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Papers of the Week

Papers: 8 Jul 2023 - 14 Jul 2023

Basic Science

Animal Studies, Neurobiology, Pharmacology/Drug Development

2023 Jul 21





Mu-opioid receptor selective superagonists produce prolonged respiratory depression.


Malcolm NJ, Palkovic B, Sprague DJ, Calkins MM, Lanham JK, Halberstadt AL, Stucke AG, McCorvy JD


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, -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 -desethyl isotonitazene show high potency in mouse analgesia tail-flick assays, but -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.