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Abstract
Background and PurposeGPCRs 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 ApproachThe 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 ResultsOur consensus results unequivocally demonstrate that the prototypical μ‐opioid agonist morphine (3.75–100 mg·kg−1 s.c. or 3–30 mg·kg−1 i.p.) as well as the potent opioid fentanyl (0.05–0.35 mg·kg−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 ImplicationsOur 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.
Highlights
Regulatory β-arrestin proteins, downstream of GPCRs, are widely understood to mediate receptor desensitisation
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
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 induce respiratory depression and constipation in β-arrestin2 knockout mice in a dose-dependent manner indistinguishable from that observed in wild-type mice
Summary
Regulatory β-arrestin proteins, downstream of GPCRs, are widely understood to mediate receptor desensitisation. In the development of new opioid analgesic drugs, a key driving force was a study published in 2005 on β-arrestin knockout mice that reported enhanced and prolonged analgesic effects after morphine application, presumably due to decreased receptor desensitisation, and reduced respiratory depressant and constipatory effects (Raehal, Walker, & Bohn, 2005). These results led to the novel concept that opioid analgesia is mediated via G protein signalling, while respiratory depression and constipation are mediated predominantly via β-arrestin-dependent signalling pathways. What is the clinical significance These results question G protein-biased agonists as a strategy for safer opioid analgesic drugs
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