BACKGROUND New treatments for stress-related disorders including depression, anxiety, and substance use disorder are greatly needed. Kappa opioid receptors are expressed in the central nervous system, including areas implicated in analgesia and affective state. Although kappa opioid receptor agonists share the antinociceptive effects of mu opioid receptor agonists, they also tend to produce negative affective states. In contrast, selective kappa opioid receptor antagonists have antidepressant- and anxiolytic-like effects, stimulating interest in their therapeutic potential. The prototypical kappa opioid receptor antagonists (e.g., norBNI, JDTic) have an exceptionally long duration of action that complicates their use in humans, particularly in tests to establish safety. This study was designed to test dose- and time-course effects of novel kappa opioid receptor antagonists with the goal of identifying short-acting lead compounds for future medication development. METHODS We screened 2 novel, highly selective kappa opioid receptor antagonists (CYM-52220 and CYM-52288) with oral efficacy in the warm water tail flick assay in rats to determine initial dose and time course effects. For comparison, we tested existing kappa opioid receptor antagonists JDTic and LY-2456302 (also known as CERC-501 or JNJ-67953964). RESULTS In the tail flick assay, the rank order of duration of action for the antagonists was LY-2456302 < CYM-52288 < CYM-52220 << JDTic. Furthermore, LY-2456302 blocked the depressive (anhedonia-producing) effects of the kappa opioid receptor agonist U50,488 in the intracranial self-stimulation paradigm, albeit at a higher dose than that needed for analgesic blockade in the tail flick assay. CONCLUSIONS These results suggest that structurally diverse kappa opioid receptor antagonists can have short-acting effects and that LY-2456302 reduces anhedonia as measured in the intracranial self-stimulation test.

中文翻译：

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新型Kappa阿片受体拮抗剂在大鼠中的行为药理学。

背景技术非常需要用于与压力有关的疾病的新疗法，所述疾病包括抑郁症，焦虑症和药物滥用疾病。κ阿片受体在中枢神经系统中表达，包括与镇痛和情感状态有关的区域。尽管κ阿片受体激动剂具有μ阿片受体激动剂的镇痛作用，但它们也倾向于产生负面的情感状态。相反，选择性κ阿片受体拮抗剂具有抗抑郁和抗焦虑样作用，激发了对其治疗潜力的兴趣。原型κ阿片受体拮抗剂（例如norBNI，JDTic）具有异常长的作用时间，这使它们在人体中的使用复杂化，尤其是在建立安全性的测试中。这项研究旨在测试新型kappa阿片受体拮抗剂的剂量和时程效应，目的是确定用于未来药物开发的短效先导化合物。方法我们在大鼠温水甩尾试验中筛选了2种具有口服药效的新型高选择性κ阿片受体拮抗剂（CYM-52220和CYM-52288），以确定初始剂量和时程效应。为了进行比较，我们测试了现有的κ阿片受体拮抗剂JDTic和LY-2456302（也称为CERC-501或JNJ-67953964）。结果在甩尾试验中，拮抗剂的作用持续时间的等级顺序为LY-2456302 <CYM-52288 <CYM-52220 << JDTic。此外，LY-2456302阻断了κ阿片受体激动剂U50的抑制（产生性快感）颅内自我刺激范例中的488，尽管剂量比甩尾试验中止痛药所需的剂量高。结论这些结果表明，在颅内自我刺激试验中测得，结构多样的κ阿片受体拮抗剂可能具有短效作用，而LY-2456302可以降低快感。