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.

G蛋白偶联受体的偏向激动剂可能会提供一种以分离副作用和治疗特性的方式改善受体信号传导的方法。几项研究表明，激动剂激活κ阿片受体（KOR）的方式比细胞培养中的β-arrestin2募集更有利于G蛋白偶联，这可能是一种治疗疼痛和瘙痒而又避免镇静和烦躁不安的方法。尽管推测G蛋白信号传导和β-arrestin2募集之间的偏倚是造成这些差异行为的原因很有吸引力，但几乎没有证据表明这些信号通路在神经元环境中会产生差异。我们进一步探索了细胞背景对KOR配体定向的G信号通路上的β受体阻滞剂依赖性途径的G激动剂偏向激动作用的影响，并发现这种偏倚在纹状体神经元中持续存在。这些发现使我们进一步了解了G蛋白偏向激动剂信号在细胞系和原代神经元之间是如何不同的，证明了测量[³⁵ S]GTPγS的结合和腺苷酸环化酶活性的调节不一定是细胞系中的正交测定，而是强调环境对评估偏向激动性的贡献。