Biased Opioid Receptor Agonists: Balancing Analgesic Efficacy and Side-Effect Profiles

作者：Jie Ju, Zheng Li, Jie Liu, Xiaoling Peng, Feng Gao · 发表于：International Journal of Molecular Sciences · 年份：2025 · DOI：10.3390/ijms26051862 · 被引用次数：16 · 研究领域：Receptor Mechanisms and Signaling、Neuropeptides and Animal Physiology、Pharmacological Receptor Mechanisms and Effects

Opioids are the most effective option for severe pain. However, it is well documented that the side effects associated with prolonged opioid use significantly constrain dosage in the clinical setting. Recently, researchers have concentrated on the development of biased opioid receptor agonists that preferentially activate the G protein signaling pathway over β-arrestin signaling. This approach is based on the hypothesis that G protein signaling mediates analgesic effects, whereas β-arrestin signaling is implicated in adverse side effects. Although certain studies have demonstrated that the absence or inhibition of β-arrestin signaling can mitigate the incidence of side effects, recent research appears to challenge these earlier findings. In-depth investigations into biased signal transduction of opioid receptor agonists have been conducted, potentially offering novel insights for the development of biased opioid receptors. Consequently, this review elucidates the contradictory roles of β-arrestin signaling in the adverse reactions associated with opioid receptor activation. Furthermore, a comparative analysis was conducted to evaluate the efficacy of the classic G protein-biased agonists, TRV130 and PZM21, relative to the traditional non-biased agonist morphine. This review aims to inform the development of novel analgesic drugs that can optimize therapeutic efficacy and safety, while minimizing adverse reactions to the greatest extent possible.