LAUSR

Triazole 1.1 is a G protein–biased agonist of the κ-opioid receptor in striatal neurons. Biasing pain treatment against side effects Stimulating opioid receptors with targeted agonists can treat pain, but such drugs often cause unwanted and even dangerous side effects because they induce multiple intracellular pathways downstream of the receptor. Studies in cell lines and mouse models have proposed that so-called “biased” agonists, those that activate only antinociceptive G protein signaling, may lessen pain and itch without causing side effects. Ho et al. confirm this potential for targeting the κ-opioid receptor (KOR) by showing the biochemical and physiological effects of biased KOR agonists specifically on striatal neurons in mice. These findings indicate that cell culture–based predictions of biased KOR agonists may hold true in vivo and therefore may be a better way to treat pain in patients. Biased agonists of G protein–coupled receptors may present a means to refine receptor signaling in a way that separates side effects from therapeutic properties. Several studies have shown that agonists that activate the κ-opioid receptor (KOR) in a manner that favors G protein coupling over β-arrestin2 recruitment in cell culture may represent a means to treat pain and itch while avoiding sedation and dysphoria. Although it is attractive to speculate that the bias between G protein signaling and β-arrestin2 recruitment is the reason for these divergent behaviors, little evidence has emerged to show that these signaling pathways diverge in the neuronal environment. We further explored the influence of cellular context on biased agonism at KOR ligand–directed signaling toward G protein pathways over β-arrestin–dependent pathways and found that this bias persists in striatal neurons. These findings advance our understanding of how a G protein–biased agonist signal differs between cell lines and primary neurons, demonstrate that measuring [35S]GTPγS binding and the regulation of adenylyl cyclase activity are not necessarily orthogonal assays in cell lines, and emphasize the contributions of the environment to assessing biased agonism.