RECENT ADVANCES IN THE MOLECULAR EFFECTS OF OPIATES

Acute and chronic stimulation of opiate receptors induce multiple cell ular modifications. Depending on the duration of the stimulation, acut e or chronic, the effects are often diametrically opposed. Binding of opiates on their receptors for a short period of time, (acute stimulat ion), leads to inhibition of adenylyl cyclase activity. On the other h and, binding of opiates on their receptors for a long period of time, (chronic stimulation), induces an increase in adenylylcyclase activity . Calcium and potassium channels as well as protein phosphorylation (m orphine cAMP regulated phosphoproteins or MARPPs, cAMP responsive elem ent binding protein or CREB and synapsins) are also differently affect ed depending on the duration of the stimulation. Chronic stimulation l eads to longterm changes such as modifications of messenger RNA and pr otein levels. The modulation of gene expression induced by opiates req uires the transcription factors CREB and c-Fos in order to maintain ce llular adaptation to opiates. Cyclic AMP and calcium would act as seco nd messenger, phosphorylation of CREB by protein. kinase A or of unkno wn proteins by protein kinase C as third messenger and immediate early genes such as c-fos would function as fourth messenger. These modific ations would allow the cell to adapt to a new environment and play a k ey role in the dramatic, protracted cellular modifications involved in dependance to opiates.