Endosomal signaling of delta opioid receptors is an endogenous mechanism and therapeutic target for relief from inflammatory pain

Nestor N. Jimenez-Vargas, Jing Gong, Matthew J. Wisdom, Dane D. Jensen, Rocco Latorre, Alan Hegron, Shavonne Teng, Jesse J. DiCello, Pradeep Rajasekhar, Nicholas A. Veldhuis, Simona E. Carbone, Yang Yu, Cintya Lopez-Lopez, Josue Jaramillo-Polanco, Meritxell Canals, David E. Reed, Alan E. Lomax, Brian L. Schmidt, Kam W. Leong, Stephen J. VannerMichelle L. Halls, Nigel W. Bunnett, Daniel P. Poole

Research output: Contribution to journalArticlepeer-review

Abstract

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 -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 Gi/o and -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.

Original languageEnglish (US)
Pages (from-to)15281-15292
Number of pages12
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number26
DOIs
StatePublished - Jun 30 2020

Keywords

  • G protein-coupled receptors
  • Inflammation
  • Nanomedicine
  • Signaling
  • pain

ASJC Scopus subject areas

  • General

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