Endosomal signaling of delta opioid receptors is an endogenous mechanism and therapeutic target for relief from inflammatory pain.
Animals
Colon
/ innervation
Enkephalin, Leucine-2-Alanine
/ administration & dosage
HEK293 Cells
Humans
Inflammation
/ complications
Mice
Nanoparticles
/ administration & dosage
Neurons
Nociceptors
/ metabolism
Pain
/ drug therapy
Receptors, Opioid, delta
/ agonists
Signal Transduction
/ drug effects
G protein-coupled receptors
inflammation
nanomedicine
pain
signaling
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
30 06 2020
30 06 2020
Historique:
pubmed:
18
6
2020
medline:
2
9
2020
entrez:
18
6
2020
Statut:
ppublish
Résumé
Whether G protein-coupled receptors signal from endosomes to control important pathophysiological processes and are therapeutic targets is uncertain. We report that opioids from the inflamed colon activate δ-opioid receptors (DOPr) in endosomes of nociceptors. Biopsy samples of inflamed colonic mucosa from patients and mice with colitis released opioids that activated DOPr on nociceptors to cause a sustained decrease in excitability. DOPr agonists inhibited mechanically sensitive colonic nociceptors. DOPr endocytosis and endosomal signaling by protein kinase C (PKC) and extracellular signal-regulated kinase (ERK) pathways mediated the sustained inhibitory actions of endogenous opioids and DOPr agonists. DOPr agonists stimulated the recruitment of Gα
Identifiants
pubmed: 32546520
pii: 2000500117
doi: 10.1073/pnas.2000500117
pmc: PMC7334524
doi:
Substances chimiques
Receptors, Opioid, delta
0
Enkephalin, Leucine-2-Alanine
63631-40-3
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
15281-15292Subventions
Organisme : NIDCR NIH HHS
ID : R01 DE026806
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK118971
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS102722
Pays : United States
Organisme : NHLBI NIH HHS
ID : T32 HL120826
Pays : United States
Déclaration de conflit d'intérêts
Competing interest statement: N.W.B. is a founding scientist of Endosome Therapeutics Inc. Research in the laboratories of N.A.V., N.W.B., and D.P.P. is funded in part by Takeda Pharmaceuticals International.
Références
Annu Rev Neurosci. 2018 Jul 8;41:453-473
pubmed: 29852083
Proc Natl Acad Sci U S A. 2009 Oct 20;106(42):17615-22
pubmed: 19822761
Trends Pharmacol Sci. 2007 Jan;28(1):23-31
pubmed: 17150262
Adv Mater. 2015 Apr 8;27(14):2278-97
pubmed: 25728711
J Biol Chem. 2018 May 11;293(19):7466-7473
pubmed: 29523687
J Cell Sci. 2013 Nov 15;126(Pt 22):5305-12
pubmed: 24046449
J Neurosci. 2016 Mar 23;36(12):3541-51
pubmed: 27013682
ACS Nano. 2009 Jan 27;3(1):16-20
pubmed: 19206243
Am J Gastroenterol. 2013 Oct;108(10):1634-43
pubmed: 23958521
J Neurosci. 2010 Dec 8;30(49):16459-68
pubmed: 21147985
Nature. 2013 Mar 28;495(7442):534-8
pubmed: 23515162
Int J Nanomedicine. 2008;3(2):133-49
pubmed: 18686775
Br J Pharmacol. 1996 Aug;118(7):1829-35
pubmed: 8842450
ACS Nano. 2013 Oct 22;7(10):8870-80
pubmed: 24041122
J Control Release. 2000 Mar 1;65(1-2):271-84
pubmed: 10699287
Pharmacol Rev. 2017 Jul;69(3):256-297
pubmed: 28626043
Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):7686-9
pubmed: 7644477
Trends Pharmacol Sci. 2018 Feb;39(2):148-157
pubmed: 29054309
Acta Biomater. 2018 Aug;76:164-177
pubmed: 29890267
Adv Mater. 2018 May 28;:e1801198
pubmed: 29808576
Br J Pharmacol. 2018 Jul;175(13):2622-2634
pubmed: 29579315
PLoS One. 2017 Apr 20;12(4):e0175642
pubmed: 28426733
Curr Opin Cell Biol. 2014 Apr;27:109-16
pubmed: 24680436
J Neurosci. 1999 Jan 1;19(1):56-63
pubmed: 9870938
Nat Protoc. 2014 Jul;9(7):1592-606
pubmed: 24922269
PLoS Biol. 2009 Aug;7(8):e1000172
pubmed: 19688034
J Cell Biol. 1993 Aug;122(3):565-78
pubmed: 8335685
J Cell Biol. 2000 Mar 20;148(6):1267-81
pubmed: 10725339
Am J Physiol Gastrointest Liver Physiol. 2018 Oct 1;315(4):G544-G559
pubmed: 29927325
Gastroenterology. 2004 Jul;127(1):166-78
pubmed: 15236183
Methods Mol Biol. 2015;1335:131-61
pubmed: 26260599
Neuron. 2015 Nov 18;88(4):635-49
pubmed: 26590341
Curr Protoc Pharmacol. 2015 Sep 01;70:2.14.1-2.14.14
pubmed: 26331887
Nat Nanotechnol. 2019 Dec;14(12):1150-1159
pubmed: 31686009
Trends Pharmacol Sci. 2018 Oct;39(10):879-891
pubmed: 30180973
J Biol Chem. 1991 Aug 25;266(24):15771-81
pubmed: 1874734
Neurogastroenterol Motil. 2013 Jan;25(1):39-46.e4
pubmed: 22963585
Gastroenterology. 2011 Sep;141(3):982-991.e18
pubmed: 21699782
Gastroenterology. 2014 Jan;146(1):166-75
pubmed: 24055279
Neuron. 2018 Jun 6;98(5):963-976.e5
pubmed: 29754753
Proc Natl Acad Sci U S A. 2018 Jul 31;115(31):E7438-E7447
pubmed: 30012612
J Biol Chem. 2014 Jul 18;289(29):20283-94
pubmed: 24898255
Gastroenterology. 2006 May;130(6):1721-8
pubmed: 16697736
Proc Natl Acad Sci U S A. 2000 Sep 26;97(20):11086-91
pubmed: 10995467
PLoS One. 2009;4(5):e5425
pubmed: 19412545
Cell Signal. 2018 Jan;41:17-24
pubmed: 28711719
Sci Transl Med. 2017 May 31;9(392):
pubmed: 28566424
Nat Commun. 2016 Jul 11;7:12178
pubmed: 27397672
Nat Rev Drug Discov. 2017 Dec;16(12):829-842
pubmed: 29075003
Nat Protoc. 2014 Apr;9(4):851-70
pubmed: 24651498
Gut. 2017 Dec;66(12):2121-2131
pubmed: 27590998
Proc Natl Acad Sci U S A. 2006 Jun 20;103(25):9691-6
pubmed: 16766653
Proc Natl Acad Sci U S A. 2017 Nov 14;114(46):12309-12314
pubmed: 29087309
Gut. 2009 Oct;58(10):1333-41
pubmed: 19324867
Chem Rev. 1999 Nov 10;99(11):3181-98
pubmed: 11749514