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Acetaminophen Recruits Spinal p42/p44 MAPKs and GH/IGF-1 Receptors to Produce Analgesia via the Serotonergic System

Institut National de la Santé et de la Recherche Médicale (INSERM) U766, Pharmacologie Fondamentale et Clinique de la Douleur, Facultés de Médecine et de Pharmacie and Université Clermont 1, Facultéde Médecine, Laboratoire de Pharmacologie Médicale, Clermont-Ferrand, France (J.B., L.D., M.E., E.Ch., C.M., J.-P.C., A.E.), Laboratoire de Biostatistiques, Télématique et Traitement d'Image, Clermont-Ferrand, France (L.O.); Service de Pharmacologie (A.E.) and Laboratoire de Santé Publique, Unité de Biostatistiques (L.O.), Centre Hospitalier Universitaire Clermont-Ferrand, Hôpital G. Montpied, Clermont-Ferrand, France; Institut National de la Recherche Agronomique, Unité de Nutrition et Métabolisme Protéique, Centre de Clermont-Ferrand - Theix, Saint-Genès Champanelle, France (C.D.). INSERM U484, Etude Métabolique des Molécules Marquées, Clermont-Ferrand, France (M.F.); and Institut de Pharmacologie et de Biologie Structurale, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5089, Toulouse, France (E.Cl.)

The mechanism of action of acetaminophen is currently widely discussed. Direct inhibition of cyclooxygenase isoforms remains the commonly advanced hypothesis. We combined behavioral studies with molecular techniques to investigate the mechanism of action of acetaminophen in a model of tonic pain in rats. We show that acetaminophen indirectly stimulates spinal 5-hydroxytryptamine (5-HT)_1A receptors in the formalin test, thereby increasing transcript and protein levels of low-affinity neurotrophin receptor, insulin-like growth factor-1 (IGF-1) receptor subunit, and growth hormone receptor and reducing the amount of somatostatin 3 receptor (sst3R) mRNA. Those cellular events seem to be important for the antinociceptive activity of acetaminophen. Indeed, down-regulation of sst3R mRNA depends on acetaminophen-elicited, 5-HT_1A receptordependent increase in neuronal extracellular signal-regulated kinase 1/2 (ERK1/2) activities that mediate antinociception. In addition, spinal growth hormone (GH) and IGF-1 receptors would also be involved in the antinociceptive activity of the analgesic at different degrees. Our results show the involvement of specific 5-HT_1A receptor-dependent cellular events in acetaminophen-produced antinociception and consequently indicate that inhibition of cyclooxygenase activities is not the exclusive mechanism involved. Furthermore, we propose that the mechanisms of 5-HT_1A receptor-elicited antinociception and the role of the spinal ERK1/2 pathway in nociception are more intricate than suspected so far and that the GH/IGF-1 axis is an interesting new player in the regulation of spinal nociception.

Address correspondence to: Pr Alain Eschalier, INSERM U766 Pharmacologie Fondamentale et Clinique de la Douleur, Facultés de Médecine et de Pharmacie, 28 place Henri Dunant, 63001 Clermont-Ferrand, France. E-mail: alain.eschalier{at}u-clermont1.fr