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First published on July 8, 2008; DOI: 10.1124/mol.108.048512
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Received for publication May 5, 2008.
Revised July 7, 2008.
Accepted for publication July 7, 2008.

Differential Activation and Trafficking of Mu-opioid Receptors in Brain Slices

Seksiri Arttamangkul 1, Nidia Quillinan 1, Malcolm Low 1, Mark vonZastrow 2, John Pintar 3, John T. Williams 1*

1 Oregon Health Science University 2 UCSF 3 Robert Wood Johnson Medical School

* Address correspondence to: E-mail: williamj{at}ohsu.edu

Abstract

The activation of G-protein coupled receptors results in a cascade of events that include acute signaling, desensitization and internalization and it is thought that not all agonists affect each process to the same extent. The early steps in opioid receptor signaling, including desensitization, have been characterized electrophysiologically using brain slice preparations, while most previous studies of opioid receptor trafficking have been conducted in heterologous cell models. This study used transgenic mice that express an epitope-tagged (Flag) mu opioid receptor (FlagMOR) targeted to catecholamine neurons by regulatory elements from the tyrosine hydroxylase gene. Brain slices from there mice were used to study of tagged MOR receptors in neurons of the locus coeruleus (LC). Activation of the FlagMOR with [Met5]enkephalin (ME) produced a hyperpolarization that desensitized acutely to the same extent as native MOR in slices from wild type mice. A series of opioid agonists was then used to study desensitization and receptor trafficking in brain slices, which was monitored with a monoclonal antibody against the Flag epitope (M1) conjugated to Alexa594. Three patterns of receptor trafficking and desensitization were observed: 1. ME, etorphine and methadone resulted in both receptor desensitization and internalization; 2. Morphine and oxymorphone caused significant desensitization without evidence for internalization; 3. Oxycodone was ineffective in both processes. These results show that two distinct forms of signaling were differentially engaged depending on the agonist used to activate the receptor and support the hypothesis that ligand-specific regulation of opioid receptors occurs in neurons maintained in brain slices from adult animals.


Key words: Neuropeptides, Opioid, Desensitization/uncoupling, Sequestration/Internalization, GRKs, barrestins, Recycling, Fluorescence techniques, Opioids




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