**6. Conclusion**

In light of evidence showing that paracetamol and *p*-aminophenol involved CB1

that CB1

antinociception.

**to target brain TRPV1 receptors**

214 Pain Relief - From Analgesics to Alternative Therapies

 **Figure 3.** FAAH-dependent formation of arvanil and olvanil from HMBA.

tors in the antinociceptive effect of arachidonyl-2′-chloroethylamide (ACEA), a CB1

**5. New strategies to alleviate pain: pharmacological vectorization** 

we investigated the serotonergic descending bulbospinal pathways and spinal 5-HT recep-

agonist. Our results showed that ACEA needed intact descending bulbospinal serotonergic pathways. Elsewhere, it was shown that the antinociceptive action of ACEA was suppressed by intrathecal injection of WAY-100,635 and tropisetron in the formalin test and the paw pressure test, respectively [5]. The similar serotonergic profiles of ACEA and paracetamol suggest

A high-concentration of capsaicin, an 8% patch (Qutenza®) is used clinically in Europe and the USA to alleviate neuropathic pain. It has been suggested that its action is due to defunctionalization of peripheral TRPV1 [57]. A systemic use of TRPV1 activators is to be avoided

receptor is an important link between paracetamol and serotonin in the production of

receptors [5],

receptor

All these recent findings prompt us to propose a novel view of paracetamol as a prodrug that needs to overcome a two-step metabolism to form AM404, its active metabolite, which mediates the analgesic effect via different supra-spinal targets to activate the bulbospinal serotonergic pathways (**Figure 4**).

Interestingly, the involvement of the FAAH metabolic pathway and cannabinoid system is specifically related to their antinociceptive action and not to their hypothermic/antipyretic action [63, 64].

Several other concepts of the mechanism of action of paracetamol have been forwarded, including the involvement of the opioid [13, 65–68], adrenergic [69–71] and cholinergic [72, 73] systems and that of nitric oxide synthetase [74–77], adenosine receptors [48, 78, 79] and calcium channel TRPA1 [80]. However, other studies have yielded conflicting findings notably concerning the opioid [40, 81, 82], adrenergic [37, 71, 83] and cholinergic [84] systems.

The huge number of putative targets for the action of paracetamol and the complex relationship between all the different neurological systems complicate the study of the molecular mechanism of its analgesic action. The relationship between the putative targets needs further investigation to provide an overall view of the action of paracetamol. The understanding of the neurological and molecular actions of clinically used analgesics such as paracetamol could pave the way for the discovery of new analgesic compounds.

 **Figure 4.** Proposed sequential mechanisms for the antinociceptive effect of paracetamol. (1) Deacetylation of paracetamol in *p*-aminophenol in the liver. (2) FAAH-dependent metabolism of *p*-aminophenol into AM404 in the brain. (3) Direct and/or indirect involvement of supra-spinal CB1 receptors by this metabolite. (4) Reinforcement of the serotonergic bulbospinal pathways and (5) Involvement of spinal pain-suppressing serotonergic receptors. © Frédérique Koulkoff/ Inserm from Mallet/UMR 1107/Neuro-Dol Inserm.
