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NEUROPHARMACOLOGY

Converging Protein Kinase Pathways Mediate Adenylyl Cyclase Superactivation upon Chronic -Opioid Agonist Treatment

Departments of Pharmacology (E.V.V., M.K.R., D.S., M.S., V.G. W.R.R., H.I.Y.), Biochemistry and Psychiatry (H.I.Y.), Medicine (W.R.R.), and Chemistry (V.J.H.), and the Sarver Heart Center (E.V.V., W.R.R., H.I.Y.), The University of Arizona Health Sciences Center, Tucson, Arizona; and National Institute of Diabetes and Digestive and Kidney Diseases, Laboratory of Medicinal Chemistry (K.C.R.), National Institutes of Health, Bethesda, Maryland

Adenylyl cyclase (AC) superactivation is thought to play an important role in opioid tolerance, dependence, and withdrawal. In the present study, we investigated the involvement of protein kinases in chronic -opioid agonist-mediated AC superactivation in Chinese hamster ovary (CHO) cells stably expressing the human -opioid receptor (hDOR/CHO). Maximal forskolin-stimulated cAMP formation in hDOR/CHO cells increased by 472 ± 91, 399 ± 2, and 433 ± 73% after chronic treatment with the -opioid agonists (+)-4-[(R)--((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxy-benzyl]-N,N-diethyl benzamide (SNC 80), [D-Pen²,D-Pen⁵]-enkephalin, and deltorphin II, respectively. Concurrently, chronic SNC 80 (1 µM, 4-h) treatment augmented ³²P incorporation into a 200-kDa protein immunoreactive with the ACV/VI antibody by 300 ± 60% in hDOR/CHO cell lysates. The calmodulin antagonist calmidazolium significantly attenuated chronic deltorphin II-mediated AC superactivation. Tyrosine kinase (genistein) and protein kinase C (chelerythrine) inhibitors individually had minimal effect on chronic -opioid agonist-mediated AC superactivation. Conversely, simultaneous treatment with both genistein and chelerythrine significantly attenuated AC superactivation. Because we showed previously that the Raf-1 inhibitor 3-(3,5-dibromo-4-hydroxybenzylidene-5-iodo-1,3-dihydro-indol-2-one (GW5074) attenuates AC superactivation, we hypothesize that parallel calmidazolium-, chelerythrine-, and genistein-sensitive pathways converge at Raf-1 to mediate AC superactivation by phosphorylating AC VI in hDOR/CHO cells.

Address correspondence to: Dr. Henry I. Yamamura, Department of Pharmacology, College of Medicine, University of Arizona Health Sciences Center, Tucson, AZ 85724. E-mail: hiy{at}u.arizona.edu

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