David André Barrière1,2,3, Fawzi Boumezbeur3, Romain Dalmann1,2, Roberto Cadeddu1,2, Damien Richard1,2, Jérémy Pinguet1,2, Laurence Daulhac1,2, Philippe Sarret4, Kevin Whittingstall5, Matthieu Keller6, Sébastien Mériaux3, Alain Eschalier1,2, Christophe Mallet1,2. 1. Université Clermont Auvergne, INSERM, CHU, NEURO-DOL Basics and Clinical Pharmacology of Pain, Clermont-Ferrand, France. 2. Analgesia Institute, Faculty of Medicine, Clermont-Ferrand, France. 3. NeuroSpin, CEA, Université Paris-Saclay, Gif-sur-Yvette, France. 4. Département de Physiologie et Biophysique/Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, Québec, Canada. 5. Département de Radiologie Diagnostique, Université de Sherbrooke, Sherbrooke, Québec, Canada. 6. UMR Physiologie de la Reproduction et des Comportements, INRA/CNRS/Université de Tours/IFCE, Nouzilly, France.
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.
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.
Authors: Eugene P Duff; William Vennart; Richard G Wise; Matthew A Howard; Richard E Harris; Michael Lee; Karolina Wartolowska; Vishvarani Wanigasekera; Frederick J Wilson; Mark Whitlock; Irene Tracey; Mark W Woolrich; Stephen M Smith Journal: Sci Transl Med Date: 2015-02-11 Impact factor: 17.956
Authors: D A Barrière; R Magalhães; A Novais; P Marques; E Selingue; F Geffroy; F Marques; J Cerqueira; J C Sousa; F Boumezbeur; M Bottlaender; T M Jay; A Cachia; N Sousa; S Mériaux Journal: Nat Commun Date: 2019-12-13 Impact factor: 14.919
Authors: Hernan A Bazan; Surjyadipta Bhattacharjee; Carolina Burgos; Javier Recio; Valentina Abet; Amanda R Pahng; Bokkyoo Jun; Jessica Heap; Alexander J Ledet; William C Gordon; Scott Edwards; Dennis Paul; Julio Alvarez-Builla; Nicolas G Bazan Journal: Eur J Med Chem Date: 2020-06-30 Impact factor: 6.514