Melanocortin receptor 4 agonist setmelanotide treats opioid-induced respiratory depression

Ramos Amorim, M.; Williams, N. R.; Ruiz, M. A.; de Deus, J. L.; Aung, O.; Dergacheva, O.; Escobar, J.; Shin, M.-K.; Winston, C. R.; Furquim, T. H. C.; Berger, J. S.; Mendelowitz, D.; Polotsky, V. Y.

doi:10.64898/2026.03.08.708886

bioRxiv · 10.64898/2026.03.08.708886

Melanocortin receptor 4 agonist setmelanotide treats opioid-induced respiratory depression

Ramos Amorim, M.·Williams, N. R.·Ruiz, M. A.·de Deus, J. L.·Aung, O.·Dergacheva, O.·Escobar, J.·Shin, M.-K.·Winston, C. R.·Furquim, T. H. C.·Berger, J. S.·Mendelowitz, D.·Polotsky, V. Y.

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Abstract

BackgroundThe primary cause of death associated with opioids is opioid-induced respiratory depression (OIRD). Naloxone is used to reverse OIRD, but this drug is a competitive antagonist of {micro}-opioid receptor (MOR) and reverses analgesia, which limits its therapeutic use. Alternative non-opioid receptor antagonist-based approaches to OIRD treatment and prevention are needed. The aim of this study was to evaluate if setmelanotide (SET) is capable of reversing OIRD in a mouse model. MethodsC57BL/6J male and female mice and Sprague-Dawley rats were given IP morphine or fentanyl and then treated 15 min later with either SET or vehicle VEH (IP) in a random order. Breathing was recorded by barometric plethysmography, and pain sensitivity was measured by the tail-flick test. ResultsIn mice with OIRD, SET induced a 3-fold reduction of the apnea index, and decreased apnea duration as compared to the VEH treatment. SET increased respiratory rate and did not affect opioid-induced analgesia. Photostimulation of MC4R+ ChR2-expressing fibers in the parafacial region of MC4R-Cre mice elicited short-latency excitatory postsynaptic current in rostral ventral respiratory group (rVRG) pre-motoneurons projecting to the phrenic nucleus in the C3-C4 ventral horns of the spinal cord. Fentanyl inhibited the activity of rVRG neurons and SET reversed this effect. ConclusionsSET effectively treated OIRD by increasing respiratory rate and inducing a significant decrease in the number of apneas without decreasing analgesia.

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Ramos Amorim, M., Williams, N. R., Ruiz, M. A., de Deus, J. L., Aung, O., Dergacheva, O., Escobar, J., Shin, M.-K., Winston, C. R., Furquim, T. H. C., Berger, J. S., Mendelowitz, D., Polotsky, V. Y.. 2026-03-10. Melanocortin receptor 4 agonist setmelanotide treats opioid-induced respiratory depression. https://doi.org/10.64898/2026.03.08.708886

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