Chronic morphine-mediated adenylyl cyclase superactivation is attenuated by the Raf-1 inhibitor, GW5074

descriptionPublicationkeyboard_double_arrow_right Article 01 Jul 2006 English Publisher:Elsevier BVJournal:European Journal of Pharmacology, volume 540, pages 57-59 (issn: 0014-2999,

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Authors: Xu, Yue; Eva V, Varga; Dagmar, Stropova; Todd W, Vanderah; Henry I, Yamamura; William R, Roeske;

doi: 10.1016/j.ejphar.2006.04.033

pmid: 16750187

Chronic morphine-mediated adenylyl cyclase superactivation is attenuated by the Raf-1 inhibitor, GW5074

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Abstract

The utility of morphine for the treatment of chronic pain is limited by the development of analgesic tolerance. Adenylyl cyclase (AC) superactivation, induced by chronic opioid agonist administration, is regarded as one of the molecular mechanisms leading to tolerance. In the present work, we tested the role of Raf-1 in morphine-mediated AC superactivation in CHO cells stably expressing the human micro-opioid receptor. We found that pretreatment of CHO cells stably expressing the human micro-opioid receptor with the selective Raf-1 inhibitor, 3-(3,5-dibromo-4-hydroxybenzylidene)-5-iodo-1,3-dihydroindol-2-one (GW5074, 10 microM, 60 min) completely abolished chronic morphine-mediated AC superactivation (P < 0.01). This finding indicates that Raf-1 may have a crucial role in compensatory feedback regulation of cellular cAMP levels by clinically important opioid analgesics.

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University of Arizona
United States

Keywords

Indoles, Morphine, Naloxone, Narcotic Antagonists, Colforsin, Receptors, Opioid, mu, CHO Cells, Transfection, Analgesics, Opioid, Enzyme Activation, Proto-Oncogene Proteins c-raf, Cricetulus, Phenols, Cricetinae, Cyclic AMP, Animals, Humans, Adenylyl Cyclases

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