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

Int J Neuropsychopharmacol. 2014 Oct 31;18(2):pyu036. doi: 10.1093/ijnp/pyu036.


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 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 50mg naltrexone, and LY2456302 dose-dependently blocked miosis at 25 and 60 mg (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.

Keywords: LY2456302; dynorphin; kappa opioid receptor; pupillometry; translational biomarker.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • Benzamides / blood
  • Benzamides / pharmacology*
  • Cross-Over Studies
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Fentanyl / pharmacology
  • Humans
  • Male
  • Middle Aged
  • Miosis / chemically induced
  • Miosis / drug therapy
  • Morphine / pharmacology
  • Mydriasis / chemically induced
  • Mydriasis / drug therapy
  • Naltrexone / pharmacology
  • Narcotic Antagonists / blood
  • Narcotic Antagonists / pharmacology*
  • Narcotics / pharmacology
  • Pupil / drug effects*
  • Pupil / physiology
  • Pyrrolidines / blood
  • Pyrrolidines / pharmacology*
  • Rats, Sprague-Dawley
  • Receptors, Opioid, kappa / agonists
  • Receptors, Opioid, kappa / antagonists & inhibitors*
  • Receptors, Opioid, kappa / metabolism
  • Young Adult


  • Benzamides
  • Narcotic Antagonists
  • Narcotics
  • Pyrrolidines
  • Receptors, Opioid, kappa
  • Naltrexone
  • Morphine
  • Aticaprant
  • Fentanyl