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功能选择性无法预测阿片受体激动剂的抗伤害感受/运动功能损害效能。

Functional Selectivity Does Not Predict Antinociceptive/Locomotor Impairing Potencies of NOP Receptor Agonists.

作者信息

Azevedo Neto Joaquim, Ruzza Chiara, Sturaro Chiara, Malfacini Davide, Pacifico Salvatore, Zaveri Nurulain T, Calò Girolamo

机构信息

Section of Pharmacology, Department of Neuroscience and Rehabilitation, University of Ferrara, Ferrara, Italy.

Technopole of Ferrara, LTTA Laboratory for Advanced Therapies, Ferrara, Italy.

出版信息

Front Neurosci. 2021 Mar 30;15:657153. doi: 10.3389/fnins.2021.657153. eCollection 2021.

DOI:10.3389/fnins.2021.657153
PMID:33859548
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8042269/
Abstract

Nociceptin/orphanin FQ controls several functions, including pain transmission, via stimulation of the N/OFQ peptide (NOP) receptor. Here we tested the hypothesis that NOP biased agonism may be instrumental for identifying innovative analgesics. experiments were performed with the dynamic mass redistribution label free assay and the NOP non-peptide agonists Ro 65-6570, AT-403 and MCOPPB. studies were performed in wild type and β-arrestin 2 knockout mice using the formalin, rotarod and locomotor activity tests. all compounds mimicked the effects of N/OFQ behaving as potent NOP full agonists. Ro 65-6570 demonstrated a slightly higher therapeutic index (antinociceptive vs. motor impairment effects) in knockout mice. However, all NOP agonists displayed very similar therapeutic index in normal mice despite significant differences in G protein biased agonism. In conclusion the different ability of inducing G protein vs. β-arrestin 2 recruitment of a NOP agonist cannot be applied to predict its antinociceptive vs. motor impairment properties.

摘要

痛敏肽/孤啡肽FQ通过刺激痛敏肽/孤啡肽（N/OFQ）肽（NOP）受体来控制多种功能，包括疼痛传递。在此，我们测试了NOP偏向性激动作用可能有助于鉴定新型镇痛药的假说。使用动态质量再分布无标记分析以及NOP非肽激动剂Ro 65-6570、AT-403和MCOPPB进行实验。在野生型和β-抑制蛋白2基因敲除小鼠中使用福尔马林、转棒和运动活性测试进行研究。所有化合物均模拟N/OFQ的作用，表现为强效的NOP完全激动剂。Ro 65-6570在基因敲除小鼠中显示出略高的治疗指数（抗伤害感受与运动损伤效应）。然而，尽管在G蛋白偏向性激动作用方面存在显著差异，但所有NOP激动剂在正常小鼠中均表现出非常相似的治疗指数。总之，NOP激动剂诱导G蛋白与β-抑制蛋白2募集的不同能力无法用于预测其抗伤害感受与运动损伤特性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b592/8042269/9c6d68b6dda5/fnins-15-657153-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b592/8042269/31520fd3377d/fnins-15-657153-g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b592/8042269/280a2a058ce2/fnins-15-657153-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b592/8042269/d94608f86c6b/fnins-15-657153-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b592/8042269/39f626d341ad/fnins-15-657153-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b592/8042269/20edca077f00/fnins-15-657153-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b592/8042269/9c6d68b6dda5/fnins-15-657153-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b592/8042269/31520fd3377d/fnins-15-657153-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b592/8042269/6202cba7e625/fnins-15-657153-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b592/8042269/280a2a058ce2/fnins-15-657153-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b592/8042269/d94608f86c6b/fnins-15-657153-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b592/8042269/39f626d341ad/fnins-15-657153-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b592/8042269/20edca077f00/fnins-15-657153-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b592/8042269/9c6d68b6dda5/fnins-15-657153-g007.jpg

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Molecules. 2022 Jan 18;27(3):595. doi: 10.3390/molecules27030595.
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J Psychopharmacol. 2019 Dec;33(12):1540-1549. doi: 10.1177/0269881119864942. Epub 2019 Jul 24.
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