Fig. 9.

Summary of the three effects caused by an increase in adenylyl cyclase during withdrawal from chronic morphine.1, In control, μ-opioids inhibit GABA release, and D1-dopamine receptors increase GABA release. Under normal conditions, the inhibition of adenylyl cyclase by opioids does not have an influence on the inhibition of GABA release. The regulation of GABA release is changed in three ways during withdrawal from chronic morphine treatment. 2, An upregulation of adenylyl cyclase increased adenosine tone. This upregulation tonically inhibited GABA IPSPs by activation of A1 adenosine receptors. The upregulated adenylyl cyclase was dependent on D1 dopamine receptors because the D1 antagonist SCH23390 caused a larger inhibition of the IPSP after adenosine receptors were blocked. 3, A low concentration of DAMGO increased the IPSP in withdrawn slices. This increase was blocked or occluded after blockade of adenosine receptors. This observation suggests that μ-opioid receptors may couple more efficiently to the inhibition of adenylyl cyclase. Finally,4, μ-opioid receptor-mediated inhibition was augmented in withdrawn slices after blockade of adenosine receptors. After activation of adenylyl cyclase by forskolin, the inhibition by opioids was increased in both control and withdrawn slices. The results indicate that an opioid-sensitive adenylyl cyclase can be activated to the same extent in both control and withdrawn slices but that the basal activity is higher in withdrawn slices.