Oxygen fluctuations in the brain and periphery induced by intravenous fentanyl: effects of dose and drug experience.

ABSTRACT

Fentanyl is the leading contributor to drug overdose deaths in the US. Its potency, rapid onset of action, and lack of effective reversal treatment make the drug more lethal than other opioids. Although it is understood that fentanyl is dangerous at higher doses, literature surrounding fentanyl's physiological effects remains contradictory at lower doses. To explore this discrepancy, we designed a study incorporating electrochemical assessment of oxygen in the brain (nucleus accumbens; NAc) and subcutaneous (SC) space, multi-site thermorecording (brain, skin, muscle), and locomotor activity at varying doses of fentanyl (1.0, 3.0, 10, 30, 90 µg/kg) in rats. In the NAc, lower doses of fentanyl (3.0, 10 µg/kg) led to an increase in oxygen levels while higher doses (30, 90 µg/kg) led to a biphasic pattern, with initial dose-dependent decrease followed by increase. In the SC space, oxygen decreases started to appear at relatively lower doses (>3 µg/kg), had shorter onset latencies, and were stronger and prolonged. In the temperature experiment, lower doses of fentanyl (1.0, 3.0, 10 µg/kg) led to an increase in brain, skin, and muscle temperatures, while higher doses (30 and 90 µg/kg) resulted in a dose-dependent biphasic temperature change, with an increase followed by a prolonged decrease. We also compared oxygen and temperature responses induced by fentanyl over six consecutive days and found no evidence of tolerance in both parameters. In conclusion, we report that fentanyl's effects are highly dose-dependent, drawing attention to the importance of better characterization to adequately respond in emergent cases of fentanyl misuse.