Tolerance to high‐internalizing δ opioid receptor agonist is critically mediated by arrestin 2

Background and Purpose Opioid δ receptor agonists are potent antihyperalgesics in chronic pain models, but tolerance develops after prolonged use. Previous evidence indicates that distinct forms of tolerance occur depending on the internalization properties of δ receptor agonists. As arrestins are important in receptor internalization, we investigated the role of arrestin 2 (β‐arrestin 1) in mediating the development of tolerance induced by high‐ and low‐internalizing δ receptor agonists. Experimental Approach We evaluated the effect of two δ receptor agonists with similar analgesic potencies, but either high‐(SNC80) or low‐(ARM390) internalization properties in wild‐type (WT) and arrestin 2 knockout (KO) mice. We compared tolerance to the antihyperalgesic effects of these compounds in a model of inflammatory pain. We also examined tolerance to the convulsant effect of SNC80. Furthermore, effect of chronic treatment with SNC80 on δ agonist‐stimulated [ 35 S]‐GTPγS binding was determined in WT and KO mice. Key Results Arrestin 2 KO resulted in increased drug potency, duration of action and decreased acute tolerance to the antihyperalgesic effects of SNC80. In contrast, ARM390 produced similar effects in both WT and KO animals. Following chronic treatment, we found a marked decrease in the extent of tolerance to SNC80‐induced antihyperalgesia and convulsions in arrestin 2 KO mice. Accordingly, δ receptors remained functionally coupled to G proteins in arrestin 2 KO mice chronically treated with SNC80. Conclusions and Implications Overall, these results suggest that δ receptor agonists interact with arrestins in a ligand‐specific manner, and tolerance to high‐ but not low‐internalizing agonists are preferentially regulated by arrestin 2.