Topic: β-arrestin-biased δ-opioid receptor (δOR) signaling: a novel therapeutic target for anxiety disorders

Presenter: Mee Jung Ko
                  Ph.D. candidate, Department of Medicinal Chemistry and Molecular Pharmacology Integrative Neuroscience Training Group

Abstract:

Anxiety disorders are one of the most common mental disorders in the States affecting approximately 18 % of the population. Although psychoactive drugs and antidepressants are the first-line medications for anxiety disorders, the ubiquitous targets (e.g. GABA receptors and 5-HT receptors) of these drugs give rise to serious side effects such as drowsiness, nausea, and dependence. For this reason, there remains a significant need for discovering novel therapeutic targets with restricted mechanisms of action. Our research has focused on intracellular singaling pathways of a novel target, δ-opioid receptor (δOR). The δOR is a G-protein coupled receptor (GPCR) that has been known to modulate anxiety-like behavior. In our studies, we utilized the concept of ‘biased signaling’ to selectively investigate specific GPCR-mediated signaling pathways such as G-protein or β-arrestin pathways. Based on our previous research, we hypothesized that the β-arrestin-mediated pathways play a key role in δOR- mediated anxiolysis-like behavior. We employed a δOR-selective agonist, SNC80, that strongly promotes β- arrestin recruitment to investigate our hypothesis. Anxiety-like behavior and conditioned fear responses in mice were measured using the elevated plus maze (EPM), the dark-light transition box, and the fear-potentiated startle (FPS) test. We found that SNC80 (20 mg/kg i.p) significantly alleviated anxiety-like behavior and FPS responses in wild-type mice, but the SNC80-mediated anxiolysis-like behavior was ablated in β-arrestin2 knockout mice. In vitro characterization of δOR signaling following SNC80 further revealed that phosphorylation of Mitogen- activated protein kinase 1/2 (ERK1/2) was increased in CHO cells endogenously overexpressing δOR and β- arrestin2. Inhibiton of the ERK1/2 phosphorylation abolished SNC80-mediated anxiolysis-like behavior in wild- type mice, which indicates that the ERK1/2 phosphorylation is required for β-arrestin2-mediated anxiolysis-like behavior. Taken together, we suggest that β-arrestin2-biased signaling at δOR ameliorates anxiety-like behavior through ERK1/2 phosphorylation. Our findings provide novel insight into δOR pharmacology and the development of medicinal interventions for treating anxiety disorders.