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bioRxiv2026

Melanocortin receptor 4 agonist setmelanotide treats opioid-induced respiratory depression

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.

physiology↗

bioRxiv2026

Oxytocin treats respiratory depression and reduces mortality from fentanyl and the combination of xylazine-fentanyl

Opioid addiction and misuse are a serious national crisis that affects public health, as well as social and economic welfare. Mortality due to opioid misuse is further exasperated by the combination of opioids with non-opioid respiratory depressants such as xylazine that are resistant to mu opioid receptor antagonists such as naloxone. This study tested the hypothesis that oxytocin can mitigate the severe opioid induced respiratory depression (OIRD) and mortality induced by high doses of fentanyl or the combination of fentanyl with xylazine. Our results show OXT can improve survival and respiratory function in both male and female rats with opioid induced respiratory depression caused by fentanyl, as well as a combination of fentanyl and xylazine. The improvement in respiratory function by OXT post fentanyl-xylazine was significantly greater than the recovery using only naloxone. Chemogenetic activation of OXT receptor positive neurons in the ventral respiratory group (VRG) provided similar benefits to that of OXT administration in reversing OIRD. These results indicate OXT is a promising therapeutic target for reversing OIRD and the respiratory depression that occurs with the combination of opioids and xylazine, a situation where naloxone is only partially effective. Additional translational benefits of OXT include it can be repurposed as it is already a FDA approved drug for other uses, has a high safety profile, and is unlikely to induce the withdrawal or reversal of analgesia that occurs with naloxone. Key PointsO_LIOxytocin (OXT) improves survival and respiratory function in both male and female rats with opioid induced respiratory depression (OIRD) caused by fentanyl C_LIO_LIOXT also reverses OIRD induced by the combination of fentanyl and xylazine C_LIO_LIThe improvement in respiratory function by OXT post fentanyl-xylazine was significantly greater than the recovery using only naloxone C_LIO_LIChemogenetic activation of OXT receptor positive neurons in the ventral respiratory group (VRG) provided similar benefits to that of OXT administration in reversing OIRD C_LIO_LIThese results indicate OXT is a promising therapeutic target for reversing OIRD and the respiratory depression that occurs with the combination of opioids and xylazine C_LI

pharmacology and toxicology↗