Papers of the Week

The synergistic antinociceptive effects of α-adrenergic agonists and intrathecal (i.t.) opioids were initially linked to pharmacodynamics. However, the α-agonist dexmedetomidine also enhances brain delivery of CSF-administered drugs by increasing glymphatic influx. Here, fadolmidine, a hydrophilic α-agonist designed for spinal analgesia, was studied for its sedative, antinociceptive, and pharmacokinetic effects with co-administered lumbar intrathecal morphine. Subcutaneous and i.t. dexmedetomidine served as comparators. Forty-eight male Sprague-Dawley rats received i.t. lumbar catheters. Sedative effects of i.t. fadolmidine (1-10 μg) and i.t. dexmedetomidine (1-10 μg) were assessed by open field and rotarod tests. The antinociceptive effects of morphine alone (1.5 μg i.t.) and co-administered with i.t. fadolmidine (3 and 10 μg) were evaluated using the tail-flick test. Effects of i.t. fadolmidine and subcutaneous dexmedetomidine (0.2 mg/kg) on morphine concentration within CNS were assessed by liquid chromatography-tandem mass spectrometry at 60 minutes. While i.t. dexmedetomidine was sedating, i.t fadolmidine was not. The antinociceptive effects of other treatment regimens weaned at latest after 90 minutes, whereas the combination of fadolmidine 10 μg i.t. and morphine 1.5 μg i.t. provided antinociception until the end of the measurement period (maximum possible effect of 77.5 ± 11.5 vs saline 10.6 ± 11.1, p = 0.0002 at 120 minutes). Subcutaneous dexmedetomidine effectively targeted lumbar morphine towards the injection site resulting in a 3335-fold (95% CI: 929-11978) lower brain-to-injection site ratio, versus a 355-fold (95% CI: 196-641) difference with saline. By improving spinal opioid targeting, α-adrenergic agonists dexmedetomidine and fadolmidine may reduce supraspinal side effects, enabling safe and efficacious intrathecal analgesia.