Novel chimeric peptides of endomorphin-2 and the active fragments of ghrelin exhibit blood-brain barrier permeability and central antinociceptive effects with reduced opioid-related side effects

IF 4.6 2区 医学 Q1 NEUROSCIENCES
Yongling Liu , Biao Xu , Songxia Cheng , Yan Wang , Jiali Ding , Xiaoyu Shen , Bing Wu , Liangquan Xu , Jie Wei
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引用次数: 0

Abstract

Pharmacological research has showed that multi-targeted drug therapies offer superior efficacy and reduced side effects compared to single-target drug therapies. In this study, we designed and characterized four novel chimeric peptides G (1–5)-EM2, EM2-G (1–5), G (1–9)-EM2 and EM2-G (1–9) which incorporate endomorphin-2 (EM-2) and the active fragments of ghrelin. Calcium mobilization assays revealed that these four chimeric peptides acted as weak mixed agonists for the μ-opioid receptor (MOR), κ-opioid receptor (KOR), and growth hormone secretagogue receptor 1α (GHS-R1α). The results of fluorescence imaging experiments indicated that G (1–5)-EM2 and G (1–9)-EM2 could penetrate the blood-brain barrier (BBB) following intravenous (i.v.) injection. All chimeric peptides induced almost equal antinociceptive effects compared with EM-2 or better antinociceptive effects than EM-2 after intracerebroventricular (i.c.v.) injection in the acute pain in mice. Among them, G (1–5)-EM2 could cross the BBB and enter the brain to induce antinociceptive effect through central opioid receptors after i. v. Injection. Our findings demonstrated that the chimeric peptides produced significant antinociception mainly via MOR, DOR and GHS-R1α without inducing antinociceptive tolerance, or with a lower tendency for antinociceptive tolerance after i. c.v. Injection in the acute pain in mice. Furthermore, the chimeric peptides mitigated or eliminated the digestive side effects associated with EM-2. The collective results highlight G (1–5)-EM2 as the most promising candidate among the chimeric peptides. The chimeric peptides represent a promising class of potential analgesics for clinical pain management. However, further optimization is necessary to maximize their therapeutic potential.
内啡肽-2和胃饥饿素活性片段的新型嵌合肽具有血脑屏障通透性和中枢抗痛觉作用,减少阿片类药物相关副作用。
药理研究表明,与单靶点药物治疗相比,多靶点药物治疗具有更好的疗效和更小的副作用。在这项研究中,我们设计并表征了四种新的嵌合肽G(1-5)-EM2、EM2-G(1-5)、G(1-9)-EM2和EM2-G(1-9),它们结合了内啡肽-2 (EM-2)和胃饥饿素的活性片段。钙动员实验表明,这4种嵌合肽对μ-阿片受体(MOR)、κ-阿片受体(KOR)和生长激素促分泌素受体1α (GHS-R1α)具有弱混合激动剂的作用。荧光成像实验结果表明,静脉注射后G(1-5)-EM2和G(1-9)-EM2能穿透血脑屏障(BBB)。所有嵌合肽在小鼠急性疼痛脑室注射后的抗痛觉作用与EM-2几乎相同或优于EM-2。其中G(1-5)-EM2经静脉注射后可穿过血脑屏障进入大脑,通过中枢阿片受体诱导抗伤害感受作用。我们的研究结果表明,嵌合肽主要通过MOR、DOR和GHS-R1α产生显著的抗痛觉性,但不诱导抗痛觉性耐受,或者在小鼠急性疼痛注射后抗痛觉性耐受倾向较低。此外,嵌合肽减轻或消除了与EM-2相关的消化副作用。综上所述,G(1-5)-EM2是这些嵌合肽中最有希望的候选。嵌合肽代表了一类有前途的潜在镇痛药的临床疼痛管理。然而,进一步优化是必要的,以最大限度地发挥其治疗潜力。
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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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