Determining pharmacological selectivity of the kappa opioid receptor antagonist LY2456302 using pupillometry as a translational biomarker in rat and human

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

Research output: Contribution to journalArticlepeer-review

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 (3 mg/kg, which produced 90% mu opioid receptor occupancy), while 100 and 300 mg/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 50 mg naltrexone, and LY2456302 dose-dependently blocked miosis at 25 and 60 mg (minimal-to-no blockade at 4-10 mg). 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.

Original languageEnglish (US)
Pages (from-to)1-11
Number of pages11
JournalInternational Journal of Neuropsychopharmacology
Volume18
Issue number2
DOIs
StatePublished - Jan 1 2015

Keywords

  • Dynorphin
  • Kappa opioid receptor
  • LY2456302
  • Pupillometry
  • Translational biomarker

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health
  • Pharmacology (medical)

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