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.