title: Enhancement of the analgesic activity of paracetamol and nitroparacetamol by the oral administration of all-trans retinoic acid.
abstract: All-trans retinoic acid (ATRA), the active metabolite of vitamin A, is involved in the inflammatory reaction and modulates the expression of cyclooxygenase (COX) enzymes and nitric oxide (NO) activity. Since COX enzymes are the substrate of action of COX inhibitors, we studied the analgesic activity of paracetamol (PAR) and its NO-derivative nitroparacetamol (NOP) in the presence and absence of oral ATRA. Nociceptive responses were studied using the recording of single motor units technique in alpha-chloralose anesthetized normal and monoarthritic male Wistar rats. Intravenous PAR was not effective in normal rats. However, after pre-treatment with ATRA, PAR reduced dose-dependently the responses to noxious mechanical stimulation (ID50: 60+/-7 micromol/kg; 9.1 mg/kg), but not wind-up. The analgesic activity of NOP was enhanced after pre-treatment with ATRA either on responses to noxious mechanical stimulation (ID50s: 147+/-2 vs. 46+/-2 micromol/kg) or wind-up (maximal effect of 46+/-1% with 480 micromol/kg vs. 33+/-3% of control with 240 micromol/kg). The administration of ATRA did not modify the effect of PAR and NOP in monoarthritic rats. We conclude that pre-treatment with oral ATRA enhances the analgesic activity of PAR and NOP in acute pain, probably due to a positive modulation of their activity on spinal cord COX enzymes.
authors.affiliation: Departamento de Fisiología, Facultad de Medicina, Campus Universitario, Universidad de Alcalá, Alcalá de Henares, 28871 Madrid, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Alfonso Romero-Sandoval
authors.forename: Carlos
authors.initials: C
authors.lastname: Molina
authors.forename: Juan F
authors.initials: JF
authors.lastname: Herrero
mesh_terms: D000082:Acetaminophen / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000284:Administration, Oral; D000700:Analgesics / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006930:Hyperalgesia / Q000188:drug therapy* / Q000209:etiology; D008297:Male; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D009566:Nitrates / Q000494:pharmacology*; D010147:Pain Measurement; D010812:Physical Stimulation / Q000009:adverse effects; D051381:Rats; D017208:Rats, Wistar; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D000700:Analgesics; D000970:Antineoplastic Agents; D009566:Nitrates; D000082:Acetaminophen; D014212:Tretinoin; C478738:4-(nitroxy)butanoic acid 4-acetylaminophenyl ester