Changes in murine respiratory dynamics induced by aerosolized carfentanil inhalation: Efficacy of naloxone and naltrexone

•Exposure to carfentanil reduced respiratory minute volume for up to 24 h post-exposure.•Naloxone and naltrexone treatment mitigated carfentanil-induced decreases in minute volume.•Carfentanil-induced changes in respiratory duty cycle were not alleviated by treatment.•Prophylactic treatment may be a...

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Bibliographic Details
Published in:Toxicology letters 2019-11, Vol.316, p.127-135
Main Authors: Tuet, Wing Y., Pierce, Samuel A., Racine, Michelle C., Tressler, Justin, McCranor, Bryan J., Sciuto, Alfred M., Wong, Benjamin
Format: Article
Language:English
Subjects:
Carfentanil
Inhalation exposure
Naloxone
Naltrexone
Physiology based pharmacokinetics
Prophylaxis
Respiratory dynamics
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Summary:•Exposure to carfentanil reduced respiratory minute volume for up to 24 h post-exposure.•Naloxone and naltrexone treatment mitigated carfentanil-induced decreases in minute volume.•Carfentanil-induced changes in respiratory duty cycle were not alleviated by treatment.•Prophylactic treatment may be a viable option to protect first responders. Carfentanil (CRF) is an extremely potent opioid capable of inducing fatal respiratory depression. Naloxone (NX) and naltrexone (NTX) are opioid antagonists for which the efficacy against CRF remains largely unexplored. In this study, the effects of aerosolized CRF on respiratory function were investigated using adult male CD-1 mice. Mice were exposed to 0.4 mg/m3 of CRF for 15 min using custom whole-body plethysmograph units. Minute volume (MV), respiratory frequency (f), duty cycle (DC), and tidal volume (TV) were monitored and compared to control animals exposed to aerosolized H2O. CRF exposure induced respiratory depression, characterized by a marked decrease in MV, which was sustained throughout 24 h post-exposure. Prophylactic and therapeutic treatment with intramuscular (i.m.) NX marginally improved MV, with slight dose-dependent effects. Analogous treatment with i.m. NTX returned MV to baseline levels, with all doses and intervention times performing similarly. Despite improvements in MV, treatment administration did not reverse changes in DC, a measure of respiratory timing. Overall, NX and NTX administration alleviated volumetric aspects of opioid-induced respiratory toxicity, while changes in respiratory timing remained unresolved throughout post-exposure observation. These sustained changes and differences in recovery between two aspects of respiratory dynamics may provide insights for further exploration into the underlying mechanism of action of opioids and opioid antagonists.
ISSN:0378-4274
1879-3169
DOI:10.1016/j.toxlet.2019.09.012