Archives

  • 2018-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • To discriminate the peripheral and central involvement of FA

    2022-05-11

    To discriminate the peripheral and central involvement of FAAH in paracetamol action, we proposed a pharmacological strategy challenging the analgesic action of paracetamol observed in an inflammatory context with either a peripherally-restricted FAAH inhibitor (URB937, Clapper et al., 2010, Moreno-Sanz et al., 2011, Moreno-Sanz et al., 2012), or a global FAAH inhibitor known to cross the blood–brain barrier (URB597, Clapper et al., 2010). To avoid the intrinsic anti-nociceptive effect of FAAH inhibitors (Booker et al., 2012, Sasso et al., 2012), we have preliminarily tested different doses of each URB compound in thermal and mechanical nociceptive modalities. The dose of 0.3 mg/kg (i.p.) was chosen because it did not elicit an anti-nociceptive effect as previously shown (Costa et al., 2010, Moreno-Sanz et al., 2012). Moreover, Clapper et al. (2010) elegantly demonstrated that, after administration of these inhibitors at the same dose, FAAH activity was robustly reduced both in the bv8 and peripheral organs for URB597 and only in the periphery for URB937. We showed that, contrary to the peripherally-restricted FAAH inhibitor URB937, the global FAAH inhibitor URB597 significantly abrogated the analgesic action of paracetamol assessed by different nociceptive tests. To confirm these results and to explore the contribution of brain FAAH in paracetamol action, the counter proof of this experiment was performed. We assessed the analgesic effect of paracetamol after the injection of the peripherally-restricted FAAH inhibitor directly into the brain. Under these conditions, the effect of paracetamol was drastically reduced, highlighting the specific contribution of brain FAAH in paracetamol action. These results are in line with the Högestätt et al. (2005) study, which describes a FAAH-dependent metabolism of systemic paracetamol (300 mg/kg, i.p.) administration into AM404 in the brain but not in the periphery (blood and liver). However, these results contrast with the study of Ruggieri et al. (2008), which observed AM404 formation in the periphery (plasma). The difference between the two studies can be explained by the higher dose of paracetamol (400 mg/kg, i.p.) used in the latter study. Whether AM404 was present in blood or not, our study shows that peripheral FAAH would not be involved in the analgesic action of paracetamol because the effect of paracetamol was unchanged after a co-administration of a brain-impermeant inhibitor. AM404 synthesized by the brain-located FAAH could have different actions putatively involved in its analgesic effect such as inhibiting cellular anandamide reuptake leading to an increased level of endogenous anandamide or activating TRPV1 receptors (Zygmunt et al., 2000). Both mechanisms could contribute to the analgesic action of paracetamol. We previously demonstrated that brain TRPV1 inhibition suppressed the analgesic action of paracetamol (administered per os) or AM404 (injected i.c.v., Mallet et al., 2010), suggesting that TRPV1 activation could be the main mechanism. Moreover, the involvement of central FAAH in the analgesic effect of paracetamol is also consistent with our previous data showing that paracetamol acts as a central analgesic. For example, inhibition of the descending serotonergic pathway or the blockade of spinal serotonin receptors inhibited paracetamol-induced analgesia in animals (Bonnefont et al., 2007, Bonnefont et al., 2005, Mallet et al., 2008). In healthy volunteers submitted to acute pain stimuli, both inhibition of descending pathways and 5-HT3 receptor antagonists also reduced the effect of paracetamol in conditions of non-inflammatory pain (Pickering et al., 2008, Pickering et al., 2006). In conclusion, the mechanism of action of systemically administered paracetamol is certainly complex and involves several metabolic and neuronal pathways (Mallet and Eschalier, 2010). Using both genetic and pharmacological strategies, the current results demonstrate that (i) the FAAH enzyme is not only required for the anti-nociceptive action of paracetamol in naive animals but also for its analgesic effect in a pathological context of inflammatory pain; and (ii) only brain, but not peripheral, FAAH is involved, which confirms the central action of paracetamol. Based on these discoveries and previous ones (Barrière et al., 2013), new molecules, substrates of FAAH, would be a novel avenue for pharmacological management of pain. This strategy of pharmacological vectorization, would allow, as for paracetamol, targeting supra-spinal TRPV1 receptors to induce pain alleviation. A proof of concept has been recently performed using HMBA (4-hydroxy-3-methoxybenzylamine), a para-aminophenol analog, metabolized by FAAH into arvanil and olvanil (Barrière et al., 2013). HMBA has been shown to induce a FAAH-dependent analgesia involving supra-spinal TRPV1 receptors.