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Morphine-related metabolites differentially activate adenylyl cyclase isozymes after acute and chronic administration.

Abstract
Morphine-3- and morphine-6-glucuronide are morphine's major metabolites. As morphine-6-glucuronide produces stronger analgesia than morphine, we investigated the effects of acute and chronic morphine glucuronides on adenylyl cyclase (AC) activity. Using COS-7 cells cotransfected with representatives of the nine cloned AC isozymes, we show that AC-I and V are inhibited by acute morphine and morphine-6-glucuronide, and undergo superactivation upon chronic exposure, while AC-II is stimulated by acute and inhibited by chronic treatment. Morphine-3-glucuronide had no effect. The weak opiate agonists codeine and dihydrocodeine are also addictive. These opiates, in contrast to their 3-O-demethylated metabolites morphine and dihydromorphine (formed by cytochrome P450 2D6), demonstrated neither acute inhibition nor chronic-induced superactivation. These results suggest that metabolites of morphine (morphine-6-glucuronide) and codeine/dihydrocodeine (morphine/dihydromorphine) may contribute to the development of opiate addiction.
AuthorsK Eckhardt, I Nevo, R Levy, G Mikus, M Eichelbaum, Z Vogel
JournalFEBS letters (FEBS Lett) Vol. 470 Issue 3 Pg. 309-14 (Mar 31 2000) ISSN: 0014-5793 [Print] England
PMID10745087 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Adenylyl Cyclase Inhibitors
  • Isoenzymes
  • Morphine Derivatives
  • Receptors, Opioid, mu
  • morphine-6-glucuronide
  • Morphine
  • Thyrotropin
  • Dihydromorphine
  • Adenylyl Cyclases
  • morphine-3-glucuronide
  • Codeine
Topics
  • Adenylyl Cyclase Inhibitors
  • Adenylyl Cyclases (genetics, metabolism)
  • Animals
  • CHO Cells
  • Codeine (administration & dosage, analogs & derivatives, pharmacology)
  • Cricetinae
  • Dihydromorphine (administration & dosage, metabolism, pharmacology)
  • Dose-Response Relationship, Drug
  • Enzyme Activation (drug effects)
  • Isoenzymes (antagonists & inhibitors, genetics, metabolism)
  • Morphine (administration & dosage, metabolism, pharmacology)
  • Morphine Derivatives (administration & dosage, metabolism, pharmacology)
  • Opioid-Related Disorders
  • Receptors, Opioid, mu (genetics, metabolism)
  • Thyrotropin (pharmacology)
  • Transfection

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