Central opioid mu₁-receptors are responsible for sudden death induced by acute inhalation of carfentanil (CRF) aerosol

Previous studies have shown that inhalation of aerosolized CRF could result in rapid death in humans and respiratory depression in animals. The respiratory depression is mediated by activation of peripheral and particularly central opioid receptors (ORs), among which opioid mu 1 -recetpors (µ 1 -ORs) may be critical. To date, the mechanisms underlying CRF exposure-induced cardiorespiratory failure and sudden death remain unclear. In this study, we first compared the CRF exposure-induced cardiorespiratory failure and sudden death between sexes. Both male and female conscious rats were exposed to aerosolized CRF at a concentration of 12.86 mg/m 3 for 15 min in a double-chamber plethysmograph to record cardiorespiratory activities for 60 min. CRF exposure led to sudden death in 2/6 male rats, but not in any of the females (0/7). Compared to aerosolized vehicle, CRF exposure initially decreased minute ventilation (V E ) by 50% (primarily via reduction of respiratory frequency and prolongation of expiratory duration) and heart rate (HR) by 25% within 1 min and by 80% and 40% respectively 10 min after the onset of the exposure. These responses were generally maintained to the end of experiment and disappeared on the next day in the survived rats. The V E depression and bradycardia were much more aggravated after 15 min CRF exposure in the dead rats, leading to ventilatory and then cardiac arrest within ~60 min after the onset of the exposure. Secondly, the impacts of the following pretreatments on the cardiorespiratory responses and the mortality were tested in male rats: a) naloxone hydrochloride (NLX) and naloxone methiodide (NLM) to systemically and peripherally block ORs respectively; and b) β-funaltrexamine (β-FNA) and naloxonazine (NLZ) to systemically antagonize both µ 1 - and µ 2 -Rs and only µ 1 -Rs respectively. NLX blocked the CRF-induced VE depression, bradypnea and bradycardia, while NLM had limited effect. β-FNA and NLZ similarly and significantly alleviated VE depression, bradypnea and bradycardia. The pretreatments prevented CRF-caused death except that NLM still caused death in 3/7 rats. Therefore, our experiments not only establish a model of CRF exposure-induced cardiorespiratory failure and sudden death in conscious rats, but also reveal a key role of central ORs, especially µ 1 -Rs, in the CRF exposure-induced cardiorespiratory failure. This study is supported National Institutes of Health (NIH), Bethesda. Grant numbers: DA059063 and HL163512. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.