Down-regulation of ľ-Opioid Receptor by Full but Not Partial Agonists Is Independent of G Protein Coupling

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Molecular Pharmacology, Volume 52, Issue 5, 896-902

Down-regulation of µ-Opioid Receptor by Full but Not Partial Agonists Is Independent of G Protein Coupling

Nirmala Yabaluri and Fedor Medzihradsky

Departments of Biological Chemistry and Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan 48109

In C₆ glial cells stably expressing rat µ-opioid receptor, opioid agonist activation is negatively coupled to adenylyl cyclasethrough pertussis toxin-sensitive G proteins. In membranes, [D-Ala²,N-MePhe⁴,Gly-ol⁵]enkephalin (DAMGO) increases guanosine-5 $'$ -O-(3-[³⁵S]thio)triphosphate (GTP[ $gamma$ -³⁵S]) binding by 367% with an EC₅₀ value of 28 nM. Prolonged exposureto agonists induced desensitization of the receptor as estimatedby a reduction in the maximal stimulation of GTP[ $gamma$ -³⁵S] binding by DAMGO and rightward shifts in the dose-responsecurves. In cells treated with 10 µM concentrations of etorphine,DAMGO, $beta$ -endorphin, morphine, and butorphanol, DAMGO-stimulatedGTP[ $gamma$ -³⁵S] binding was 58%, 149%, 205%, 286%, and 325%, respectively.Guanine nucleotide regulation of agonist binding was correspondinglylower in membranes from tolerant cells. Furthermore, chronic opioidtreatment increased forskolin-stimulated adenylyl cyclase activity,and potency of DAMGO to inhibit cAMP accumulation was lower inmorphine- and DAMGO-tolerant cells (EC₅₀ = 55 and 170 nM versus18 nM for control). Chronic treatment with agonists reduced [³H]DAMGO binding in membranes with the rank order of etorphine> DAMGO = $beta$ -endorphin > morphine > butorphanol, and the affinityof DAMGO in alkaloid- but not peptide-treated membranes was significantlylower in comparison with control. Pertussis toxin treatment ofthe cells before agonist treatment did not prevent the down-regulationby full agonists; DAMGO and etorphine exhibited ~80% internalization,whereas the ability of partial agonists was greatly impaired.In addition to establishing this cell line as a good model forfurther studies on the mechanisms of opioid tolerance, these resultsindicate important differences in the inactivation pathways ofreceptor triggered by full and partial agonists.

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