Cardiorespiratory failure and sudden death induced by carfentanil exposure: Involvement of central mu1 opioid receptors

Toxicol Appl Pharmacol. 2025 Sep 11:117550. doi: 10.1016/j.taap.2025.117550. Online ahead of print.

ABSTRACT

Inhalation of aerosolized carfentanil (CRF) could result in death, but the relevant mechanisms remain unclear. To establish a model of CRF-induced death, we recorded cardiorespiratory activities in rats placed in a double-chamber plethysmograph. CRF exposure (10.0 mg/m³ for 15 min) failed to cause death in any of the tested female rats (0/8), but induced death in 3/8 of the male rats. CRF exposure decreased ventilation (60 %) and heart rate (25 %) within the first 5 min exposure, which was maintained to the end of the experiment and dissipated on the next day in the surviving rats. In contrast, ventilatory depression and bradycardia were suddenly aggravated 45 min after the onset of CRF exposure, which led to ventilatory and cardiac arrest within the following 15 min in the dead rats. Subsequently, the cardiorespiratory responses were recorded in male rats after the following pretreatment: a) naloxone (NLX) and b) naloxone methiodide (NLM) to systemically and peripherally block opioid receptors (ORs) respectively; and c) β-funaltrexamine (β-FNA) and d) naloxonazine (NLZ) to systemically antagonize both mu1 and mu2 opioid receptors (mu1Rs and mu2Rs) and only mu1Rs respectively. NLX blocked all cardiorespiratory responses, while NLM only slightly attenuated the initial V_E depression. β-FNA and NLZ nearly blocked V_E depression with little impact on bradycardia. All antagonists, except NLM, prevented CRF-caused death. In conclusion, our results establish a rat model of CRF exposure-induced cardiorespiratory failure and sudden death and reveal a key role of central ORs, especially mu1Rs, in the genesis of the cardiorespiratory failure.

PMID:40945866 | DOI:10.1016/j.taap.2025.117550