The Effects of RGS4 on Delta Opioid Receptor‐mediated Behaviors in Mice

Abstract

The delta opioid receptor (DOPr) is member of the opioid receptor family of G protein‐coupled receptors. Activation of DOPr induces antinociception and antidepressant‐like effects in animal models without the constipation, respiratory depression, and abuse liability associated with mu opioid receptor agonists such as morphine. In addition, some DOPr agonists cause convulsions, hindering their development as therapeutics in humans. Regulator of G protein signaling 4 (RGS4) proteins have been shown to act as negative modulators of DOPr‐mediated G protein signaling in vitro. However, the role of RGS4 in modulating DOPr‐mediated behaviors in vivo has yet to be determined. To this end, we compared the ability of the DOPr agonist SNC80 to induce antinociception, antidepressant‐like effects, and convulsions in wildtype and RGS4 knockout mice. Loss of RGS4 potentiated SNC80‐induced peripherally‐mediated antinociception in the acetic acid stretch assay and centrally‐mediated antihyperalgesia in a nitroglycerin‐induced thermal hyperalgesia assay in a DOPr‐dependent manner. There was no change in the dose of SNC80 needed to induce a convulsion. Furthermore, in the tail suspension test, RGS4 knockout mice showed no significant difference in SNC80‐induced antidepressant‐like effects. Taken together, these data suggest that RGS4 negatively modulates some, but not all DOPr‐mediated behaviors. Because RGS4 modulates DOPr‐mediated G protein signaling, these data are consistent with G protein‐independent signaling mechanisms generating DOPr‐mediated antidepressant‐like effects and convulsions. Future studies will focus on determining the mechanisms underlying differential modulation of DOPr‐mediated behaviors by RGS4. Research support was provided by start‐up funds to EMJ.