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

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.
Authors	Xu Yue, Eva V Varga, Dagmar Stropova, Todd W Vanderah, Henry I Yamamura, William R Roeske
Journal	European journal of pharmacology (Eur J Pharmacol) Vol. 540 Issue 1-3 Pg. 57-9 (Jul 01 2006) ISSN: 0014-2999 [Print] Netherlands
PMID	16750187 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References	Analgesics, Opioid Indoles Narcotic Antagonists Phenols Receptors, Opioid, mu Colforsin Naloxone Morphine Cyclic AMP Proto-Oncogene Proteins c-raf Adenylyl Cyclases 5-iodo-3-((3,5-dibromo-4-hydroxyphenyl)methylene)-2-indolinone
Topics	Adenylyl Cyclases (metabolism) Analgesics, Opioid (pharmacology) Animals CHO Cells Colforsin (pharmacology) Cricetinae Cricetulus Cyclic AMP (metabolism) Enzyme Activation (drug effects) Humans Indoles (pharmacology) Morphine (pharmacology) Naloxone (pharmacology) Narcotic Antagonists (pharmacology) Phenols (pharmacology) Proto-Oncogene Proteins c-raf (antagonists & inhibitors, metabolism) Receptors, Opioid, mu (agonists, antagonists & inhibitors, genetics) Transfection

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