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.
Opioids, such as morphine, fentanyl, and hydrocodone, are extensively utilized in clinical practice as the mainstay for managing various types of moderate to severe pain. Despite potent analgesic properties, the extensive range of side effects greatly limits the use of opioid drugs, such as nausea and vomiting, constipation, respiratory depression, addiction, tolerance, opioid-induced hyperalgesia (OIH), etc. Even the Enhanced Recovery After Surgery (ERAS) protocols have increasingly advocated for the reduction or elimination of opioids, aiming for opioid-free analgesia. However, opioids continue to be the most effective treatment for moderate to severe pain. Therefore, the limitations inherent to conventional opioid drugs present significant challenges in clinical management. The addictive properties and euphoric effects of opioids threaten a significant market share in the illicit drug trade. Furthermore, the mortality rate associated with opioids has remained consistently elevated in recent years, imposing considerable burdens on families and society. These factors have made the development of analgesics targeting opioid receptors a challenging yet essential endeavor. Consequently, the pursuit of more potent analgesics with improved efficacy and minimal side effects has become a focused objective.
To mitigate the severe side effects caused by opioid receptor agonists as much as possible, researchers have proposed various strategies. Personalized administration is tailored to individual patients, using sustained-release formulations to reduce overall dosage and combined with low-dose antagonists to reduce adverse reactions. Multiple opioid receptor agonists can also be used to counteract the side effects caused by one subtype, while preserving positive therapeutic efficacy through simultaneous activation of multiple opioid receptors. Designing opioid receptor subtype-selective agonists and positive allosteric modulators has not effectively mitigated multiple side effects. The advancement of selective agonists has consistently been a focal point for researchers. G protein-selective agonists, which are engineered to specifically interact with opioid receptors and specific second messenger systems, have demonstrated a substantial reduction in the incidence of adverse opioid reactions, including compounds such as TRV130 and PZM21. Notably, TRV130 has received formal approval for clinical use.
In recent years, novel insights have emerged into the MOR-mediated biased agonistic signaling pathway, providing robust support for the prospective development of more precise and efficacious biased agonists. This review synthesizes the mechanisms underlying G protein-biased opioid receptor agonists and evaluates the therapeutic efficacy of classical biased opioid receptor agonists in comparison to the non-biased agonist morphine in both preclinical research and clinical practice. This comparative analysis establishes a foundational framework for the advancement of analgesics that are safer and have fewer side effects.
Opioid receptors, which are G protein-coupled receptors (GPCRs), are primarily categorized into four subtypes: mu (μ)-opioid receptor (MOR), delta (δ)-opioid receptor (DOR), kappa (k)-opioid receptor (KOR), and nociceptive nocicepin/orphanin FQ peptide receptors (NOPR). All opioid receptor subtypes have analgesic implications. The analgesic mechanisms of opioids have been the subject of extensive investigation. Most clinically utilized opioids exert analgesic effects through interaction with MOR, an inhibitory G protein-coupled receptor that is abundantly expressed in the central nervous system and gastrointestinal tract.
Upon binding to MOR, exogenous opioids induce conformational changes in the receptor, thereby modulating cellular activities through G protein and β-arrestin signaling pathways. MOR is activated and coupled with G protein, which subsequently dissociates into alpha (Gα) and beta-gamma (Gβ/γ) subunits. Gα inhibits the activity of adenylate cyclase (AC), thereby preventing adenosine triphosphate (ATP) from producing cyclic adenosine monophosphate (cAMP). Gβ/γ leads to the inactivation of calcium channels (reducing Ca 2+ influx) and activates potassium channels (increasing K+ efflux). Consequently, these effects inhibit the release of nociceptive neurotransmitters, thereby reducing the transmission of pain signals and exerting analgesic effects. In contrast, MOR is phosphorylated by G protein-coupled receptor kinase (GRK), which recruits β-arrestin. The binding of β-arrestin hinders the interaction between MOR and G protein, thereby blocking G protein-dependent signaling. Additionally, β-arrestin recruitment leads to endocytosis and desensitization of MOR and activation of the mitogen-activated protein kinase (MAPK) signaling pathway. These processes are implicated in various adverse effects. Empirical evidence has also confirmed these findings; for instance, in mice genetically deficient in β-arrestin, morphine administration has been associated with a reduction in constipation, respiratory suppression, and tolerance, among others.
Intracellular signaling mediated by opioid receptors. Activation of opioid receptors by exogenous agonists leads to dissociation of G protein heterotrimers into α and βγ subunits. Gα inhibits adenylate cyclase activity, thereby preventing adenosine ATP from producing cAMP. Gβ/γ leads to the inactivation of calcium channels and activation of potassium channels. Consequently, these effects inhibit the release of nociceptive neurotransmitters, thereby reducing the transmission of pain signals and exerting analgesic effects. The interaction of β-arrestin with phosphorylated MOR results in receptor internalization and desensitization, and activates the MAPK cascade pathways.
The adverse effects of opioids can be reversed by MOR antagonists and are absent in animals with MOR gene knockout, suggesting that the incidence of side effects may not be associated with receptor selectivity. Previous studies have established that the analgesic effect of opioid receptor agonism is mediated by G protein signaling, whereas side effects such as respiratory depression, gastrointestinal dysfunction, and tolerance are mediated by β-arrestin signaling. However, a recent study demonstrated that both G protein signaling and β-arrestin contribute to side effects induced by morphine. This study found that the β-arrestin pathway is involved in morphine tolerance, whereas the G protein signaling pathway is implicated in respiratory depression and constipation, achieved through the design of permeable peptides in combination with morphine. This challenges existing theories. Initially, β-arrestin was regarded as a negative regulator of the G protein signaling pathway. However, it was later discovered that β-arrestin can also function as a signal transducer of GPCR, mediating the transmission of downstream signals independently of G protein. Indeed, the role of the β-arrestin signaling pathway in mediating the side effects of opioids remains unclear, and numerous studies investigating the adverse effects of opioids have focused on β-arrestin-2, although the findings remain contentious.
Early research in rodents revealed that the absence or reduction in the β-arrestin-2 gene amplifies the anti-nociceptive effects while simultaneously reducing tolerance to opioids, implying a role for β-arrestin-2 in the mechanisms underlying opioid-induced antinociceptive tolerance. Nonetheless, methadone, an opioid drug, exhibits a high affinity for β-arrestin-2, yet results in less tolerance and dependency than morphine. This phenomenon blurs the role of β-arrestin-2 in analgesic tolerance. Subsequently, He and colleagues administered various G protein-biased and non-biased agonists to WT mice, revealing an inverse correlation between β-arrestin-2 recruitment and analgesic tolerance. Additionally, mice with the RMOR (Recycling MOR) genotype exhibit resistance to analgesic to
