RGS proteins 4 and 9 regulate µ-opioid receptor-induced potentiation of dopamine D1-like receptor signaling in mouse medial prefrontal cortex.

Increasing evidence indicates that Regulator of G protein Signaling (RGS) proteins are involved in modulation of opioid receptor activity and in development of opioid tolerance and dependence. Whit regard to the adenylyl cyclase (AC) system, a major signal transduction pathway of opioid receptors, most of the studies on RGS proteins have focused on the opioid inhibitory effects, whereas less is known on the opioid-induced stimulation of cyclic AMP. Previously, we have reported that in mouse medial prefrontal cortex (mpfc), activation of opiod receptors enhances dopamine (DA) D1-like receptor stimulation of adenylyl cyclase activity likely through βγ-mediated activation of AC 2 and AC 4. In the present study we show that in membranes of cyclic AMP elicited by the µ-opioid receptor agonist DAMGO. The potentiation mainly consists in a leftward shift in the opioid agonist concentration-response curve. Similarly, membrane exposure to the RGS4 inhibitor CCG-4986 markedly enhances the DAMGO potentiation. These data indicate that in mpfc RGS9 and 4 regulate the positive coupling of µ-opioid receptors to DA D1-stimulated adenylyl cyclase and may constitute a critical mechanism in the development of adaptive responses to opioids.