title: The role of 5-HT1A/B autoreceptors in the antinociceptive effect of systemic administration of acetaminophen.
abstract: BACKGROUND
  It has been proposed that serotonin participates in the central antinociceptive effect of acetaminophen. The serotonin activity in the brainstem is primarily under the control of 5-HT1A somatodendritic receptors, although some data also suggest the involvement of 5-HT1B receptors. In the presence of serotonin, the blockade of 5-HT(1A/B) receptors at the level of the raphe nuclei leads to an increase in serotonin release in terminal areas, thus improving serotonin functions. This study examines the involvement of 5-HT(1A/B) receptors in the antinociceptive effect of acetaminophen in mice.
  
  
  METHODS
  The effects of acetaminophen (600 mg/kg intraperitoneal) followed by different doses of antagonists (WAY 100635 [0.2-0.8 mg/kg subcutaneous] and SB 216641 [0.2-0.8 mg/kg subcutaneous]) or agonists (8-OH-DPAT [0.25-1 mg/kg subcutaneous] and CP 93129 [0.125-0.5 mg/kg subcutaneous]) of 5-HT1A and 5-HT1B receptors, respectively, were determined in the hot-plate test in mice.
  
  
  RESULTS
  Acetaminophen (300-800 mg/kg) showed a dose-dependent antinociceptive effect in the hot-plate test in mice. WAY 100635 (0.2-0.8 mg/kg; 5-HT1A antagonist) induced an increase in the antinociceptive effect of 600 mg/kg acetaminophen, but this increase was not dose related. Conversely, 8-OH-DPAT (0.25-1 mg/kg; 5-HT1A agonist) decreased the antinociceptive effect of acetaminophen. SB 216641 (0.2-0.8 mg/kg; 5-HT1B antagonist) induced a dose-related increase in the antinociceptive effect of acetaminophen, and CP 93129 (0.25 mg/kg; 5-HT1B agonist) significantly decreased the antinociceptive effect of acetaminophen.
  
  
  CONCLUSIONS
  These results suggest that the combination of acetaminophen with compounds having 5-HT1A and 5-HT1B antagonist properties could be a new strategy to improve the analgesia of acetaminophen, thanks to its mild serotonergic properties.
authors.affiliation: Department of Neuroscience, Faculty of Medicine, University of Cádiz, Spain.
authors.forename: Aránzazu
authors.initials: A
authors.lastname: Roca-Vinardell
authors.forename: Antonio
authors.initials: A
authors.lastname: Ortega-Alvaro
authors.forename: Juan
authors.initials: J
authors.lastname: Gibert-Rahola
authors.forename: Juan A
authors.initials: JA
authors.lastname: Micó
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000082:Acetaminophen / Q000494:pharmacology*; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D000818:Animals; D017660:Autoreceptors / Q000502:physiology*; D001549:Benzamides / Q000494:pharmacology; D008297:Male; D051379:Mice; D010069:Oxadiazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin / Q000502:physiology*; D044263:Receptors, Serotonin, 5-HT1
chemical_list: D018712:Analgesics, Non-Narcotic; D017660:Autoreceptors; D001549:Benzamides; C108531:N-(3-(2-dimethylamino)ethoxy-4-methoxyphenyl)-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-(1,1'-biphenyl)-4-carboxamide; D010069:Oxadiazoles; D011725:Pyridines; D011758:Pyrroles; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; C065046:3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo(3,2-b)pyrid-5-one; D000082:Acetaminophen; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin