CR4056, a powerful analgesic imidazoline-2 receptor ligand, inhibits the inflammation-induced PKCε phosphorylation and membrane translocation in sensory neurons.
Amino Acid Sequence
Analgesics
/ metabolism
Animals
Cell Membrane
/ drug effects
Cells, Cultured
Dose-Response Relationship, Drug
Freund's Adjuvant
/ toxicity
Humans
Imidazoles
/ metabolism
Imidazoline Receptors
/ metabolism
Inflammation
/ chemically induced
Male
Pain
/ chemically induced
Phosphorylation
/ drug effects
Protein Kinase C-epsilon
/ antagonists & inhibitors
Quinazolines
/ metabolism
Rats
Rats, Wistar
Sensory Receptor Cells
/ drug effects
Journal
British journal of pharmacology
ISSN: 1476-5381
Titre abrégé: Br J Pharmacol
Pays: England
ID NLM: 7502536
Informations de publication
Date de publication:
01 2020
01 2020
Historique:
received:
25
07
2018
revised:
10
08
2019
accepted:
12
08
2019
pubmed:
28
8
2019
medline:
10
4
2021
entrez:
28
8
2019
Statut:
ppublish
Résumé
CR4056 is a first-in-class imidazoline-2 (I Effects of CR4056 on bradykinin-induced PKCε translocation were studied in rat sensory neurons by immunocytochemistry. PKCε activation was investigated by immunohistochemistry analysis of DRG from complete Freund's adjuvant-treated animals developing local hyperalgesia. The analgesic activity of CR4056 was tested on the same animals. CR4056 inhibited PKCε translocation with very rapid and long-lasting activity. CR4056 decreased hyperalgesia and phospho-PKCε immunoreactivity in the DRG neurons innervating the inflamed paw. The effect of CR4056 on PKCε translocation was blocked by pertussis toxin, implying that the intracellular pathways involved G Our results demonstrate that CR4056 shares the ability to inhibit PKCε translocation with other analgesics. Whether the inhibition of PKCε involves binding to specific subtype(s) of I
Sections du résumé
BACKGROUND AND PURPOSE
CR4056 is a first-in-class imidazoline-2 (I
EXPERIMENTAL APPROACH
Effects of CR4056 on bradykinin-induced PKCε translocation were studied in rat sensory neurons by immunocytochemistry. PKCε activation was investigated by immunohistochemistry analysis of DRG from complete Freund's adjuvant-treated animals developing local hyperalgesia. The analgesic activity of CR4056 was tested on the same animals.
KEY RESULTS
CR4056 inhibited PKCε translocation with very rapid and long-lasting activity. CR4056 decreased hyperalgesia and phospho-PKCε immunoreactivity in the DRG neurons innervating the inflamed paw. The effect of CR4056 on PKCε translocation was blocked by pertussis toxin, implying that the intracellular pathways involved G
CONCLUSIONS AND IMPLICATIONS
Our results demonstrate that CR4056 shares the ability to inhibit PKCε translocation with other analgesics. Whether the inhibition of PKCε involves binding to specific subtype(s) of I
Identifiants
pubmed: 31454418
doi: 10.1111/bph.14845
pmc: PMC6976787
doi:
Substances chimiques
Analgesics
0
CR4056
0
Imidazoles
0
Imidazoline Receptors
0
Quinazolines
0
imidazoline receptor 2
0
Freund's Adjuvant
9007-81-2
Protein Kinase C-epsilon
EC 2.7.11.13
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
48-64Subventions
Organisme : Fondazione Cassa di Risparmio di Carpi
Pays : International
Organisme : Fondazione Cassa di Risparmio di Modena
Pays : International
Organisme : Consorzio Futuro in Ricerca
Pays : International
Organisme : Ministero dell'Università e della Ricerca Scientifica e Tecnologica
Pays : International
Organisme : Rottapharm Biotech
Pays : International
Informations de copyright
© 2019 The British Pharmacological Society.
Références
Osteoarthritis Cartilage. 2020 Jan;28(1):22-30
pubmed: 31526875
Brain Res. 2011 Mar 24;1381:31-7
pubmed: 21241671
Neuron. 1999 Jul;23(3):617-24
pubmed: 10433272
J Pain Res. 2017 May 04;10:1033-1043
pubmed: 28496359
Br J Pharmacol. 2014 Aug;171(15):3693-701
pubmed: 24758515
Br J Pharmacol. 2010 Aug;160(7):1577-9
pubmed: 20649561
J Physiol. 2001 Aug 1;534(Pt 3):813-25
pubmed: 11483711
J Neurosci. 2000 Nov 15;20(22):8614-9
pubmed: 11069970
J Pain. 2008 May;9(5):457-62
pubmed: 18342576
Trends Neurosci. 2009 Dec;32(12):611-8
pubmed: 19781793
Proc Natl Acad Sci U S A. 2000 Sep 12;97(19):10584-9
pubmed: 10984543
Neuron. 1999 Sep;24(1):253-60
pubmed: 10677042
Br J Pharmacol. 1997 Jul;121(5):901-12
pubmed: 9222546
Br J Pharmacol. 1998 Sep;125(1):175-85
pubmed: 9776358
Eur J Pharmacol. 2011 May 11;658(2-3):49-56
pubmed: 21371460
PLoS One. 2015 Oct 29;10(10):e0141142
pubmed: 26512901
Pharmacol Ther. 2017 Oct;178:48-56
pubmed: 28322973
Eur J Pharmacol. 2015 Feb 15;749:133-41
pubmed: 25617792
J Pain Res. 2012;5:151-67
pubmed: 22792002
BMC Anesthesiol. 2007 Jul 07;7:6
pubmed: 17617920
Br J Pharmacol. 2018 Apr;175(7):987-993
pubmed: 29520785
Mol Pain. 2010 Sep 27;6:61
pubmed: 20875131
J Pain. 2006 Dec;7(12):884-91
pubmed: 17157774
Nucleic Acids Res. 2018 Jan 4;46(D1):D1091-D1106
pubmed: 29149325
Br J Pharmacol. 2017 Sep;174(17):2801-2804
pubmed: 28801996
Br J Pharmacol. 2018 May;175(9):1519-1534
pubmed: 29451703
J Neurosci. 2000 Jun 15;20(12):4680-5
pubmed: 10844037
Indian J Pharmacol. 2015 Sep-Oct;47(5):472-8
pubmed: 26600633
Cochrane Database Syst Rev. 2011 Mar 16;(3):CD007938
pubmed: 21412914
Br J Pharmacol. 2020 Jan;177(1):48-64
pubmed: 31454418
Proc Natl Acad Sci U S A. 1999 Jul 6;96(14):7658-63
pubmed: 10393876
J Biol Chem. 2002 Apr 19;277(16):13375-8
pubmed: 11884385
Br J Pharmacol. 1992 May;106(1):101-8
pubmed: 1324063
Br J Pharmacol. 2000 May;130(1):146-52
pubmed: 10781010
Neuroscience. 2001;108(3):507-15
pubmed: 11738263
Br J Pharmacol. 2017 Dec;174 Suppl 1:S272-S359
pubmed: 29055034
Pharmacol Res. 2010 Dec;62(6):475-88
pubmed: 20832472
Ann N Y Acad Sci. 2003 Dec;1009:1-20
pubmed: 15028565
J Neurochem. 2003 May;85(3):571-80
pubmed: 12694383
Mol Pharmacol. 2008 Feb;73(2):525-38
pubmed: 17989349
J Biol Chem. 1995 Apr 28;270(17):9856-61
pubmed: 7730367
J Pharmacol Exp Ther. 1995 Feb;272(2):681-8
pubmed: 7853182
DNA Cell Biol. 2000 Jun;19(6):319-29
pubmed: 10882231
J Pain Res. 2011;4:177-87
pubmed: 21811393
EMBO Rep. 2012 Apr 02;13(4):291-6
pubmed: 22421999
Br J Pharmacol. 2010 Aug;160(7):1573-6
pubmed: 20649560
J Pain. 2005 Aug;6(8):535-49
pubmed: 16084468
Br J Pharmacol. 2018 Feb;175(3):407-411
pubmed: 29350411
Ann N Y Acad Sci. 1999 Jun 21;881:392-409
pubmed: 10415944
J Neurosci. 2006 May 10;26(19):5109-16
pubmed: 16687502
Eur J Pharmacol. 2006 Dec 28;553(1-3):73-81
pubmed: 17081513
J Physiol. 2004 Oct 15;560(Pt 2):391-401
pubmed: 15319421
Protein Sci. 1997 Feb;6(2):477-80
pubmed: 9041654
J Pain Res. 2013;6:111-20
pubmed: 23429763
Br J Pharmacol. 2017 Dec;174 Suppl 1:S17-S129
pubmed: 29055040
Naunyn Schmiedebergs Arch Pharmacol. 2013 Jul;386(7):575-87
pubmed: 23584602
J Pain Res. 2011;4:111-25
pubmed: 21647215
Ann N Y Acad Sci. 2003 Dec;1009:106-15
pubmed: 15028574
Physiol Rev. 2008 Oct;88(4):1341-78
pubmed: 18923184
Sci Rep. 2014 Oct 13;4:6605
pubmed: 25308382
Behav Pharmacol. 2014 Apr;25(2):130-6
pubmed: 24518265
Brain Res. 2009 Jul 7;1279:21-8
pubmed: 19410564
Am J Hypertens. 2000 Jun;13(6 Pt 2):84S-88S
pubmed: 10921526
Biochemistry. 1993 Feb 2;32(4):1032-9
pubmed: 8424932
EMBO J. 2000 Feb 15;19(4):496-503
pubmed: 10675318
Br J Pharmacol. 2015 Jul;172(13):3189-93
pubmed: 25964986
Pain. 1983 Jun;16(2):109-10
pubmed: 6877845
Cochrane Database Syst Rev. 2013 Nov 11;(11):CD010567
pubmed: 24217986
ScientificWorldJournal. 2017;2017:3595903
pubmed: 28299349