**5. New strategies to alleviate pain: pharmacological vectorization to target brain TRPV1 receptors**

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

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

because of their high toxicity, which entails the risk of, notably, pulmonary and cardiovascular adverse effects [58–60]. Metabolites of capsaicin could be mutagenic at very high doses as well [61]. On the basis of the study of the mechanism of action of paracetamol, we propose that brain TRPV1 should be specifically targeted for the pharmacological management of pain. New substrates of FAAH, analogs of paracetamol or *p*-aminophenol, can be synthesized with the idea that the arachidonic acid-conjugated metabolites would be a potent TRPV1 activators.

To validate this strategy, we studied, with E.D. Högestätt and P.M. Zygmunt, 4-hydroxy-3-methoxybenzylamine (HMBA), a primary amine analog of *p*-aminophenol. HMBA produced arvanil and olvanil *in vitro* in brain homogenates and *in vivo* in mouse brain [6] (**Figure 3**).

Administered in mice or in rats, it had an analgesic effect. Both the formation of arvanil and olvanil and the analgesic effect induced by HMBA were FAAH-dependent. These two effects were lower in FAAH−/− mice than in their FAAH+/+ littermates. Arvanil and olvanil are potent TRPV1 activators [6, 62]. This mechanism of action contributed to the action of HMBA because, like that of paracetamol and *p*-aminophenol, its analgesic effect was suppressed after a genetic (TRPV1−/− mice) or pharmacological (rats pretreated with capsazepine) blockade of TRPV1. Finally, as with paracetamol or *p*-aminophenol, intracerebroventricular injection of the TRPV1 blocker capsazepine prevented the antinociceptive effect of HMBA [6].

Taken together, these data provide evidence of concept for the use of a pharmacological vectorization strategy aimed specifically at activating supraspinal TRPV1 to alleviate pain.
