Cardiorespiratory Failure Induced by Inhalation of Carfentanil (CRF) Aerosol: Roles of Opioid Receptors (ORs) in the CNS and Vagal Afferents

Our previous studies in rats have shown that exposure to CRF aerosol initially induces rapid ventilation (V E ) depression, bradypnea and bradycardia followed by subsequent persistent cardiorespiratory depression. Moreover, blockade of peripheral ORs only slightly attenuates the initial response, while systemic antagonism of ORs fully abolishes all of cardiorespiratory responses. It is known that peripheral ORs in vagal afferents play a significant role in triggering the immediate cardiorespiratory responses to fentanyl, while ORs in the central nervous system (CNS) are essential for generating the opioid-induced respiratory depression. Thus, this study aimed to further define contributions of ORs in vagal afferents and the CNS to cardiorespiratory responses to CRF exposure. The rats were placed in a double-chamber plethysmograph and exposed to CRF aerosol at a concentration of 12.86 mg/m 3 for 15 min. Prior to the exposure, four groups of rats were respectively pretreated with intra-vagal microinjection of saline (IVG SAL ) and naloxone (IVG NLX ), and intrathecal injection of saline (IT SAL ) and NLX (IT NLX ). We found that CRF exposure caused death within 20 min after the onset of the exposure in 2 of 6 rats pretreated with IVG SAL . In the remaining 4 survived rats, CRF exposure triggered an immediate cardiorespiratory depression during the first 2 min exposure and decreased V E by 80% (mainly via reducing respiratory frequency by 75%) associated with 35% decrease in heart rate at the end of the 15-min exposure. The cardiorespiratory depression was generally maintained 45 min after the onset of the exposure with limited recovery, and disappeared on the next day. IVG NLX only significantly reduced the initial bradypnea without remarkable impact on the subsequent cardiorespiratory depression with death occurring in 3/6 rats. In contrast, IT NLX blocked the bradypnea and bradycardia and markedly blunted V E depression without death. Our results suggest that the initial bradypnea and bradycardia are mediated by ORs in both vagal afferents and the CNS, while the subsequent cardiorespiratory depression and failure are predominantly mediated by central ORs. 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.