The role of central versus peripheral opioid receptors in fentanyl-induced brain hypoxia.

Naloxone is the prototypical opioid receptor antagonist, whereas naloxone-methiodide, a quaternary naloxone analog, is widely used as a peripherally restricted antagonist based on the assumption that it does not cross the blood-brain barrier. This assumption has been central to arguments that peripheral opioid receptors contribute to fentanyl-induced respiratory depression. However, mass spectrometry studies show that although naloxone-methiodide has very limited permeability, it is detectable in brain tissue at an ∼1:50 concentration ratio compared with naloxone. Even such small amounts may be sufficient to act on brain receptors, raising the possibility of central involvement. To test this hypothesis, we used oxygen sensors coupled with amperometry in freely moving rats to examine the roles of central versus peripheral opioid receptors in fentanyl-induced brain hypoxia. We compared naloxone with naloxone-methiodide on oxygen responses in the brain and subcutaneous space following intravenous fentanyl administration (30 µg/kg). Naloxone-methiodide at a dose of 2.0 mg/kg (but not 0.2 mg/kg) blocked fentanyl-induced hypoxia. Naloxone-methiodide's effect was weaker and shorter than that produced by 0.2 mg/kg naloxone. In addition, naloxone at doses 50- and 250-times lower (0.04 and 0.008 mg/kg), but not 1,000-times lower (0.002 mg/kg), also blocked fentanyl-induced hypoxia, mimicking the effect of 2.0 mg/kg naloxone-methiodide. These findings suggest that naloxone-methiodide is not a strictly peripheral antagonist. At moderate to high doses, naloxone-methiodide's ability to reverse fentanyl-induced hypoxia may be partially mediated by the drug's action on central opioid receptors.NEW & NOTEWORTHY It is widely believed that opioids cause brain hypoxia through direct central nervous system action. This was challenged using naloxone-methiodide, which is believed to not cross the blood-brain barrier. However, mass-spectrometry data show limited brain entry, sufficient to block fentanyl-induced hypoxia. Our data reveal that naloxone is effective at 40 and 8 μg/kg doses, whereas naloxone-methiodide is not selective for peripheral opioid receptors. Its effects at higher doses arise mainly from central opioid receptor blockade.