Role of signalling molecules in behaviours mediated by the δ opioid receptor agonist SNC80

Background and Purpose GPCRs exist in multiple conformations that can engage distinct signalling mechanisms which in turn may lead to diverse behavioural outputs. In rodent models, activation of the δ opioid receptor (δ‐receptor) has been shown to elicit antihyperalgesia, antidepressant‐like effects and convulsions. We recently showed that these δ‐receptor‐mediated behaviours are differentially regulated by the GTPase‐activating protein regulator of G protein signalling 4 (RGS4), which facilitates termination of G protein signalling. To further evaluate the signalling mechanisms underlying δ‐receptor‐mediated antihyperalgesia, antidepressant‐like effects and convulsions, we observed how changes in Gαo or arrestin proteins in vivo affected behaviours elicited by the δ‐receptor agonist SNC80 in mice. Experimental Approach Transgenic mice with altered expression of various signalling molecules were used in the current studies. Antihyperalgesia was measured in a nitroglycerin‐induced thermal hyperalgesia assay. Antidepressant‐like effects were evaluated in the forced swim test. Mice were also observed for convulsive activity following SNC80 treatment. Key Results In Gαo RGS‐insensitive heterozygous knock‐in mice, the potency of SNC80 to produce antihyperalgesia and antidepressant‐like effects was enhanced with no change in SNC80‐induced convulsions. Conversely, in Gαo heterozygous knockout mice, SNC80‐induced antihyperalgesia was abolished while antidepressant‐like effects and convulsions were unaltered. No changes in SNC80‐induced behaviours were observed in arrestin 3 knockout mice. SNC80‐induced convulsions were potentiated in arrestin 2 knockout mice. Conclusions and Implications Taken together, these findings suggest that different signalling molecules may underlie the convulsive effects of the δ‐receptor relative to its antihyperalgesic and antidepressant‐like effects.