Baynard Caroline, Prisinzano Thomas E, Butelman Eduardo R
Laboratory on the Biology of Addictive Diseases, The Rockefeller University, New York, NY, United States.
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, United States.
Front Pharmacol. 2021 Nov 22;12:775317. doi: 10.3389/fphar.2021.775317. eCollection 2021.
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), . 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.
在转化动物模型中，κ-阿片受体（KOR）/强啡肽系统与应激暴露（包括大量滥用药物）的行为和神经生物学效应有关。因此，一些KOR拮抗剂可以减轻应激暴露引起的厌恶、抑郁样和焦虑样效应。第一代选择性KOR拮抗剂起效缓慢（数小时），作用持续时间极长（数天至数周）。新一代起效迅速、作用持续时间较短的KOR拮抗剂可能会减轻转化模型中应激暴露的影响，并且可能对药物开发具有重要意义。本研究在成年雄性和雌性C57BL/6 J小鼠的单次开放空间游泳（OSS）应激范式（持续15分钟）中，检测了一种作用时间较短的新型KOR拮抗剂（LY2795050，即3-氯-4-（4-（（（2S）-2-吡啶-3-基吡咯烷-1-基）甲基）苯氧基）苯甲酰胺）的快速起效抗应激作用。基于其对KOR激动剂U50,488（10 mg/kg）运动抑制作用的阻断，LY2795050（0.32 mg/kg，腹腔注射）具有快速起效（15分钟内）和短持续时间（<3小时）的KOR拮抗作用。LY2795050（0.32 mg/kg）在OSS应激范式前仅1分钟给药时，可减少雄性小鼠的不动时间，但对雌性小鼠无效。预处理时间稍长（15分钟）时，该剂量的LY‘2795050可减少雄性和雌性小鼠的不动时间。剂量小10倍的LY2795050（0.032 mg/kg）在OSS中无活性，表明这种抗应激作用具有剂量依赖性。总体而言，这些研究表明，一种新型KOR拮抗剂在这种急性应激暴露模型中可产生非常快速起效的抗不动作用。
