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Acetaminophen: A Central Analgesic Drug That Involves a Spinal Tropisetron-Sensitive, Non–5-HT₃ Receptor-Mediated Effect

Institut National de la Santé et de la Recherche Médicale/UdA E9904, Faculté de Médecine, Service de Pharmacologie, Centre Hospitalier Universitaire, Clermont-Ferrand, France (F.L., J.B., A.A., A.E.); Centre National de la Recherche Scientifique–Unité Propre de Recherche 1142 141, Montpellier, France (E.B., J.N.); and Institut National de la Santé et de la Recherche Médicale U288 Centre Hospitalier Universitaire Pitié-Salpêtrière, Faculté de Médecine, Paris, France (E.D., M.H.)

The reversal of the antinociceptive effect of systemically administered acetaminophen (paracetamol) by intrathecal administration of the potent 5-HT₃ receptor antagonist tropisetron has been reported in rats subjected to the paw pressure test, suggesting that acetaminophen action is mediated through spinal 5-HT₃ receptors. However, more recent data, showing differences between the pharmacological profiles of various 5-HT₃ receptor antagonists, led us to reconsider the involvement of spinal 5-HT₃ receptors. To address this question, two different approaches were used: 1) electrophysiological recordings to assess whether acetaminophen directly modulates 5-HT₃ receptor activity and 2) pharmacological investigations with various 5-HT₃ receptor antagonists and spinal 5-HT₃ receptors antisense oligodeoxynucleotides (AODNs) to determine how those treatments might affect the antinociceptive action of acetaminophen. Electrophysiological studies demonstrated that acetaminophen had no direct agonist or antagonist effects on 5-HT_3A receptors. Unlike tropisetron, other 5-HT₃ receptor antagonists, such as ondansetron and granisetron, injected intrathecally were unable to reverse the antinociceptive effect of acetaminophen. Moreover, pretreatment with AODNs did not reverse the acetaminophen-induced antinociceptive effect, although it suppressed the antinociceptive effect of m-chlorophenylbiguanide, a specific agonist of 5-HT₃ receptors, and significantly reduced (30%) the expression of these receptors in the dorsal horn of the spinal cord. These results suggest that acetaminophen-induced antinociceptive action involves a spinal tropisetron-sensitive receptor that is not the 5-HT₃ receptor and that remains to be identified.

Address correspondence to: Alain Eschalier, INSERM/UdA E9904, Faculté de médecine, Place Henri-Dunant - B.P. 38, 63001 Clermont-Ferrand Cedex 1-France. E-mail: alain.eschalier{at}u-clermont1.fr