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.

By Linda M. Rorick-Kehn, PhD, Jennifer W. Witcher, PhD, Stephen L. Lowe, PhD, Celedon R. Gonzales, MS, Mary Ann Weller, PhD, Robert L. Bell, MS, John C. Hart, HSD, Anne B. Need, PhD, Jamie H. McKinzie, MS, Michael A. Statnick, PhD, Jeffrey G. Suico, MD, David L. McKinzie, PhD, Sitra Tauscher-Wisniewski, MD, Charles H. Mitch, PhD, Randall R. Stoltz, MD and Conrad J. Wong, PhD