title: A PTEN-Regulated Checkpoint Controls Surface Delivery of δ Opioid Receptors.
abstract: The δ opioid receptor (δR) is a promising alternate target for pain management because δR agonists show decreased abuse potential compared with current opioid analgesics that target the μ opioid receptor. A critical limitation in developing δR as an analgesic target, however, is that δR agonists show relatively low efficacyin vivo, requiring the use of high doses that often cause adverse effects, such as convulsions. Here we tested whether intracellular retention of δR in sensory neurons contributes to this low δR agonist efficacyin vivoby limiting surface δR expression. Using direct visualization of δR trafficking and localization, we define a phosphatase and tensin homolog (PTEN)-regulated checkpoint that retains δR in the Golgi and decreases surface delivery in rat and mice sensory neurons. PTEN inhibition releases δR from this checkpoint and stimulates delivery of exogenous and endogenous δR to the neuronal surface bothin vitroandin vivoPTEN inhibitionin vivoincreases the percentage of TG neurons expressing δR on the surface and allows efficient δR-mediated antihyperalgesia in mice. Together, we define a critical role for PTEN in regulating the surface delivery and bioavailability of the δR, explain the low efficacy of δR agonistsin vivo, and provide evidence that active δR relocation is a viable strategy to increase δR antinociception.SIGNIFICANCE STATEMENTOpioid analgesics, such as morphine, which target the μ opioid receptor (μR), have been the mainstay of pain management, but their use is highly limited by adverse effects and their variable efficacy in chronic pain. Identifying alternate analgesic targets is therefore of great significance. Although the δ opioid receptor (δR) is an attractive option, a critical limiting factor in developing δR as a target has been the low efficacy of δR agonists. Why δR agonists show low efficacy is still under debate. This study provides mechanistic and functional data that intracellular localization of δR in neurons is a key factor that contributes to low agonist efficacy, and presents a proof of mechanism that relocating δR improves efficacy.
authors.affiliation: Department of Biological Sciences, Center for the Neural Basis of Cognition, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213.
authors.forename: Daniel J
authors.identifier: 0000-0001-6978-303X
authors.initials: DJ
authors.lastname: Shiwarski
authors.affiliation: Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois 60612.
authors.forename: Alycia
authors.initials: A
authors.lastname: Tipton
authors.affiliation: Department of Anesthesiology and Pittsburgh Center for Pain Research, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, and.
authors.forename: Melissa D
authors.initials: MD
authors.lastname: Giraldo
authors.affiliation: Molecular Biosensors and Imaging Center, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213.
authors.forename: Brigitte F
authors.identifier: 0000-0002-2892-493X
authors.initials: BF
authors.lastname: Schmidt
authors.affiliation: Department of Anesthesiology and Pittsburgh Center for Pain Research, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, and.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Gold
authors.affiliation: Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois 60612.
authors.forename: Amynah A
authors.initials: AA
authors.lastname: Pradhan
authors.affiliation: Department of Biological Sciences, Center for the Neural Basis of Cognition, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213, map3@andrew.cmu.edu.
authors.forename: Manojkumar A
authors.identifier: 0000-0002-3177-4231
authors.initials: MA
authors.lastname: Puthenveedu
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D016716:PC12 Cells; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors / Q000502:physiology*; D010616:Phenanthrenes / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000378:metabolism*
chemical_list: D010616:Phenanthrenes; D017465:Receptors, Opioid, delta; C000619508:SF1670; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse
keywords: Golgi export; exocytosis; nociception; opioid; trafficking