@article {Libert728, author = {F. Libert and J. Bonnefont and E. Bourinet and E. Doucet and A. Alloui and M. Hamon and J. Nargeot and A. Eschalier}, title = {Acetaminophen: A Central Analgesic Drug That Involves a Spinal Tropisetron-Sensitive, Non{\textendash}5-HT3 Receptor-Mediated Effect}, volume = {66}, number = {3}, pages = {728--734}, year = {2004}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {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-HT3A 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.}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/66/3/728}, eprint = {https://molpharm.aspetjournals.org/content/66/3/728.full.pdf}, journal = {Molecular Pharmacology} }