Mu-opioid receptor selective superagonists produce prolonged respiratory depression

Synthetic opioids are increasingly challenging to combat the opioid epidemic and act primarily at opioid receptors, chiefly the G protein-coupled receptor (GPCR) m-opioid receptor (MOR), which signals through G protein-dependent and beta-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 beta-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.

Automated summary

Synthetic opioids, such as nitazenes, have been proven to be potent MOR-selective superagonists, exhibiting properties distinct from conventional opioids. These drugs cause overdose and death due to their prolonged respiratory depression effects. Therefore, it is necessary to examine the pharmacological properties of these substances for future development of opioid analgesics.