Partially countering the physiological effects of fentanyl with naloxone or d-cysteine ethyl ester in adult goats.

Fentanyl is the leading contributor to opioid-involved overdose (OD) mortality in the United States. Despite the demonstrated efficacy, safety, and wide availability of naloxone (NAL), opioid-involved OD fatalities remain high. This suggests our understanding of the negative integrated physiological effects of fentanyl remains incomplete, and highlights the need to develop additional novel countermeasures. Here we tested whether the physiological and behavioral effects of intravenous fentanyl in adult female goats (n = 12) could be mitigated with NAL or the potential countermeasure d-cysteine ethyl ester (d-CYSee). As hypothesized, intravenous injections of high doses (HD) fentanyl caused immediate ventilatory suppression via reduced breathing frequency leading to hypoventilation and hypoxemia (≥10 min). HD fentanyl elicited immediate and sustained (≥90 min) increases in diaphragm, intercostal, abdominal, and laryngeal constrictor muscle activity along with an increased alveolar to arterial oxygen (A-a O2) gradient and hypertension. Intravenous NAL administered immediately following HD fentanyl mitigated most of these effects except the increased activation of respiratory pump and airway muscles. In contrast, d-CYSee administration immediately following HD fentanyl countered the initial hypoventilation but did not mitigate the increases in muscle activation and persistent hypoxemia. Neither treatment prevented acute withdrawal-like behaviors emerging >90 min after fentanyl administration. The data suggest that there are physiological effects of HD fentanyl that are NAL-insensitive, and d-CYSee can transiently normalize blood gases and counter opioid-induced respiratory depression (OIRD) in adult goats.NEW & NOTEWORTHY Here we determined whether any of the deleterious physiological effects of high-dose fentanyl could be countered by naloxone and/or d-cysteine ethyl ester (d-CYSee) in adult goats. Fentanyl induced hypoventilation and sustained increases in respiratory and airway muscle activity and hypoxemia. Naloxone reversed all fentanyl effects except tonic muscle activation, and d-CYSee reversed fentanyl-induced hypoventilation. These data suggest some effects of fentanyl are naloxone-insensitive and that d-CYSee may be a valuable countermeasure for OIRD.