Rapid-Onset Anti-Stress Effects of a Kappa-Opioid Receptor Antagonist, LY2795050, Against Immobility in an Open Space Swim Paradigm in Male and Female Mice.

Caroline Baynard,Eduardo R Butelman,Thomas E Prisinzano

doi:10.3389/fphar.2021.775317

Caroline Baynard, Eduardo R Butelman + Show 1 more

Open Access

https://doi.org/10.3389/fphar.2021.775317

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Abstract

The kappa-opioid receptor (KOR) / dynorphin system is implicated with behavioral and neurobiological effects of stress exposure (including heavy exposure to drugs of abuse) in translational animal models. Thus some KOR-antagonists can decrease the aversive, depressant-like and anxiety-like effects caused by stress exposure. The first generation of selective KOR-antagonists have slow onsets (hours) and extremely long durations of action (days-weeks), in vivo. A new generation of KOR antagonists with rapid onset and shorter duration of action can potentially decrease the effects of stress exposure in translational models, and may be of interest for medication development. This study examined the rapid onset anti-stress effects of one of the shorter acting novel KOR-antagonists (LY2795050, (3-chloro-4-(4-(((2S)-2-pyridin-3-ylpyrrolidin-1-yl)methyl) phenoxy)benzamide)) in a single-session open space swim (OSS) stress paradigm (15 min duration), in adult male and female C57BL/6 J mice. LY2795050 (0.32 mg/kg, i.p.) had rapid onset (within 15 min) and short duration (<3 h) of KOR-antagonist effects, based on its blockade of the locomotor depressant effects of the KOR-agonist U50,488 (10 mg/kg). LY2795050 (0.32 mg/kg), when administered only 1 min prior to the OSS stress paradigm, decreased immobility in males, but not females. With a slightly longer pretreatment time (15 min), this dose of LY2795050 decreased immobility in both males and females. A 10-fold smaller dose of LY2795050 (0.032 mg/kg) was inactive in the OSS, showing dose-dependence of this anti-stress effect. Overall, these studies show that a novel KOR-antagonist can produce very rapid onset anti-immobility effects in this model of acute stress exposure.

Highlights

Acute stress exposure can cause behavioral and neurobiological changes (Reed et al, 2012; Carter et al, 2020; Varlinskaya et al, 2020; Becker et al, 2021), and can result in psychiatric sequeleae in humans, including acute stress disorder
We recently reported that one of the shorter acting KORantagonists, LY2795050, produced anti-immobility effects in the forced swim test (FST) in male, but not female, mice (Butelman et al, 2021)
This study shows that the short-acting kappa-opioid receptor (KOR)-antagonist LY2795050 can produce very rapid-onset anti-immobility effects in a model of acute stress exposure

Summary

Introduction

Acute stress exposure can cause behavioral and neurobiological changes (Reed et al, 2012; Carter et al, 2020; Varlinskaya et al, 2020; Becker et al, 2021), and can result in psychiatric sequeleae in humans, including acute stress disorder. Several studies have shown that the earliest known selective KOR-antagonists, including norbinaltorphimine (nor-BNI), decreased immobility in the standard forced swim test (FST), as well as other behavioral consequences of stress exposure (Portoghese et al, 1987; Zhang et al, 2007; Carroll and Carlezon, 2013; Falcon et al, 2014) Some of these early selective KOR-antagonists, such as nor-BNI, have slow onsets of action (e.g., several hours), and extremely long-lasting profiles in vivo (days-weeks, depending on the assay) (Horan et al, 1992; Broadbear et al, 1994; Butelman et al, 1998; Carroll and Carlezon, 2013). The antagonist potency of LY2795050 in vitro (Kb) at KOR, MOR and DOR is 0.63, 6.8 and 83.3 nM respectively (Zheng et al, 2013)

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