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

Abstract:

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 1 H-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.

journal_name

Br J Pharmacol

authors

Barrière DA,Boumezbeur F,Dalmann R,Cadeddu R,Richard D,Pinguet J,Daulhac L,Sarret P,Whittingstall K,Keller M,Mériaux S,Eschalier A,Mallet C

doi

10.1111/bph.14934

subject

Has Abstract

pub_date

2020-04-01 00:00:00

pages

1773-1792

issue

8

eissn

0007-1188

issn

1476-5381

journal_volume

177

pub_type

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