Endosomal signaling of delta opioid receptors is an endogenous mechanism and therapeutic target for relief from inflammatory pain
| Autor: | Shavonne Teng, Stephen Vanner, Alan Hegron, Jesse J. DiCello, Yang Yu, Josue Jaramillo-Polanco, Michelle L. Halls, Daniel P. Poole, Dane D. Jensen, Nicholas A. Veldhuis, Kam W. Leong, Nestor N. Jiménez-Vargas, Meritxell Canals, Brian L. Schmidt, Cintya Lopez-Lopez, Jing Gong, Alan E. Lomax, Simona E. Carbone, Matthew J. Wisdom, David E. Reed, Pradeep Rajasekhar, Nigel W. Bunnett, Rocco Latorre |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Agonist MAPK/ERK pathway medicine.drug_class Endosome Colon Pain Endocytosis 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Receptors Opioid delta medicine Animals Humans Protein kinase C Endogenous opioid G protein-coupled receptor Inflammation Neurons Multidisciplinary Chemistry Nociceptors Biological Sciences Enkephalin Leucine-2-Alanine Cell biology 030104 developmental biology HEK293 Cells Nanoparticles DADLE 030217 neurology & neurosurgery Signal Transduction |
| Zdroj: | Proc Natl Acad Sci U S A |
| ISSN: | 1091-6490 |
| Popis: | 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(i/o) and β-arrestin1/2 to endosomes. Analysis of compartmentalized signaling revealed a requirement of DOPr endocytosis for activation of PKC at the plasma membrane and in the cytosol and ERK in the nucleus. We explored a nanoparticle delivery strategy to evaluate whether endosomal DOPr might be a therapeutic target for pain. The DOPr agonist DADLE was coupled to a liposome shell for targeting DOPr-positive nociceptors and incorporated into a mesoporous silica core for release in the acidic and reducing endosomal environment. Nanoparticles activated DOPr at the plasma membrane, were preferentially endocytosed by DOPr-expressing cells, and were delivered to DOPr-positive early endosomes. Nanoparticles caused a long-lasting activation of DOPr in endosomes, which provided sustained inhibition of nociceptor excitability and relief from inflammatory pain. Conversely, nanoparticles containing a DOPr antagonist abolished the sustained inhibitory effects of DADLE. Thus, DOPr in endosomes is an endogenous mechanism and a therapeutic target for relief from chronic inflammatory pain. |
| Databáze: | OpenAIRE |
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