Journal article

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 Vanner Show all

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | NATL ACAD SCIENCES | Published : 2020

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 DO..

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Funding Acknowledgements

We thank Lih En Tiah for technical support and Dr. Malvin Janal for statistical support. The tdRGFP-Rab5a plasmid was designed and validated by Christian LeGouill and Lucas Tabajara Parreiras e Silva from the laboratory of Dr. Michel Bouvier. RGFP-CAAX and beta-arrestin2-Rluc2 were provided by the Bouvier laboratory. This work was supported by grants from the NIH (NS102722, DE026806, and DK118971 to B.L.S. and N.W.B.), Department of Defense (W81XWH1810431, to B.L.S. and N.W.B.), Crohn's Colitis Canada (D.E. R., A.E. L., and S.J.V.), National Health and Medical Research Council (63303, 1049682, 1031886, 1049730, 1121029, and 1083480 to M.C., M. L.H., N.W.B., and D.P.P.), and Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology (N.W.B.).