Received for publication April 20, 2006.
Revised November 3, 2006.
Accepted for publication November 3, 2006.

Acetaminophen recruits spinal p42/p44 MAPKs and GH/IGF-1 receptors to produce analgesia via the serotonergic system

Abstract

The mechanism of action of acetaminophen is currently widely discussed. Direct inhibition of cyclooxygenase isoforms is still 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-HT_1A receptors in the formalin test, thereby increasing transcript and protein levels of p75^NTR, IGF-1R and GHR and reducing the amount of sst3R mRNA. Those cellular events appear to be important for the antinociceptive activity of acetaminophen. Indeed, downregulation of sst3R mRNA depends on acetaminophen-elicited, 5-HT_1A receptor-dependent increase in neuronal ERK1/2 activities which mediate antinociception. In addition, spinal 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.

Key words: Serotonin, Regulation of gene expression