Morphine‐induced respiratory depression is independent of β‐arrestin2 signalling

Abstract

Background and Purpose: GPCRs can signal through both G proteins and β-arrestin2.For the μ-opioid receptor, early experimental evidence from a single study suggested that G protein signalling mediates analgesia, whereas β-arrestin2 signalling mediates respiratory depression and constipation. Consequently, for more than a decade, much research effort has been focused on developing biased μ-opioid agonists that preferentially target G protein signalling over β-arrestin signalling, as it was believed that such drugs would be analgesics devoid of respiratory depressant activity. However, the prototypical compounds that have been developed based on this concept have so far failed in clinical and preclinical development.Experimental Approach: The present study was set up to re-examine opioid-induced respiratory depression in β-arrestin2 knockout mice. To this end, a consortium was formed consisting of three different laboratories located in different countries to evaluate independently opioid-induced respiratory depression.Key Results: Our consensus results unequivocally demonstrate that the prototypical μ-opioid agonist morphine (3.75-100 mgÁkg −1 s.c. or 3-30 mgÁkg −1 i.p.) as well as the potent opioid fentanyl (0.05-0.35 mgÁkg −1 s.c.) do indeed induce respiratory depression and constipation in β-arrestin2 knockout mice in a dose-dependent manner indistinguishable from that observed in wild-type mice.Conclusion and Implications: Our findings do not support the original suggestion that β-arrestin2 signalling plays a key role in opioid-induced respiratory depression and call into question the concept of developing G protein-biased μ-opioid receptor agonists as a strategy for the development of safer opioid analgesic drugs.Abbreviation: βarr2−/−, β-arrestin2 knockout.

ß2-Arrestin germline knockout does not attenuate opioid respiratory depression

“…This would be akin to providing a lower dose of standard opioid drugs. Regardless, our results, along with similar data from another recent study 18 , call into question the foundational model that Arrb2 selectively mediates OIRD and suggest that in the future, we must reconsider and reinvestigate the mechanism of biased agonism in vivo. Animals Arrb2 20 has been described.…”

“…More recently, however, results of these studies have been called into question 17,18 , prompting us to independently investigate the underlying necessity of Arrb2 in mediating ORID.…”

Biased Opioid Ligands

“…The whole concept which states that G-protein biased agonists of the MOR that do not recruit β-arrestin could significantly improve the therapeutic window and are less prone to the development of classical opioids side effects still remains under very sensitive scrutiny. Indeed, several recent studies ask for very careful consideration of the in vitro/in vivo data, given that β-arrestin 2 signaling might not be directly or indirectly involved in opioid-induced respiratory depression, constipation, or withdrawal [ 27 , 53 , 54 ]. Among the most important findings, the respiration of morphine was found to be β-arrestin 2-independent.…”

A novel luminescence-based β-arrestin membrane recruitment assay for unmodified GPCRs

“…As an example, a "β-blocker" that antagonizes G protein activation but recruits β-arrestin has been found to increase survival rates in patients suffering from heart failure (1). At the μ-opioid receptor G protein signaling has been proposed to be responsible for analgesia, with side effects such as respiratory depression resulting from arrestin-mediated signaling (2,3), although this paradigm has recently been challenged (4)(5)(6). We have demonstrated that β-arrestin recruitment to the dopamine D2 receptor in indirect pathway neurons in the ventral striatum leads to enhanced locomotion, whereas G protein signaling is necessary for incentive behavior (7), further emphasizing the potential importance of biased signaling in more targeted therapeutics.…”