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

Dalmann, Romain; Daulhac, Laurence; Antri, Myriam; Eschalier, Alain; Mallet, Christophe

doi:10.1016/j.neuropharm.2014.11.006

Cited by 21 publications

(20 citation statements)

References 35 publications

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“…Finally, we found that paracetamol directly injected in the vlPAG did not modify thermal or mechanical pain thresholds, whereas systemic administration of paracetamol and intra‐vlPAG administration of p ‐aminophenol induced analgesia through an FAAH‐dependent mechanism. In conclusion, all these functional changes induced by paracetamol in the PAG are dependent on the availability of the enzyme FAAH, in line with published results showing that paracetamol is a pro‐drug acting centrally (Barrière et al, ; Dalmann et al, ; Högestätt et al, ; Mallet et al, ).…”

Section: Discussionsupporting

confidence: 84%

“…Taken together, these results support the hypothesis that the AM404 production in the PAG supports paracetamol‐induced analgesia. Following the suggestions of an involvement of TRPV1 channels and CB 1 receptors in the analgesic effect of paracetamol through AM404 (Barrière et al, ; Dalmann et al, ; Mallet et al, ; Ottani et al, ), we therefore investigated the role of these PAG‐located receptors. We first found that both TRPV1 channels and CB 1 receptors were co‐located in the vlPAG.…”

Section: Discussionmentioning

confidence: 99%

“…For example, paracetamol (acetaminophen) is one of the most popular analgesics used daily worldwide to relieve light‐to‐moderate pain, but its hepatotoxicity is a major limitation, and its mechanism of action is still a matter of debate (Mallet & Eschalier, ; Smith, ). Recent work on the mechanism of action of paracetamol suggests that it is metabolised by the liver into p ‐aminophenol, which is then conjugated with arachidonic acid, especially in the brain, to form AM404 ( N ‐(4‐hydroxyphenyl)‐5 Z ,8 Z ,11 Z ,14 Z ‐eicosatetraenamide) through the activity of the enzyme, fatty acid amide hydrolase (FAAH) (Dalmann, Daulhac, Antri, Eschalier, & Mallet, ; Högestätt et al, ; Mallet et al, ). In the brain, AM404 may then promote activation of the central endocannabinoid system through action at both TRPV1 channels and cannabinoid CB 1 receptors (Ottani, Leone, Sandrini, Ferrari, & Bertolini, ; Mallet et al, ; Mallet et al, ; Barrière et al, ; Kerckhove et al, ; Fukushima, Mamada, Iimura, & Ono, ; Klinger‐Gratz et al, ).…”

Section: Introductionmentioning

confidence: 99%

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Paracetamol is a centrally acting analgesic using mechanisms located in the periaqueductal grey

Barrière

Boumezbeur

Dalmann

et al. 2020

British J Pharmacology

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Background and Purpose We previously demonstrated that paracetamol has to be metabolised in the brain by fatty acid amide hydrolase enzyme into AM404 (N‐(4‐hydroxyphenyl)‐5Z,8Z,11Z,14Z‐eicosatetraenamide) to activate CB1 receptors and TRPV1 channels, which mediate its analgesic effect. However, the brain mechanisms supporting paracetamol‐induced analgesia remain unknown. Experimental Approach The effects of paracetamol on brain function in Sprague‐Dawley rats were determined by functional MRI. Levels of neurotransmitters in the periaqueductal grey (PAG) were measured using in vivo 1H‐NMR and microdialysis. Analgesic effects of paracetamol were assessed by behavioural tests and challenged with different inhibitors, administered systemically or microinjected in the PAG. Key Results Paracetamol decreased the connectivity of major brain structures involved in pain processing (insula, somatosensory cortex, amygdala, hypothalamus, and the PAG). This effect was particularly prominent in the PAG, where paracetamol, after conversion to AM404, (a) modulated neuronal activity and functional connectivity, (b) promoted GABA and glutamate release, and (c) activated a TRPV1 channel‐mGlu5 receptor‐PLC‐DAGL‐CB1 receptor signalling cascade to exert its analgesic effects. Conclusions and Implications The elucidation of the mechanism of action of paracetamol as an analgesic paves the way for pharmacological innovations to improve the pharmacopoeia of analgesic agents.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Paracetamol is a centrally acting analgesic using mechanisms located in the periaqueductal grey

Barrière

Boumezbeur

Dalmann

et al. 2020

British J Pharmacology

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“…Accordingly, APAP analgesia has been ascribed to AM404 activation of TRPV1 in the central nervous system 4 5 20 and activation of TRPA1 in the spinal cord by local formation of the electrophilic NAPQI 3 . Other studies have suggested that the cannabinoid receptor system contributes to APAP analgesia 36 37 . The antipyretic and hypothermic actions of APAP are not well understood.…”

Section: Discussionmentioning

confidence: 97%

TRPA1 mediates the hypothermic action of acetaminophen

Gentry

Andersson

Bevan

2015

Sci Rep

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Acetaminophen (APAP) is an effective antipyretic and one of the most commonly used analgesic drugs. Unlike antipyretic non-steroidal anti-inflammatory drugs, APAP elicits hypothermia in addition to its antipyretic effect. Here we have examined the mechanisms responsible for the hypothermic activity of APAP. Subcutaneous, but not intrathecal, administration of APAP elicited a dose dependent decrease in body temperature in wildtype mice. Hypothermia was abolished in mice pre-treated with resiniferatoxin to destroy or defunctionalize peripheral TRPV1-expressing terminals, but resistant to inhibition of cyclo-oxygenases. The hypothermic activity was independent of TRPV1 since APAP evoked hypothermia was identical in wildtype and Trpv1−/− mice, and not reduced by administration of a maximally effective dose of a TRPV1 antagonist. In contrast, a TRPA1 antagonist inhibited APAP induced hypothermia and APAP was without effect on body temperature in Trpa1−/− mice. In a model of yeast induced pyrexia, administration of APAP evoked a marked hypothermia in wildtype and Trpv1−/− mice, but only restored normal body temperature in Trpa1−/− and Trpa1−/−/Trpv1−/− mice. We conclude that TRPA1 mediates APAP evoked hypothermia.

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“…Unlike opioids, it is almost ineffective in intense pain and has no depressant effect on respiration. A novel and original view of this molecule now proposes acetaminophen to be a pro-drug needed to be biotransformed to be analgesic [19] by (i) hepatic deacetylation of into para-aminophenol; (ii) conjugation by the cerebral fatty acid amide hydrolase enzyme into AM404 [20] involving the activation of TRPV1 receptors [19,20], followed by the inhibition of Cav3.2 [21] and the modulation of CB1 receptors [22]. This complex mechanism disinhibits the periaqueductal grey matter output neurons, which could promote activation of the descending serotonergic inhibitory pathways as shown both in animals [23][24][25] and humans [26].…”

Section: Analgesic Drugs Acetaminophen: New Targetsmentioning

confidence: 99%

Pharmacogenomics in pain treatment

Peiró

Planelles

Juhász³

et al. 2016

Drug Metabolism and Personalized Therapy

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The experience of chronic pain is one of the commonest reasons for seeking medical attention, being a major issue in clinical practice. While pain is a universal experience, only a small proportion of people who felt pain develop pain syndromes. In addition, painkillers are associated with wide inter-individual variability in the analgesic response. This may be partly explained by the presence of single nucleotide polymorphisms in genes encoding molecular entities involved in pharmacodynamics and pharmacokinetics. However, uptake of this information has been slow due in large part to the lack of robust evidences demonstrating clinical utility. Furthermore, novel therapies, including targeting of epigenetic changes and gene therapy-based approaches are further broadening future options for the treatment of chronic pain. The aim of this article is to review the evidences behind pharmacogenetics (PGx) to individualize therapy (boosting the efficacy and minimizing potential toxicity) and genes implicated in pain medicine, in two parts: (i) genetic variability with pain sensitivity and analgesic response; and (ii) pharmacological concepts applied on PGx.

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

Cited by 21 publications

References 35 publications

Paracetamol is a centrally acting analgesic using mechanisms located in the periaqueductal grey

Paracetamol is a centrally acting analgesic using mechanisms located in the periaqueductal grey

TRPA1 mediates the hypothermic action of acetaminophen

Pharmacogenomics in pain treatment

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