Farkas Sándor, Bölcskei Kata, Markovics Adrienn, Varga Anita, Kis-Varga Ágnes, Kormos Viktória, Gaszner Balázs, Horváth Csilla, Tuka Bernadett, Tajti János, Helyes Zsuzsanna
Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pécs, Szigeti u. 12, H-7624 Pécs, Hungary; Research Division, Gedeon Richter Plc., H-1103 Budapest, Gyömrői út 19-21, Hungary.
Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pécs, Szigeti u. 12, H-7624 Pécs, Hungary; János Szentágothai Research Centre, University of Pécs, Ifjúság út 20, H-7624 Pécs, Hungary.
J Pharmacol Toxicol Methods. 2016 Jan-Feb;77:33-44. doi: 10.1016/j.vascn.2015.09.006. Epub 2015 Oct 9.
Majority of the work for establishing nitroglycerin (NTG)-induced migraine models in animals was done in rats, though recently some studies in mice were also reported. Different special formulations of NTG were investigated in various studies; however, NTG treated groups were often compared to simple saline treated control groups. The aim of the present studies was to critically assess the utility of a panel of potential outcome measures in mice by revisiting previous findings and investigating endpoints that have not been tested in mice yet.
We investigated two NTG formulations, Nitrolingual and Nitro Pohl, at an intraperitoneal dose of 10mg/kg, in comparison with relevant vehicle controls, and evaluated the following outcome measures: light aversive behaviour, cranial blood perfusion by laser Doppler imaging, number of c-Fos- and neuronal nitrogen monoxide synthase (nNOS)-immunoreactive neurons in the trigeminal nucleus caudalis (TNC) and trigeminal ganglia, thermal hyperalgesia and tactile allodynia of the hind paw and orofacial pain hypersensitivity.
We could not confirm previous reports of significant NTG-induced changes in light aversion and cranial blood perfusion of mice but we observed considerable effects elicited by the vehicle of Nitrolingual. In contrast, the vehicle of Nitro Pohl was apparently inert. Increased c-Fos expression in the TNC, thermal hyperalgesia, tactile allodynia and orofacial hypersensitivity were apparently good endpoints in mice that were increased by NTG-administration. The NTG-induced increase in c-Fos expression was prevented by topiramate but not by sumatriptan treatment. However, the NTG-induced orofacial hypersensitivity was dose dependently attenuated by sumatriptan.
Our results pointed to utilisable NTG formulations and outcome measures for NTG-induced migraine models in mice. Pending further cross-validation with positive and negative control drugs in these mouse models and in the human NTG models of migraine, these tests might be valuable translational research tools for development of new anti-migraine drugs.
虽然最近也有一些关于小鼠的研究报道，但在动物中建立硝酸甘油（NTG）诱发偏头痛模型的大部分工作是在大鼠身上完成的。在各种研究中对不同的NTG特殊制剂进行了研究；然而，NTG处理组通常与单纯生理盐水处理的对照组进行比较。本研究的目的是通过回顾先前的研究结果并调查尚未在小鼠中测试的终点指标，来严格评估一组潜在结局指标在小鼠中的实用性。
我们以10mg/kg的腹腔注射剂量研究了两种NTG制剂，即Nitrolingual和Nitro Pohl，并与相关的赋形剂对照组进行比较，评估了以下结局指标：光厌恶行为、激光多普勒成像测量的颅部血流灌注、三叉神经尾核（TNC）和三叉神经节中c-Fos和神经元型一氧化氮合酶（nNOS）免疫反应性神经元的数量、后爪的热痛觉过敏和触觉异常性疼痛以及口面部疼痛超敏反应。
我们无法证实先前关于NTG引起小鼠光厌恶和颅部血流灌注显著变化的报道，但我们观察到Nitrolingual的赋形剂引起了相当大的影响。相比之下，Nitro Pohl的赋形剂显然是惰性的。NTG给药可使TNC中c-Fos表达增加、热痛觉过敏、触觉异常性疼痛和口面部超敏反应明显增加，这些显然是小鼠中的良好终点指标。托吡酯可阻止NTG引起的c-Fos表达增加，但舒马曲坦治疗无效。然而，舒马曲坦可剂量依赖性地减轻NTG引起的口面部超敏反应。
我们的结果指出了适用于小鼠NTG诱发偏头痛模型的NTG制剂和结局指标。在这些小鼠模型和人类NTG偏头痛模型中，在与阳性和阴性对照药物进行进一步交叉验证之前，这些测试可能是开发新型抗偏头痛药物的有价值的转化研究工具。
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