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

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

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.

Citation

Jimenez-Vargas, N. N., Gong, J., Wisdom, M. J., Jensen, D. D., Latorre, R., Hegron, A., Teng, S., DiCello, J. J., Rajasekhar, P., Veldhuis, N. A., Carbone, S. E., Yu, Y., Lopez-Lopez, C., Jaramillo-Polanco, J., Canals, M., Reed, D. E., Lomax, A. E., Schmidt, B. L., Leong, K. W., Vanner, S. J., …Poole, D. P. (2020). 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, 117(26), 15281-15292. https://doi.org/10.1073/pnas.2000500117

• Journal Article Type: Article
• Acceptance Date: May 18, 2020
• Online Publication Date: Jun 16, 2020
• Publication Date: Jun 30, 2020
• Deposit Date: Jun 19, 2020
• Publicly Available Date: Dec 17, 2020
• Journal: Proceedings of the National Academy of Sciences
• Print ISSN: 0027-8424
• Electronic ISSN: 1091-6490
• Publisher: National Academy of Sciences
• Peer Reviewed: Peer Reviewed
• Volume: 117
• Issue: 26
• Pages: 15281-15292
• DOI: https://doi.org/10.1073/pnas.2000500117
• Keywords: Multidisciplinary
• Public URL: https://nottingham-repository.worktribe.com/output/4678262
• Publisher URL: https://www.pnas.org/doi/full/10.1073/pnas.2000500117