Morphine-related metabolites differentially activate adenylyl cyclase isozymes after acute and chronic administration.
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.
Eckhardt
K
K
Dr. Margarete Fischer Bosch Institute of Clinical Pharmacology, Auerbachstr. 112, 70376, Stuttgart, Germany.
Nevo
I
I
Levy
R
R
Mikus
G
G
Eichelbaum
M
M
Vogel
Z
Z
D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D003061:Codeine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D006224:Cricetinae; D004090:Dihydromorphine / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009020:Morphine / Q000008:administration & dosage* / Q000378:metabolism / Q000494:pharmacology*; D009022:Morphine Derivatives / Q000008:administration & dosage* / Q000378:metabolism / Q000494:pharmacology*; D009293:Opioid-Related Disorders; D017450:Receptors, Opioid, mu / Q000235:genetics / Q000378:metabolism; D013972:Thyrotropin / Q000494:pharmacology; D014162:Transfection
D000067956:Adenylyl Cyclase Inhibitors; D007527:Isoenzymes; D009022:Morphine Derivatives; D017450:Receptors, Opioid, mu; C035349:morphine-6-glucuronide; D009020:Morphine; D013972:Thyrotropin; D004090:Dihydromorphine; D000262:Adenylyl Cyclases; C018108:morphine-3-glucuronide; D003061:Codeine