Endosomal signaling of delta opioid receptors is an endogenous mechanism and therapeutic target for relief from inflammatory pain
Nestor N. Jiménez-Vargas, Jing Gong, Matthew Wisdom, Dane D. Jensen, Rocco Latorre, Alan Hégron, Shavonne Teng, Jesse J. DiCello, Pradeep Rajasekhar, Nicholas A. Veldhuis, Simona Carbone, Yang Yu, Cintya López-López, Josue Jaramillo-Polanco, Meritxell Canals, David E. Reed, Alan Lomax, Brian L. Schmidt, Kam W. Leong, Stephen Vanner, Michelle L. Halls, Nigel W. Bunnett, Daniel P. Poole
Abstract
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.