Acetaminophen is the most used
analgesic/
antipyretic drug. Its unclear mechanism of action could rely on
cyclooxygenase inhibition, NO synthesis blockade or reinforcement of the serotonergic system. Here we show that in thermal, mechanical and chemical
pain tests,
AM-251, a specific CB(1) receptor antagonist, abolished the
analgesic action of
acetaminophen, which was also lost in CB(1) receptor knockout mice. Moreover,
acetaminophen was shown unable to bind to CB(1) receptors demonstrating an indirect involvement of these receptors in the
analgesic effect of this compound. Accordingly with these results, we also demonstrated that the inhibition of FAAH, an
enzyme involved in the cerebral metabolism of
acetaminophen into
AM404, known to reinforce the activity of the
endocannabinoid system, suppressed the antinociceptive effect of
acetaminophen. In addition, similarly to the interaction of
acetaminophen with bulbospinal serotonergic pathways and spinal
serotonin receptors, we observed that the antinociceptive activity of ACEA, a CB(1) receptor agonist, was inhibited by lesion of bulbospinal serotonergic pathways and antagonists of spinal
5-HT receptors. We therefore propose that
acetaminophen-induced
analgesia could involve the following sequence: (1) FAAH-dependent metabolism of
acetaminophen into
AM404; (2) indirect involvement of CB(1) receptors by this metabolite; (3)
endocannabinoid-dependent reinforcement of the serotonergic bulbospinal pathways, and (4) involvement of spinal
pain-suppressing serotonergic receptors.