Leveraging Molecular Pharmacological Principles for the Design of Novel Treatments for Drug Addiction and Mood Disorders

Abstract

The dynorphin/Kappa opioid receptor (KOR) system has been implicated in the regulation of stress, anxiety, depression, and substance use disorders. KOR antagonists have great potential as a therapeutic for these disorders, but the culmination of preclinical work over the last two decades has made for very little success in the clinic. The work here aims to identify and design a repeated dosing regimen to use with partial and G-biased KOR agonists. These agonists, specifically nalfurafine and nalmefene, activate the G-protein mediated JNK-ROS pathway that leads to long-term inactivation seen with norBNI and JDTic. Using a new tool, oROS-Gr, ROS generation was detected in ex vivo slice and in vivo fiber photometry with the treatment of these agonists. Repeated dosing caused significant KOR inactivation and blocked stress-induced aversion and aversion during opioid-withdrawal mediated by the dyn/KOR system. Low dosing combined withpreviously demonstrated high degree of safety profiles for nalfurafine and nalmefene make them promising new options for the treatment of substance use and mood disorders in humans.