Our previous study has shown that inhalation of fentanyl (100 mg/m3) for 10 min initially induces apnea, hypotension and bradycardia, leading to ventilatory and then cardiac arrest within 15 min in anesthetized rats (Zhuang J., et al, 2024). CRF acts on opioid mu-receptors (MORs) with a potency 100 times that of fentanyl. Inhalation of aerosolized CRF as a chemical weapon has been reported to cause sudden death in humans (Wax PM et al, 2003), but the cause of the death is not fully understood. Moreover, though the opioid-induced respiratory disorder is known to mainly result from the action of μ1Rs, the contribution of μ1Rs to the CRF-induced cardiorespiratory disorder remains unknown. Therefore, we asked whether acute inhalation of overdose CRF would induce cardiorespiratory disorder and sudden death via acting on μ1R in awake rats. The rats were exposed to aerosolized vehicle and CRF at 12.86 (low dose) or 20 mg/m3 (high dose) for 15 min with cardiorespiratory (VE, VT, fR, and HR) responses recorded for 60 min. The low and high doses of CRF induced sudden death in 1/6 and 2/2 rats respectively. Compared to aerosolized vehicle, the low dose of CRF initially decreased VE and HR by ~50% within 3 min exposure, which were maintained to the end of experiment, and all responses disappeared on the next day in the survived rats. Interestingly, the responses of breathing pattern to the CRF exposure were sequentially characterized by the rapid shallow breathing (within several seconds of the exposure), slow and deep breathing and then only slow breathing. In comparison, the dVE and bradycardia became much more aggravated after 15 min CRF aerosol-delivery in the dead rats than the survived ones, resulting in ventilatory and cardiac arrest within ~25 min post exposure. The cardiorespiratory responses to the low dose of CRF aerosol exposure were also performed after pretreatment with naloxone hydrochloride (NLX to systemically antagonize opioid receptors) or naloxonazine (NALZ to selectively antagonize μ1Rs). The CRF-induced dVE and bradycardia were fully blocked by NLX and largely alleviated by NALZ. In conclusion, our experiments not only establish a rat model of acute inhalation of CRF-induced cardiorespiratory disorder and sudden death, but also demonstrate a key role of opioid receptors, especially μ1Rs, in the CRF-induced cardiorespiratory disorder. Supported by NIH R01 grants HL163512 and DA059063. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.