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NEUROPHARMACOLOGY

µ-Opioid-Induced Desensitization of Opioid Receptor-Like 1 and µ-Opioid Receptors: Differential Intracellular Signaling Determines Receptor Sensitivity

Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas (K.M.S.)

µ-Opioid receptors have been shown to contribute to orphanin FQ/nociceptin (OFQ/N)-mediated analgesia and hyperalgesia, indicating that both pro- and antinociceptive actions of OFQ/N are influenced by µ-opioid receptors. A 60-min activation of µ-or opioid receptor-like 1 (ORL1) opioid receptors natively expressed in BE(2)-C human neuroblastoma cells desensitized both µ- and ORL1 receptor-mediated inhibition of cAMP accumulation. The mechanism(s) of OFQ/N-mediated µ- and ORL1 cross talk involves the conventional protein kinase C isozyme, PKC-, and G protein-coupled receptor kinases (GRKs) 2 and 3. Unlike OFQ/N-mediated desensitization of ORL1 and µ-opioid receptors, [D-Ala²,N-Me-Phe⁴,Gly⁵-ol]-enkephalin (DAMGO)-mediated ORL1 desensitization in BE(2)-C cells is PKC-independent. However, DAMGO (1 µM) pretreatment increased membrane levels of GRK2 and GRK3, indicating their translocation to the membrane upon activation. This suggests that DAMGO activation of µ-opioid receptors results in GRK2 and GRK3 inactivation of ORL1 upon challenge with OFQ/N. Antisense, but not sense, DNA selectively targeting GRK2 or GRK3 blocks DAMGO-mediated µ- and ORL1 desensitization, respectively. However, in SH-SY5Y neuroblastoma cells, DAMGO failed to desensitize ORL1 or alter membrane PKC- or GRK levels. Instead, DAMGO stimulated PKC- translocation to the cell membrane and produced µ-receptor desensitization. These results indicate that acute exposure to µ-receptor agonists can regulate ORL1 function, but the ability to do so varies from cell type to cell type. These results also confirm the existence of multiple signaling mechanisms for µ-opioid receptors and the importance of these mechanisms for µ-receptor-mediated-heterologous effects.

Address correspondence to: Dr. Kelly M. Standifer, Department of Pharmacological and Pharmaceutical Sciences, 521 Science and Research 2, University of Houston, Houston, TX 77204-5037. E-mail standifer{at}uh.edu

This article has been cited by other articles:

				H. Z. Ozsoy, D. R. Thakker, and K. M. Standifer Orphanin FQ/Nociceptin Potentiates [D-Ala2,N-Me-Phe4,Gly5-ol]-Enkephalin-Induced {micro}-Opioid Receptor Phosphorylation Mol. Pharmacol., August 1, 2005; 68(2): 447 - 456. [Abstract] [Full Text] [PDF]