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首页> 美国卫生研究院文献>The Journal of Pharmacology and Experimental Therapeutics >Discriminative Stimulus and Low Abuse Liability Effects of Novel Endomorphin Analogs Suggest a Potential Treatment Indication for Opioid Use Disorder
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Discriminative Stimulus and Low Abuse Liability Effects of Novel Endomorphin Analogs Suggest a Potential Treatment Indication for Opioid Use Disorder

机译：新型内啡肽类似物的歧视性刺激和低滥用责任效应提示阿片类药物使用障碍的潜在治疗适应症

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Opioid dependence can be difficult to manage using existing pharmacotherapies. A long-acting opioid with low abuse liability that substitutes for a shorter-acting opioid may improve treatment of opioid use disorders (OUDs). We recently characterized an endomorphin (EM) analog (ZH853) that produced a longer duration of antinociception compared with morphine, but did not produce self-administration or several other adverse effects preclinically. Here, we further characterized ZH853 in tests of antinociception, abuse liability, and drug discrimination. A conditioned place preference (CPP) procedure, that included a locomotor activity assessment, was used to test abuse liability in rats. Subsequently, dopamine (DA) cell-somas located in the ventral tegmental area (VTA) from these rats were assessed by size using immunohistochemistry and Stereo Investigator software. A hot-plate antinociception test in male and female mice confirmed central penetration. Morphine-substitution effects of several EM analogs (ZH850, ZH831, and ZH853) were tested in a drug discrimination (DD) procedure in rats. Morphine produced dose-dependent CPP and locomotor sensitization and reduced the size of DA cell somas in VTA, whereas ZH853 did not produce any of these effects relative to control. The antinociceptive effects of ZH853 were μ-receptor selective since β-funaltrexamine antagonized these effects. Rats responded on a morphine-trained lever when injected with ZH831 and ZH853 during DD experiments. The favorable morphine-substitution effects of these EM analogs relative to their low abuse liability indicate promising novel compounds that may improve treatment of OUD.SIGNIFICANCE STATEMENTIn this experiment, we investigated the preclinical effects of novel endomorphin analogs for use as substitution therapies for opioid use disorder, a problem that has contributed to an opioid overdose epidemic. Several endomorphin analogs substituted for morphine without producing adverse effects, including reward behaviors associated with abuse liability. These compounds have the potential to become important additional tools to treat opioid use disorders.
机译：使用现有的药物治疗可能难以控制阿片类药物的依赖性。具有低滥用责任的长效阿片类药物替代短效阿片类药物可能会改善阿片类药物使用障碍（OUD）的治疗。我们最近对内啡肽（EM）类似物（ZH853）进行了表征，与吗啡相比，其产生更长的镇痛作用，但在临床前并未产生自我给药或其他一些不良反应。在这里，我们进一步在抗伤害感受，滥用责任和药物歧视测试中对ZH853进行了表征。使用条件运动场所偏爱（CPP）程序（包括运动活动评估）来测试大鼠的滥用倾向。随后，使用免疫组织化学和Stereo Investigator软件通过大小评估来自这些大鼠腹侧被盖区（VTA）的多巴胺（DA）细胞体。在雄性和雌性小鼠中进行的热板抗伤害感受试验证实了中枢渗透。在大鼠中通过药物歧视（DD）程序测试了几种EM类似物（ZH850，ZH831和ZH853）的吗啡替代作用。吗啡在VTA中产生剂量依赖性CPP和运动致敏作用，并减少DA细胞体的大小，而ZH853相对于对照没有产生任何这些作用。 ZH853的抗伤害感受作用是μ受体选择性的，因为β-富氨曲明拮抗了这些作用。在DD实验中，当注射ZH831和ZH853时，大鼠对吗啡训练的杠杆有反应。这些EM类似物相对于其低滥用倾向的有利吗啡替代作用表明有希望的新型化合物，可以改善OUD的治疗。意义声明在本实验中，我们研究了新型内啡肽类似物作为阿片类药物使用障碍替代疗法的临床前作用。 ，该问题导致了阿片类药物过量的流行。几种内啡肽类似物可替代吗啡而不会产生不良影响，包括与滥用责任相关的奖励行为。这些化合物有可能成为治疗阿片类药物使用失调的重要辅助工具。

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