Repeated High-dose Fentanyl Administration in Rats Reveals Minimal Tolerance to Unconsciousness, Bradycardia, Muscle Rigidity, and Respiratory Depression.

Abstract

Background: Fentanyl is a synthetic opioid that is widely used in anesthesiology, but its illicit use is rapidly increasing. At high doses, fentanyl induces unconsciousness and muscle rigidity, the mechanisms of which are poorly understood. Since animal models are needed to study these effects, the aim of this study was to establish a rat model of fentanyl abuse and investigate the effects of repeated high-dose fentanyl injections on loss of righting reflex, heart rate, respiratory depression, muscle, and brain activity.

Methods: Male and female Sprague-Dawley rats were studied (n = 40). A bolus of 100 µg/kg fentanyl was administered intravenously twice a week for 5 consecutive weeks. Time to return of righting reflex after fentanyl injection and changes in electromyography/electroencephalography activity as well as heart rate were analyzed. Additionally, arterial blood gas analysis for evaluation of ventilation was performed. Mixed-effect models with Dunnett test and effect sizes were used for statistical analysis.

Results: Repeated injections resulted in a U-shaped change in time to return of righting reflex with the longest latency after the first exposure (median, 50 [first to third quartile, 36 to 56] min) and the shortest after the fifth exposure (16 [13 to 33] min). After fentanyl administration, heart rate dropped immediately by 225 beats/min (95% CI, 179 to 271; F = 3,952.16; P < 0.001), while electromyography activity increased by 291% (95% CI, 212 to 370; F = 27.51; P < 0.001) and partial pressure of arterial carbon dioxide increased by 49.4 mmHg (95% CI, 40.6 to 58.2; F = 75.97; P < 0.001) within 5 min after injection. Additionally, pH decreased by 0.48 (95% CI, 0.41 to 0.54; F = 142.00; P < 0.01), and partial pressure of arterial oxygen decreased by 50.4 mmHg (40.8 to 60.0; F = 57.90; P < 0.001). Repeated fentanyl exposures did not significantly affect the extent of these changes (EMG, F = 1.63, P = 0.237; partial pressure of arterial carbon dioxide, F = 1.23, P = 0.312; heart rate, F = 1.05, P = 0.400; pH, F = 3.05, P = 0.066; arterial partial pressure of oxygen, F = 3.35, P = 0.052). Electroencephalography analysis revealed that repeated fentanyl exposures elicited significantly higher absolute power in frequencies greater than 20 Hz as indicated by an area under the receiver operator characteristics curve greater than 0.7.

Conclusions: The authors established a rodent model of repeated high-dose fentanyl administration. Overall, significant evidence of tolerance was not observed after 10 exposures of high-dose fentanyl for any of the analyzed parameters. These results suggest that tolerance does not develop for fentanyl-induced unconsciousness, muscle rigidity, or respiratory depression.