2. Academic Validation
  3. Melanocortin receptor 4 agonist setmelanotide treats opioid-induced respiratory depression

Melanocortin receptor 4 agonist setmelanotide treats opioid-induced respiratory depression

  • bioRxiv. 2026 Mar 10:2026.03.08.708886. doi: 10.64898/2026.03.08.708886.
Mateus R Amorim 1 2,  Noah R Williams 2,  Melanie A Ruiz 2,  Junia L de Deus 2,  O Aung 3,  Olga Dergacheva 4,  Joan Escobar 4,  Mi-Kyung Shin 2,  Cole R Winston 2,  Thales H C Furquim 1,  Jeffrey S Berger 2,  David Mendelowitz 4,  Vsevolod Y Polotsky 2 4 5
Affiliations

Affiliations

  • 1 Department of Physiology, Medical School of Ribeirao Preto, SP, Brazil.
  • 2 Department of Anesthesiology and Critical Care Medicine, George Washington University, Washington, DC.
  • 3 Medical College of Wisconsin, Milwaukee, WI.
  • 4 Department of Pharmacology and Physiology, George Washington University, Washington, DC.
  • 5 Department of Medicine, George Washington University, Washington, DC.
PMID: 41959165 DOI: 10.64898/2026.03.08.708886
Abstract

Background: The 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 μ-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.

Methods: C57BL/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.

Results: In 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.

Conclusions: SET effectively treated OIRD by increasing respiratory rate and inducing a significant decrease in the number of apneas without decreasing analgesia.

Keywords

Melanocortin receptor 4; analgesia; plethysmography; respiratory control; synaptic transmission.

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