Determining Pharmacological Selectivity of the Kappa Opioid Receptor Antagonist LY2456302 Using Pupillometry as a Translational Biomarker in Rat and Human

Selective kappa opioid receptor antagonism is a promising experimental strategy for the treatment of depression. The kappaopioid receptor (KOR) antagonist, LY2456302, exhibits ~30-fold higher affinity for KOR over mu opioid receptors (MOR), which is the next closest identified pharmacology. Here, we determined KOR pharmacological selectivity of LY2456302 by assessing MOR antagonism using translational pupillometry in rats and humans. In rats, morphine-induced mydriasis was completely blocked by the nonselective opioid receptor antagonist naloxone (3 mg/kg, which produced 90% MOR occupancy), while 100 and 300 mg/kg LY2456302 (which produced 56% and 87% MOR occupancy, respectively) only partially blocked morphine-induced mydriasis. In humans, fentanyl-induced miosis was completely blocked by 50 mg naltrexone, while LY2456302 dose-dependently blocked miosis at 25 and 60 mg (minimal-to-no blockade at 4-10 mg). We demonstrate, for the first time, the use of translational pupillometry in the context of receptor occupancy to identify a clinical dose of LY2456302 achieving maximal KOR occupancy without evidence of significant mu receptor antagonism.