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

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 c...

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Autores principales:	Caroline Baynard, Thomas E. Prisinzano, Eduardo R. Butelman
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	open space swim kappa-opioid receptor stress acute stress disorder dynorphin Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/74195c65d3ad482d82f32479d63b6f1e
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spelling	oai:doaj.org-article:74195c65d3ad482d82f32479d63b6f1e2021-11-22T06:42:02ZRapid-Onset Anti-Stress Effects of a Kappa-Opioid Receptor Antagonist, LY2795050, Against Immobility in an Open Space Swim Paradigm in Male and Female Mice1663-981210.3389/fphar.2021.775317https://doaj.org/article/74195c65d3ad482d82f32479d63b6f1e2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fphar.2021.775317/fullhttps://doaj.org/toc/1663-9812The 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.Caroline BaynardThomas E. PrisinzanoEduardo R. ButelmanFrontiers Media S.A.articleopen space swimkappa-opioid receptorstressacute stress disorderdynorphinTherapeutics. PharmacologyRM1-950ENFrontiers in Pharmacology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	open space swim kappa-opioid receptor stress acute stress disorder dynorphin Therapeutics. Pharmacology RM1-950
spellingShingle	open space swim kappa-opioid receptor stress acute stress disorder dynorphin Therapeutics. Pharmacology RM1-950 Caroline Baynard Thomas E. Prisinzano Eduardo R. Butelman 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
description	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.
format	article
author	Caroline Baynard Thomas E. Prisinzano Eduardo R. Butelman
author_facet	Caroline Baynard Thomas E. Prisinzano Eduardo R. Butelman
author_sort	Caroline Baynard
title	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
title_short	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
title_full	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
title_fullStr	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
title_full_unstemmed	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
title_sort	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
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/74195c65d3ad482d82f32479d63b6f1e
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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

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