Endosomal Signaling of Delta Opioid Receptors Is an Endogenous Mechanism and Therapeutic Target for Relief From Inflammatory Pain

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

Research output: Contribution to journalArticleResearchpeer-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 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 Gαi/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.
Original languageEnglish
Number of pages12
JournalProceedings of the National Academy of Sciences of the United States of America
DOIs
Publication statusAccepted/In press - Jun 2020

Cite this

Jiménez-Vargas, N. N., Gong, J., Wisdom, M. J., Jensen, D. D., Latorre, R., Hegron, A., Teng, S. L., Di Cello, J., Rajasekhar, P., Veldhuis, N. A., Carbone, S., Yu, Y., Lopez, C. L., Polanco, J. J., Canals, M., Reed, D., Lomax, A. E., Schmidt, B. L., Leong, K. W., ... Poole, D. P. (Accepted/In press). Endosomal Signaling of Delta Opioid Receptors Is an Endogenous Mechanism and Therapeutic Target for Relief From Inflammatory Pain. Proceedings of the National Academy of Sciences of the United States of America. https://doi.org/10.1073/pnas.2000500117