Physiological effects of fentanyl in goats: acute withdrawal and known and novel reversal agents

Abstract

Synthetic opioids alter several vital physiological functions and discontinuation of its use can cause acute withdrawal symptoms. In this and three adjoining posters we present data on the dose-dependent physiologic and behavioral effects of intravenous (IV) fentanyl in adult awake goats. Here, we tested two hypotheses: 1) that fentanyl will lead to acute, dose-dependent withdrawal symptoms, and 2) that co-administration of a known reversal agent (naloxone (NAL)) or novel respiratory stimulant (D-cysteine ethyl ester; D-CYSee) can mitigate the acute physiological and behavioral effects of fentanyl. Acute withdrawal was measured for 4 hrs. beginning 90 min post-injection of IV vehicle or fentanyl (n=5-7) using a wearable activity tracking device (Biopac) and subjective videographic observations. Animal movement (Vector Magnitude; g) was lowest with vehicle across all time points but was increased (p<0.05) in a dose-dependent manner from 90-210 min after fentanyl administration. Additional behaviors such as pawing, vocalization, hyperphagia, itching and rearing also appeared dose-dependent and were increased from 90-210 min post-injection but waned across the 4h observation period (n=4). Based on the demonstrated efficacy of D-CYSee in reversing OIRD in rats (Getsy et al., 2022), we next tested if fentanyl-induced physiological dysfunction or withdrawal symptoms were mitigated by co-administration of either D-CYSee (500 μmol/kg) or NAL (0.06 mg/kg). Transient suppression of minute ventilation (V I ) and breathing frequency was followed by a secondary increase >10 min after 50 μg/kg fentanyl, where co-administration of D-CYSee stimulated V I and NAL prevented the secondary increase in V I (n=5-6). Fentanyl alone moderately decreased HR where D-CYSee prevented this effect, whereas NAL exacerbated the fentanyl-induced bradycardia for up to 45 min. Mean, systolic and diastolic blood pressures were increased with fentanyl for >90 min post-injection, where D-CYSee had no additional effect but NAL prevented the hypertension. Finally, NAL but not D-CYSee reversed sedation (n=7), but neither NAL or D-CYSee appeared to mitigate withdrawal behaviors. These preliminary data suggest that: 1) fentanyl causes withdrawal behaviors in goats, and 2) NAL and D-CYSee have differential effects on fentanyl-induced physiological dysfunction suggesting D-CYSee has a distinctly different mechanism of action as a potential OIRD countermeasure. Supported by NIH DA050571. This is the full abstract presented at the American Physiology Summit 2023 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.