Mu-opioid receptor selective superagonists produce prolonged respiratory depression

Nicholas J Malcolm; Barbara Palkovic; Daniel J Sprague; Maggie M Calkins; Janelle K Lanham; Adam L Halberstadt; Astrid G Stucke; John D McCorvy

doi:10.1016/j.isci.2023.107121

Mu-opioid receptor selective superagonists produce prolonged respiratory depression

iScience. 2023 Jun 13;26(7):107121. doi: 10.1016/j.isci.2023.107121. eCollection 2023 Jul 21.

Authors

Nicholas J Malcolm¹, Barbara Palkovic², Daniel J Sprague¹, Maggie M Calkins¹, Janelle K Lanham¹, Adam L Halberstadt^{3

4}, Astrid G Stucke², John D McCorvy¹

Affiliations

¹ Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
² Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
³ Department of Psychiatry, University of California San Diego, La Jolla, CA 92093, USA.
⁴ Research Service, VA San Diego Healthcare System, San Diego, CA 92108, USA.

Abstract

Synthetic opioids are increasingly challenging to combat the opioid epidemic and act primarily at opioid receptors, chiefly the G protein-coupled receptor (GPCR) μ-opioid receptor (MOR), which signals through G protein-dependent and β-arrestin pathways. Using a bioluminescence resonance energy transfer (BRET) system, we investigate GPCR-signaling profiles by synthetic nitazenes, which are known to cause overdose and death due to respiratory depression. We show that isotonitazene and its metabolite, N-desethyl isotonitazene, are very potent MOR-selective superagonists, surpassing both DAMGO G protein and β-arrestin recruitment activity, which are properties distinct from other conventional opioids. Both isotonitazene and N-desethyl isotonitazene show high potency in mouse analgesia tail-flick assays, but N-desethyl isotonitazene shows longer-lasting respiratory depression compared to fentanyl. Overall, our results suggest that potent MOR-selective superagonists may be a pharmacological property predictive of prolonged respiratory depression resulting in fatal consequences and should be examined for future opioid analgesics.

Keywords: Cellular neuroscience; Molecular neuroscience; Neuroscience.

Abstract

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