μ‐ and δ‐opioid receptor agonists inhibit DARPP‐32 phosphorylation in distinct populations of striatal projection neurons

In the striatum, DARPP‐32 (dopamine‐ and cAMP‐regulated phosphoprotein of 32 kDa) is highly expressed by virtually all projection medium‐sized spiny neurons. cAMP‐dependent phosphorylation of DARPP‐32 is stimulated via activation of dopamine D1 receptors in striatonigral neurons, and via activation of adenosine A2A receptors in striatopallidal neurons. In this study, we have examined the contribution of μ‐, δ‐ and κ‐opioid receptors to the regulation of DARPP‐32 phosphorylation, in rat striatal slices. The results show that, at low concentrations (100 pm–1 nm), the μ‐opioid agonist, Tyr‐D‐Ala‐Gly‐N‐Me‐Phe‐glycinol (DAMGO), inhibits the increase in DARPP‐32 phosphorylation induced by activation of D1, but not by activation of A2A receptors. Conversely, the δ‐receptor agonist, Tyr‐D‐Pen‐Gly‐Phe‐D‐Pen (DPDPE), inhibits DARPP‐32 phosphorylation induced by activation of A2A, but not by activation of D1 receptors. The κ‐receptor agonist, U50488, does not affect DARPP‐32 phosphorylation induced by either D1 or A2A agonists. Thus, μ‐opioid receptors interact with dopamine D1 receptors on striatonigral neurons, whereas δ‐opioid receptors interact with adenosine A2A receptors on striatopallidal neurons. These results suggest that regulation of DARPP‐32 phosphorylation is involved in mediating some of the effects exerted by enkephalin on striatal medium‐sized spiny neurons.