Conorphin-66 produces peripherally restricted antinociception via the kappa-opioid receptor with limited side effects

IF 4.6 2区 医学 Q1 NEUROSCIENCES Neuropharmacology Pub Date : 2024-09-12 DOI:10.1016/j.neuropharm.2024.110157
Kangtai Xu , Mengna Zhang , Dan Chen, Biao Xu, Xuanran Hu, Qinqin Zhang, Run Zhang, Nan Zhang, Ning Li, Quan Fang
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Abstract

With the current unmet demand for effective pain relief, analgesics without major central adverse effects are highly appealing, such as peripherally restricted kappa-opioid receptor (KOR) agonists. In this study, Conorphin-66, an analog of the selective KOR peptide agonist Conorphin T, was pharmacologically characterized in a series of experiments, with CR845 serving as the reference compound. Firstly, in vitro functional assay indicated that Conorphin-66 selectively activates KOR and exhibits weak β-arrestin2 signaling bias (−1.54 versus −4.35 for CR845). Additionally, subcutaneous Conorphin-66 produced potent antinociception in mouse pain models with ED50 values ranged from 0.02 to 3.28 μmol/kg, including tail-flick test, post-operative pain, formalin pain, and acetic acid-induced visceral pain. Similarly, CR845 exert potent antinociception in mouse pain models ranged from 0.15 to 1.47 μmol/kg. Notably, antagonism studies revealed that the analgesic effects of Conorphin-66 were mainly mediated by the peripheral KOR. Furthermore, Conorphin-66 produced non-tolerance-forming antinociception over 8 days. Unlike CR845, subcutaneous Conorphin-66 did not promote the sedation, anxiogenic effects, depressive-like effects, but did exhibit diuretic activity. Further study showed that Conorphin-66 does not have apparent antipruritic effects in an acute itch model. Overall, Conorphin-66 emerges as a novel peripherally restricted KOR agonist that produced potent antinociception with reduced side effects.

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康诺啡-66 通过卡帕-阿片受体产生外周限制性抗痛作用,副作用有限
目前,人们对有效缓解疼痛的需求尚未得到满足,因此,无严重中枢不良反应的镇痛药(如外周限制性卡巴阿片受体(KOR)激动剂)极具吸引力。本研究以 CR845 为参照化合物,通过一系列实验对选择性 KOR 肽激动剂 Conorphin T 的类似物 Conorphin-66 进行了药理学表征。首先,体外功能测试表明,Conorphin-66 可选择性地激活 KOR,并表现出微弱的 β-arrestin2 信号传导偏倚(-1.54,而 CR845 为-4.35)。此外,皮下注射 Conorphin-66 还能在小鼠疼痛模型中产生强效抗痛作用,ED50 值介于 0.02 至 3.28 μmol/kg 之间,包括尾搔试验、术后疼痛、福尔马林疼痛和醋酸诱导的内脏疼痛。同样,CR845 在小鼠疼痛模型中也发挥了 0.15 至 1.47 μmol/kg 的强效抗痛作用。值得注意的是,拮抗研究显示,Conorphin-66 的镇痛作用主要由外周 KOR 介导。此外,Conorphin-66 还能在 8 天内产生非耐受性抗痛作用。与CR845不同,皮下注射的Conorphin-66不会产生镇静、焦虑效应和抑郁样效应,但具有利尿活性。进一步的研究表明,在急性瘙痒模型中,Conorphin-66 没有明显的止痒作用。总之,Conorphin-66 是一种新型的外周限制性 KOR 激动剂,可产生强效的抗痛觉作用,且副作用较小。
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来源期刊
Neuropharmacology
Neuropharmacology 医学-神经科学
CiteScore
10.00
自引率
4.30%
发文量
288
审稿时长
45 days
期刊介绍: Neuropharmacology publishes high quality, original research and review articles within the discipline of neuroscience, especially articles with a neuropharmacological component. However, papers within any area of neuroscience will be considered. The journal does not usually accept clinical research, although preclinical neuropharmacological studies in humans may be considered. The journal only considers submissions in which the chemical structures and compositions of experimental agents are readily available in the literature or disclosed by the authors in the submitted manuscript. Only in exceptional circumstances will natural products be considered, and then only if the preparation is well defined by scientific means. Neuropharmacology publishes articles of any length (original research and reviews).
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