Partially countering the physiologic effects of fentanyl with naloxone or D-Cysteine ethyl ester (D-CYSee) 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 if the physiologic and behavioral effects of IV fentanyl in adult female goats (n=12) could be mitigated with NAL or the potential countermeasure D-cysteine ethyl ester (D-CYSee). As hypothesized, IV injections of high doses (HD) fentanyl caused immediate ventilatory suppression via reduced breathing frequency leading to hypoventilation and hypoxemia (≥ 10 minutes). HD fentanyl elicited immediate and sustained (≥ 90 minutes) increases in diaphragm, intercostal, abdominal, and laryngeal constrictor muscle activity along with an increased alveolar to arterial oxygen (A-a O, 2 ) gradient and hypertension. IV 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 minutes post-fentanyl. The data suggest there are physiologic effects of HD fentanyl that are NAL-insensitive and D-CYSee can transiently normalize blood gases and counter OIRD in adult goats.