Assessment of the potential of novel and classical opioids to induce respiratory depression in mice

Author:

Hill Rob12,Sanchez Julie12,Lemel Laura12,Antonijevic Mirjana3,Hosking Yselkla3,Mistry Shailesh N.3,Kruegel Andrew C.4,Javitch Jonathan A.56,Lane J. Robert12ORCID,Canals Meritxell12ORCID

Affiliation:

1. Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, Queen's Medical Centre University of Nottingham Nottingham UK

2. Centre of Membrane Proteins and Receptors, Universities of Nottingham and Birmingham Midlands UK

3. Division of Biomolecular Science and Medicinal Chemistry, School of Pharmacy, University of Nottingham Biodiscovery Institute University Park Nottingham UK

4. Department of Chemistry Columbia University New York New York USA

5. Departments of Psychiatry and Molecular Pharmacology and Therapeutics Columbia University Vagelos College of Physicians & Surgeons New York New York USA

6. Division of Molecular Therapeutics New York State Psychiatric Institute New York New York USA

Abstract

AbstractBackground and PurposeOpioid‐induced respiratory depression limits the use of μ‐opioid receptor agonists in clinical settings and is the main cause of opioid overdose fatalities. The relative potential of different opioid agonists to induce respiratory depression at doses exceeding those producing analgesia is understudied despite its relevance to assessments of opioid safety. Here we evaluated the respiratory depressant and anti‐nociceptive effects of three novel opioids and relate these measurements to their in vitro efficacy.Experimental ApproachRespiration was measured in awake, freely moving male CD‐1 mice using whole body plethysmography. Anti‐nociception was measured using the hot plate test. Morphine, oliceridine and tianeptine were administered intraperitoneally, whereas methadone, oxycodone and SR‐17018 were administered orally. Receptor activation and arrestin‐3 recruitment were measured in HEK293 cells using BRET assays.Key ResultsAcross the dose ranges examined, all opioids studied depressed respiration in a dose‐dependent manner, with similar effects at the highest doses, and with tianeptine and oliceridine showing reduced duration of effect, when compared with morphine, oxycodone, methadone and SR‐17018. When administered at doses that induced similar respiratory depression, all opioids induced similar anti‐nociception, with tianeptine and oliceridine again showing reduced duration of effect. These data were consistent with the in vitro agonist activity of the tested compounds.Conclusion and ImplicationsIn addition to providing effective anti‐nociception, the novel opioids, oliceridine, tianeptine and SR‐17018 depress respiration in male mice. However, the different potencies and kinetics of effect between these novel opioids may be relevant to their therapeutic application in different clinical settings.

Funder

Academy of Medical Sciences

Biotechnology and Biological Sciences Research Council

Hope for Depression Research Foundation

Publisher

Wiley

Subject

Pharmacology

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