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- Title
Determining Pharmacological Selectivity of the Kappa Opioid Receptor Antagonist LY2456302 Using Pupillometry as a Translational Biomarker in Rat and Human.
- Authors
Rorick-Kehn, Linda M.; Witcher, Jennifer W.; Lowe, Stephen L.; Gonzales, Celedon R.; Weller, Mary Ann; Bell, Robert L.; Hart, John C.; Need, Anne B.; McKinzie, Jamie H.; Statnick, Michael A.; Suico, Jeffrey G.; McKinzie, David L.; Tauscher-Wisniewski, Sitra; Mitch, Charles H.; Stoltz, Randall R.; Wong, Conrad J.
- Abstract
Background: Selective kappa opioid receptor antagonism is a promising experimental strategy for the treatment of depression. The kappa opioid receptor antagonist, LY2456302, exhibits ~30-fold higher affinity for kappa opioid receptors over mu opioid receptors, which is the next closest identified pharmacology. Methods: Here, we determined kappa opioid receptor pharmacological selectivity of LY2456302 by assessing mu opioid receptor antagonism using translational pupillometry in rats and humans. Results: In rats, morphine-induced mydriasis was completely blocked by the nonselective opioid receptor antagonist naloxone (3mg/kg, which produced 90% mu opioid receptor occupancy), while 100 and 300mg/kg LY2456302 (which produced 56% and 87% mu opioid receptor occupancy, respectively) only partially blocked morphine-induced mydriasis. In humans, fentanyl-induced miosis was completely blocked by 50mg naltrexone, and LY2456302 dose-dependently blocked miosis at 25 and 60mg (minimal-to-no blockade at 4–10mg). Conclusions: 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 kappa opioid receptor occupancy without evidence of significant mu receptor antagonism.
- Subjects
OPIOID receptors; BIOMARKERS; PUPILLOMETRY; EXPERIMENTAL pharmacology; MENTAL depression; LABORATORY rats
- Publication
International Journal of Neuropsychopharmacology, 2015, Vol 18, Issue 2, p1
- ISSN
1461-1457
- Publication type
Article
- DOI
10.1093/ijnp/pyu036