Comparison of fentanyl-induced brain oxygen responses following intravenous and intraperitoneal injections in rats

This study used oxygen sensors coupled with amperometry to examine changes in brain (nucleus accumbens) and peripheral (subcutaneous space) oxygen levels following intravenous (IV) and intraperitoneal (IP) fentanyl injections at different doses. To avoid stress associated with traditional IP injection, fentanyl was delivered via chronically implanted IP catheter. SC oxygen levels decreased in a dose-dependent monophasic manner, whereas brain oxygen responses were more complex, showing modest increases at low fentanyl doses (<3 μg/kg for IV and <10 μg/kg for IP) and biphasic effects (decrease followed by increase) at higher doses (≥10 μg/kg for IV and ≥270 μg/kg for IP). IV-delivered fentanyl elicited faster and stronger responses, with over 10-fold greater potency to induce brain hypoxia compared to IP-fentanyl. Although oxygen response patterns were similar between catheter-based and traditional needle IP injection, the latter caused an ultra-fast brain oxygen increase coupled with rapid oxygen decrease in SC space, suggesting stress as a contributing factor. Interestingly, low-dose, stress-free IP fentanyl administration also induced phasic brain oxygen increases coupled with robust but transient behavioral activation, the effect appears to be independent of drug action on opioid receptors. This effect was attributed to the acidity of fentanyl citrate solution (pH 4.8) and direct actions of H+ on receptive sites on afferents of sensory nerves innervating the abdominal cavity. These findings reveal distinct fentanyl-induced oxygen dynamics based on administration route and highlight the influence of injection stress and drug formulation on oxygen and behavioral responses.