Activation of mu opioid receptors sensitizes transient receptor potential vanilloid type 1 (TRPV1) via β-arrestin-2-mediated cross-talk

• Published in: PloS one Vol. 9; no. 4; p. e93688
• Main Authors: Rowan, Matthew P, Bierbower, Sonya M, Eskander, Michael A, Szteyn, Kalina, Por, Elaine D, Gomez, Ruben, Veldhuis, Nicholas, Bunnett, Nigel W, Jeske, Nathaniel A
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01-04-2014; Public Library of Science (PLoS)
• Subjects: Activation; Analysis; Animals; Arrestin; Arrestins - metabolism; beta-Arrestin 2; beta-Arrestins; Biology and Life Sciences; Capsaicin; Capsaicin receptors; Cells, Cultured; Dissociation; Drug therapy; Enkephalin, Ala-MePhe-Gly- - pharmacology; Enkephalins; Fluorescence Resonance Energy Transfer; Furans - pharmacology; G protein-coupled receptors; Health aspects; Hyperalgesia; Kinases; Ligands; Male; Maxillofacial surgery; Medicine and Health Sciences; Mice; Mice, Inbred C57BL; Morphine; Morphine - pharmacology; Narcotics; Neurons; Neurosciences; Opioid receptors (type mu); Pain; Pharmacology; Phosphorylation; Physiology; Post-translation; Proteins; Pyrones - pharmacology; Receptor mechanisms; Receptors; Receptors, Opioid, mu - agonists; Research and Analysis Methods; Rodents; Scaffolding; Science; Sensitivity; Sensitivity analysis; Sensory neurons; Substance abuse treatment; Surgery; Transient receptor potential proteins; TRPV Cation Channels - metabolism; Texas; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0093688

The transient receptor potential family V1 channel (TRPV1) is activated by multiple stimuli, including capsaicin, acid, endovanilloids, and heat (>42C). Post-translational modifications to TRPV1 result in dynamic changes to the sensitivity of receptor activation. We have previously demonstrated that β-arrestin2 actively participates in a scaffolding mechanism to inhibit TRPV1 phosphorylation, thereby reducing TRPV1 sensitivity. In this study, we evaluated the effect of β-arrestin2 sequestration by G-protein coupled receptors (GPCRs) on thermal and chemical activation of TRPV1. Here we report that activation of mu opioid receptor by either morphine or DAMGO results in β-arrestin2 recruitment to mu opioid receptor in sensory neurons, while activation by herkinorin does not. Furthermore, treatment of sensory neurons with morphine or DAMGO stimulates β-arrestin2 dissociation from TRPV1 and increased sensitivity of the receptor. Conversely, herkinorin treatment has no effect on TRPV1 sensitivity. Additional behavioral studies indicate that GPCR-driven β-arrestin2 sequestration plays an important peripheral role in the development of thermal sensitivity. Taken together, the reported data identify a novel cross-talk mechanism between GPCRs and TRPV1 that may contribute to multiple clinical conditions.