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J. Biol. Chem., Vol. 278, Issue 21, 18776-18784, May 23, 2003

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Opioid Agonists Have Different Efficacy Profiles for G Protein Activation, Rapid Desensitization, and Endocytosis of Mu-opioid Receptors^*

Stephanie L. Borgland , Mark Connor  , Peregrine B. Osborne ¶ ||, John B. Furness ** and MacDonald J. Christie   ¶¶

From the Department of Pharmacology, The University of Sydney, New South Wales 2006, Medical Foundation, The University of Sydney, New South Wales 2006, Pain Management Research Institute, The University of Sydney, New South Wales 2006, ^¶ Prince of Wales Medical Research Institute, University of New South Wales, Randwick, New South Wales 2031, ^** Department of Anatomy and Cell Biology, University of Melbourne, Parkville, Victoria 3010, Australia

The differential ability of various µ-opioid receptor (MOP) agonists to induce rapid receptor desensitization and endocytosis of MOP could arise simply from differences in their efficacy to activate G proteins or, alternatively, be due to differential capacity for activation of other signaling processes. We used AtT20 cells stably expressing a low density of FLAG-tagged MOP to compare the efficacies of a range of agonists to 1) activate G proteins using inhibition of calcium channel currents (I_Ca) as a reporter before and after inactivation of a fraction of receptors by -chlornaltrexamine, 2) produce rapid, homologous desensitization of I_Ca inhibition, and 3) internalize receptors. Relative efficacies determined for G protein coupling were [Tyr-D-Ala-Gly-MePhe-Glyol]enkephalin (DAMGO) (1) > methadone (0.98) > morphine (0.58) > pentazocine (0.15). The same rank order of efficacies for rapid desensitization of MOP was observed, but greater concentrations of agonist were required than for G protein activation. By contrast, relative efficacies for promoting endocytosis of MOP were DAMGO (1) > methadone (0.59) >> morphine (0.07) > pentazocine (0.03). These results indicate that the efficacy of opioids to produce activation of G proteins and rapid desensitization is distinct from their capacity to internalize µ-opioid receptors but that, contrary to some previous reports, morphine can produce rapid, homologous desensitization of MOP.

Received for publication, January 16, 2003 , and in revised form, March 5, 2003.

Supported by National Health & Medical Research Council of Australia Project Grant 153911. To whom correspondence should be addressed: Dept. of Pharmacology, D06, University of Sydney, Sydney, NSW 2006, Australia. Tel.: 612-9351-2408; Fax: 612-9351-3868; E-mail: markc{at}pharmacol.usyd.edu.au.

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