ß-arrestin 2 germline knockout does not attenuate opioid respiratory depression

Abstract

Opioids are perhaps the most effective analgesics in medicine. However, between 1999 to 2018, over 400,000 people in the United States died from opioid overdose. Excessive opioids make breathing lethally slow and shallow, a side-effect called opioid induced respiratory depression. This doubled-edged sword has sparked the desire to develop novel therapeutics that provide opioid-like analgesia without depressing breathing. One such approach has been the design of so-called 'biased agonists' that signal through some, but not all pathways downstream of the µ-opioid receptor (MOR), the target of morphine and other opioid analgesics. This rationale stems from a study suggesting that MOR-induced ß2-arrestin dependent signaling is responsible for opioid respiratory depression, whereas adenylyl cyclase inhibition produces analgesia. To verify this important result that motivated the 'biased agonist' approach, we re-examined breathing in ß2-arrestin deficient mice and instead find no connection between ß2-arrestin and opioid respiratory depression. This result suggests that any attenuated effect of 'biased agonists' on breathing is through an as-yet defined mechanism.

Discovery and Structural Explorations of G‐Protein Biased μ‐Opioid Receptor Agonists

“…However, a recent study demonstrated that an opioid receptor ligand that does not induce μOR βarrestin 2 dependent signaling still temporarily induces opioid induced respiratory depression. [24] Moreover, some results, [25] refute the foundational model that β-arrestin 2 selectively mediates opioid induced respiratory depression and suggest that reinvestigate the mechanism of biased agonism in vivo in the future. Nevertheless, there are also many recent reports showed that G-protein-biased μOR agonists worked, [26][27][28] and there are conversely results which need to be further concerned.…”

“…As described above, core premise for the development of μOR biased agonists is that β‐arrestin2 dependent signaling provides a molecular mechanism to dissociate analgesia from respiratory depression. However, a recent study demonstrated that an opioid receptor ligand that does not induce μOR β‐arrestin 2 dependent signaling still temporarily induces opioid induced respiratory depression [24] . Moreover, some results, [25] refute the foundational model that β‐arrestin 2 selectively mediates opioid induced respiratory depression and suggest that reinvestigate the mechanism of biased agonism in vivo in the future.…”

Tyrosine 7.43 is important for mu-opioid receptor downstream signaling pathways activated by fentanyl

“…It was reported that the G protein-dependent signaling pathway mediates pharmacological effects, such as analgesia and sedation, whereas the ß-arrestin-dependent signaling pathway mediates respiratory depression (Kelly, 2013). At present, the original suggestion that ß-arrestin2 signaling plays a key role in opioid-induced respiratory depression has been questioned (Kliewer et al, 2020;Bachmutsky et al, 2021). Even so, there is still a growing interest in the development of functionally selective G protein-coupled receptor (GPCR) ligands facilitated by hopes of producing more effective drugs with reduced side effects (Wacker et al, 2017).…”

Clathrin regulates the β-arrestin pathway regardless of ligand bias

“…These observations strongly suggest an important unresolved gap between the concept of biased agonism and functional selectivity. Furthermore, most recent studies reported that mutant mice lacking β-arrestin 2 or expressing phosphorylation-deficient MOP, which does not recruit β-arrestin 2, also presented with side effects following opioid administration [11][12][13] . These results critically raise the question as to whether recruitment of β-arrestin 2 to MOP is the true culprit that triggers opioid side effects 14 .…”