Journal Article

Peripheral opioid receptor antagonism alleviates fentanyl-induced cardiorespiratory depression and is devoid of aversive behavior

Roth, Caroline G, Higginbotham, Jessica A, Masud, Sarah, Kesaraju, Rohith, Angulo-Lopera, Sofia, Modh, Juhi, Lintz, Tania, Ruyle, Brian C, Tahirkheli, Mubariz, Massaly, Nicolas, Morón, Jose A

2025

Overview

Millions of Americans suffering from Opioid Use Disorders face a high risk of fatal overdose due to opioid-induced respiratory depression (OIRD). Fentanyl, a powerful synthetic opioid, is a major contributor to the rising rates of overdose deaths. Reversing fentanyl overdoses has proved challenging due to its high potency and the rapid onset of OIRD. We assessed the contributions of central and peripheral mu opioid receptors (MORs) in mediating fentanyl-induced physiological responses. The peripherally restricted MOR antagonist naloxone methiodide (NLXM) both prevented and reversed OIRD to a degree comparable to that of naloxone (NLX), indicating substantial involvement of peripheral MORs to OIRD. Interestingly, NLXM-mediated OIRD reversal did not produce aversive behaviors observed after NLX. We show that neurons in the nucleus of the solitary tract (nTS), the first central synapse of peripheral afferents, exhibit a biphasic activity profile following fentanyl exposure. NLXM pretreatment attenuates this activity, suggesting that these responses are mediated by peripheral MORs. Together, these findings establish a critical role for peripheral MORs, including ascending inputs to the nTS, as sites of dysfunction during OIRD. Furthermore, selective peripheral MOR antagonism could be a promising therapeutic strategy for managing OIRD by sparing CNS-driven acute opioid-associated withdrawal and aversion observed after NLX.

• Publisher: eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: Analgesics, Opioid - adverse effects / Animals / Aversion / Behavior / Behavior, Animal - drug effects / Drug abuse / Drug addiction / Females / Fentanyl / Fentanyl - adverse effects / Gender differences / Heart rate / Hypoxia / Male / Males / Mice / Naloxone / Naloxone - analogs & derivatives / Naloxone - pharmacology / naloxone methiodide / Narcotic Antagonists - administration & dosage / Narcotic Antagonists - pharmacology / Narcotics / Neuroscience / nTS / Opioid receptors (type mu) / Overdose / Oxygen saturation / photometry / Physiology / Receptors, Opioid, mu - antagonists & inhibitors / Receptors, Opioid, mu - metabolism / respiratory depression / Respiratory Insufficiency - chemically induced / Respiratory Insufficiency - drug therapy / Solitary Nucleus - drug effects / Solitary tract nucleus