Endocannabinoid and serotonergic systems are needed for acetaminophen-induced analgesia

Abstract

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.

Paracetamol: Update on its Analgesic Mechanism of Action

“…Involvement of this receptor in the action of paracetamol was confirmed by a study showing that CB 1 knockout mice and rats pretreated with a specific CB 1 antagonist (AM251) were insensitive to paracetamol [5,28]. Corroborating these results, we showed that the analgesic effect of p-aminophenol was also suppressed by AM251 [6].…”

“…Both strategies resulted in the abolition of paracetamol-induced (1) brain synthesis of AM404 and (2) analgesic action [5]. Likewise, the analgesic effect and brain formation of AM404 induced by p-aminophenol were decreased in FAAH −/− mice and in rats pretreated with PMSF [6].…”

“…The involvement of FAAH in the action of paracetamol was observed in different pain tests (paw pressure, von Frey, tail immersion and formalin tests) and modalities (thermal, mechanical and chemical stimuli) [5][6][7]. However, the experiments were conducted in naive animals, in a context far removed, therefore, from the clinical setting, in which paracetamol is used for pathological pain, notably nociceptive pain [8,9].…”

“…In addition, paracetamol does not bind directly CB 1 receptors [5]. Thus, the relationship between paracetamol and CB 1 remains to be elucidated.…”

Validation of the Simplified UVB Model to Assess the Pharmacodynamics of Analgesics in Healthy Human Volunteers

“…Paracetamol acts mainly on the brain and spinal cord; nevertheless, the exact mechanism of action has not been fully elucidated. [4] The prostaglandin H 2 synthase (PGHS), [5] the serotoninergic system, [6,7] and/or the cannabinoid system [8,9] have been proposed as potential targets. The action of NSAIDs mainly relies on the inhibition of prostaglandin biosynthesis at the site of the inflammation, [10] although some NSAIDs also exhibit a central action.…”