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Article Dans Une Revue Neuropharmacology Année : 2015

Supra-spinal FAAH is required for the analgesic action of paracetamol in an inflammatory context

Romain Dalmann
  • Fonction : Auteur
Laurence Daulhac
  • Fonction : Auteur
Myriam Antri
Alain Eschalier
  • Fonction : Auteur
Christophe Mallet

Résumé

Paracetamol (acetaminophen) is the most commonly used analgesic in the world. Recently, a new view of its action has emerged: that paracetamol would be a pro-drug that should be metabolized by the FAAH enzyme into AM404, its active metabolite. However, this hypothesis has been demonstrated only in naive animals, a far cry from the clinical pathologic context of paracetamol use. Moreover, FAAH is a ubiquitous enzyme expressed both in the central nervous system and in the periphery. Thus, we explored: (i) the involvement of FAAH in the analgesic action of paracetamol in a mouse model of inflammatory pain; and (ii) the contributions of central versus peripheral FAAH in this action. The analgesic effect of paracetamol was evaluated in thermal hyperalgesia, mechanical allodynia and hyperalgesia induced by an intra-plantar injection of carrageenan (3%) in FAAH knock-out mice or their littermates. Moreover, the contribution of the central and peripheral enzymes was explored by comparing the effect of a global FAAH inhibitor (URB597) to that of a peripherally restricted FAAH inhibitor (URB937) on paracetamol action. Here, we show that in a model of inflammatory pain submitted to different stimuli, the analgesic action of paracetamol was abolished when FAAH was genetically or pharmacologically inhibited. Whereas a global FAAH inhibitor, URB597 (0.3 mg/kg), reduced the anti-hyperalgesic action of paracetamol, a brain-impermeant FAAH inhibitor, URB937 (0.3 mg/kg), had no influence. However, administered intracerebroventricularly, URB937 (5 μg/mouse) reduced the action of paracetamol. These results demonstrate that the supra-spinally-located FAAH enzyme is necessary for the analgesic action of paracetamol.
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Dates et versions

hal-04326283 , version 1 (06-12-2023)

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Romain Dalmann, Laurence Daulhac, Myriam Antri, Alain Eschalier, Christophe Mallet. Supra-spinal FAAH is required for the analgesic action of paracetamol in an inflammatory context. Neuropharmacology, 2015, 91, pp.63-70. ⟨10.1016/j.neuropharm.2014.11.006⟩. ⟨hal-04326283⟩

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