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κ阿片受体激动剂介导减轻小鼠化疗诱导的神经性疼痛中的性别差异

Sex Differences in Kappa Opioid Receptor Agonist Mediated Attenuation of Chemotherapy-Induced Neuropathic Pain in Mice.

作者信息

Paton Kelly F, Luo Dan, La Flamme Anne C, Prisinzano Thomas E, Kivell Bronwyn M

机构信息

School of Biological Sciences, Centre for Biodiscovery, Victoria University of Wellington, Wellington, New Zealand.

Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY, United States.

出版信息

Front Pharmacol. 2022 Feb 18;13:813562. doi: 10.3389/fphar.2022.813562. eCollection 2022.

DOI:10.3389/fphar.2022.813562
PMID:35250563
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8894863/
Abstract

Chemotherapy-induced neuropathic pain is a common side effect for cancer patients which has limited effective treatment options. Kappa opioid receptor (KOR) agonists are a promising alternative to currently available opioid drugs due to their low abuse potential. In the current study, we have investigated the effects of Salvinorin A (SalA) analogues, 16-Ethynyl SalA, 16-Bromo SalA and ethyoxymethyl ether (EOM) SalB, and in a preclinical model of paclitaxel-induced neuropathic pain in male and female C57BL/6J mice. Using an acute dose-response procedure, we showed that compared to morphine, 16-Ethynyl SalA was more potent at reducing mechanical allodynia; and SalA, 16-Ethynyl SalA, and EOM SalB were more potent at reducing cold allodynia. In the mechanical allodynia testing, U50,488 was more potent in males and SalA was more potent in females. There were no sex differences in the acute cold allodynia testing. In the chronic administration model, treatment with U50,488 (10 mg/kg) reduced the mechanical and cold allodynia responses to healthy levels over 23 days of treatment. Overall, we have shown that KOR agonists are effective in a model of chemotherapy-induced neuropathic pain, indicating that KOR agonists could be further developed to treat this debilitating condition.

摘要

化疗诱导的神经性疼痛是癌症患者常见的副作用，目前有效的治疗选择有限。κ阿片受体（KOR）激动剂因其低滥用潜力，是现有阿片类药物有前景的替代品。在本研究中，我们在雄性和雌性C57BL/6J小鼠紫杉醇诱导的神经性疼痛的临床前模型中，研究了Salvinorin A（SalA）类似物、16-乙炔基SalA、16-溴代SalA和乙氧基甲基醚（EOM）SalB的作用。使用急性剂量反应程序，我们发现与吗啡相比，16-乙炔基SalA在减轻机械性异常性疼痛方面更有效；SalA、16-乙炔基SalA和EOM SalB在减轻冷异常性疼痛方面更有效。在机械性异常性疼痛测试中，U50,488对雄性更有效，而SalA对雌性更有效。在急性冷异常性疼痛测试中没有性别差异。在慢性给药模型中，用U50,488（10 mg/kg）治疗在23天的治疗过程中将机械性和冷异常性疼痛反应降低到健康水平。总体而言，我们已经表明KOR激动剂在化疗诱导的神经性疼痛模型中是有效的，这表明KOR激动剂可以进一步开发用于治疗这种使人衰弱的疾病。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f619/8894863/35be568b2303/fphar-13-813562-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f619/8894863/d40599b17a3d/fphar-13-813562-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f619/8894863/621a54ef26e1/fphar-13-813562-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f619/8894863/1f412813a493/fphar-13-813562-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f619/8894863/35be568b2303/fphar-13-813562-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f619/8894863/d40599b17a3d/fphar-13-813562-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f619/8894863/621a54ef26e1/fphar-13-813562-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f619/8894863/1f412813a493/fphar-13-813562-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f619/8894863/35be568b2303/fphar-13-813562-g004.jpg

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