamol(400 mg/kg, intrapertoneally) in either test wasabolished by naloxonazine or MR2266. Ondansetronprevented AM404 activity; NAN-190 and ketanserin wereineffective. Ketanserin antagonized paracetamol activity;NAN-190 and ondansetron were inactive. AM404 did notchange serotonergic activity, while paracetamol decreasedserotonin turnover. The diverse antinociceptive potency ofthe compounds might be explained by the differentinfluence on the serotonergic system, despite a similarinvolvement of opioidergic one.