Abstract

Are delta Opioid Receptor Agonists with Facilitating Effects on Fear Extinction Learning Candidates for the Treatment of Post-Traumatic Stress Disorder

Several lines of evidence have suggested that Delta Opioid Receptor (DOP) system is involved in the mechanisms underlying the pathophysiology of fear and anxiety, as DOP is abundant in brain regions involved in emotion regulation systems. Recently, DOP agonists have attracted much attention as a promising new psychotropic agent for anxiety. Post-Traumatic Stress Disorder (PTSD) is a condition in which an individual who has experienced a traumatic event continues to have recurrent flashbacks of the event, resulting in increased fear and anxiety. In the pathophysiology of PTSD, persistence of traumatic fear memories and impairment of fear extinction have been implicated. Several studies have focused on pharmacological agents to facilitate fear extinction. However, because of difficulties in the regulation of fear memory to specifically induce extinction, no clinically usable treatments have been developed to date. We recently found that a novel selective DOP agonist KNT-127 produced robust anxiolytic-like effects, and demonstrated facilitating effects on fear extinction learning in fear conditioning test of mice, a widely accepted model of PTSD that is frequently used to examine fear memory not only in rodents but also in humans. Interestingly, another DOP agonist SNC80 did not cause any facilitating effects, although anxiolytic-like effects were observed. Previous studies have shown that SNC80 effectively induces the recruitment of β-arrestin, whereas KNT-127 is an intermediate its recruiters, although the inhibitory effects on the forskolin-induced cAMP production in HEK293 cells expressing DOP showed similar effects on both these drugs. Although DOP agonists have a common robust anxiolytic-like effect, the mechanism of extinction-facilitating effect of DOP agonists is a different from the anxiolytic-like effect. The mechanism may involve the β-arrestin independent properties of DOP agonists. We propose that biased DOP agonists are expected to be an excellent candidate compound as therapeutic targets for PTSD.