Paracetamol is a centrally acting analgesic using mechanisms located in the periaqueductal grey.
Journal
British journal of pharmacology
ISSN: 1476-5381
Titre abrégé: Br J Pharmacol
Pays: England
ID NLM: 7502536
Informations de publication
Date de publication:
04 2020
04 2020
Historique:
received:
17
05
2019
revised:
01
10
2019
accepted:
24
10
2019
pubmed:
18
11
2019
medline:
22
6
2021
entrez:
18
11
2019
Statut:
ppublish
Résumé
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 CB 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 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-mGlu 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.
Sections du résumé
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 CB
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
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-mGlu
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.
Identifiants
pubmed: 31734950
doi: 10.1111/bph.14934
pmc: PMC7070177
doi:
Substances chimiques
Analgesics
0
Acetaminophen
362O9ITL9D
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1773-1792Subventions
Organisme : Agence Nationale de la Recherche
ID : I-Site CAP 20-25
Pays : International
Organisme : Bristol-Myers Squibb
ID : 197/2008
Pays : International
Organisme : Bristol-Myers Squibb
ID : 304/2011
Pays : International
Organisme : Association Nationale de la Recherche Technologique
Pays : International
Informations de copyright
© 2019 The British Pharmacological Society.
Références
Sci Transl Med. 2015 Feb 11;7(274):274ra16
pubmed: 25673761
Adv Clin Exp Med. 2015 May-Jun;24(3):419-27
pubmed: 26467129
Pain. 2005 Apr;114(3):482-90
pubmed: 15777873
Brain Res. 1979 Jul 27;171(1):176-81
pubmed: 466437
CNS Neurol Disord Drug Targets. 2012 Mar;11(2):148-61
pubmed: 22483283
Eur J Pharmacol. 2001 Nov 30;432(1):1-7
pubmed: 11734181
Eur J Pharmacol. 1996 Jul 11;308(1):31-40
pubmed: 8836629
Nat Commun. 2019 Dec 13;10(1):5699
pubmed: 31836716
Pain. 2008 Sep 30;139(1):190-200
pubmed: 18485596
Brain Res. 1976 Mar 12;104(2):367-72
pubmed: 1260435
Eur J Pharmacol. 2003 Feb 21;462(1-3):73-81
pubmed: 12591098
Naunyn Schmiedebergs Arch Pharmacol. 2001 Dec;364(6):534-7
pubmed: 11770008
Anesthesiology. 2004 Feb;100(2):292-301
pubmed: 14739803
Br J Pharmacol. 2020 Apr;177(8):1773-1792
pubmed: 31734950
Science. 1969 Apr 25;164(3878):444-5
pubmed: 4887743
N Engl J Med. 2016 Dec 22;375(25):2413-2415
pubmed: 27959718
PLoS Biol. 2015 May 20;13(5):e1002151
pubmed: 25992600
Clin Ther. 2011 Dec;33(12):1894-903
pubmed: 22101161
Eur J Pharmacol. 2006 Feb 15;531(1-3):280-1
pubmed: 16438952
J Gene Med. 2010 Jul;12(7):561-3
pubmed: 20607692
Drug Des Devel Ther. 2015 Jul 23;9:3853-62
pubmed: 26229445
Neuroscience. 2005;134(1):269-81
pubmed: 15953687
Br J Pharmacol. 2019 Dec;176 Suppl 1:S297-S396
pubmed: 31710714
Proc Natl Acad Sci U S A. 2005 Dec 13;102(50):18195-200
pubmed: 16330766
J Neurosci. 2012 Jul 11;32(28):9457-68
pubmed: 22787031
Br J Pharmacol. 2019 Dec;176 Suppl 1:S142-S228
pubmed: 31710715
PLoS One. 2010 Sep 17;5(9):
pubmed: 20862299
Neuroscience. 2005;135(1):227-34
pubmed: 16084660
Mol Pain. 2010 Oct 11;6:66
pubmed: 20937102
J Neuroinflammation. 2016 Sep 02;13(1):231
pubmed: 27589957
Nucleic Acids Res. 2018 Jan 4;46(D1):D1091-D1106
pubmed: 29149325
Nat Rev Drug Discov. 2006 May;5(5):411-24
pubmed: 16604100
Neuroimage. 2012 Feb 15;59(4):3762-73
pubmed: 22119647
Pain. 1995 Dec;63(3):365-75
pubmed: 8719538
Neuropharmacology. 2015 Apr;91:63-70
pubmed: 25448494
J Neurosci. 2007 Dec 12;27(50):13739-49
pubmed: 18077685
J Neurophysiol. 2009 May;101(5):2411-22
pubmed: 19297510
Eur J Pharmacol. 2002 Mar 29;439(1-3):69-75
pubmed: 11937094
Sci Rep. 2017 Sep 29;7(1):12452
pubmed: 28963471
J Neurosci. 2018 Jan 10;38(2):322-334
pubmed: 29167401
Mol Cell Endocrinol. 2008 Apr 16;286(1-2 Suppl 1):S79-83
pubmed: 18325659
Pain. 2014 Apr;155(4):764-72
pubmed: 24447516
J Pharmacol Exp Ther. 2006 Mar;316(3):969-82
pubmed: 16284279
J Neurophysiol. 2007 Jan;97(1):503-11
pubmed: 17065246
J Neurosci. 2011 Oct 12;31(41):14600-10
pubmed: 21994376
Gene. 2006 Mar 29;370:64-74
pubmed: 16434153
Br J Pharmacol. 2011 May;163(2):330-45
pubmed: 21232043
Br J Pharmacol. 2008 Jan;153(2):367-79
pubmed: 17965748
Pain. 2019 Oct;160(10):2241-2254
pubmed: 31145220
Hum Brain Mapp. 2012 May;33(5):1003-18
pubmed: 21391283
Eur J Pain. 2005 Aug;9(4):463-84
pubmed: 15979027
Clin Pharmacol Ther. 2008 Apr;83(4):577-88
pubmed: 18030306
Brain Res. 1975 Aug 29;94(2):279-96
pubmed: 125141
J Physiol. 1985 Feb;359:151-62
pubmed: 2582112
Neuroimage. 2012 Mar;60(1):505-22
pubmed: 22197740
Pain Physician. 2009 Jan-Feb;12(1):269-80
pubmed: 19165309
Eur J Pharmacol. 2012 Feb 29;677(1-3):93-101
pubmed: 22206817
J Neurosci. 2011 Mar 30;31(13):5067-77
pubmed: 21451044
Clin Pharmacol Ther. 2008 Jul;84(1):47-51
pubmed: 17957182
Br J Pharmacol. 2019 Dec;176 Suppl 1:S21-S141
pubmed: 31710717
Brain Res. 1972 Sep 29;44(2):692-7
pubmed: 4263075
J Biol Chem. 2005 Sep 9;280(36):31405-12
pubmed: 15987694
Trends Neurosci. 2009 Apr;32(4):215-24
pubmed: 19285736
Pain. 1994 Apr;57(1):45-54
pubmed: 8065795
Eur J Pharmacol. 1991 Feb 7;193(2):193-201
pubmed: 1904822
PLoS One. 2013 Aug 05;8(8):e70690
pubmed: 23940628
Discov Med. 2011 Mar;11(58):197-207
pubmed: 21447279
J Pharmacol Exp Ther. 2006 Mar;316(3):1088-97
pubmed: 16278311
Pain Med. 2020 Apr 1;21(4):661-669
pubmed: 30908574
J Neurosci. 2011 Feb 23;31(8):2835-42
pubmed: 21414905
N Engl J Med. 2017 Jul 27;377(4):391-394
pubmed: 28564549
Neuron. 2002 Aug 15;35(4):721-31
pubmed: 12194871
J Neurosci. 2009 Jun 3;29(22):7220-9
pubmed: 19494144
Eur J Pharmacol. 2002 May 17;443(1-3):71-7
pubmed: 12044794