Caudle Robert M, Caudle Stephanie L, Flenor Natalie D, Rohrs Eric L, Neubert John K
Department of Oral and Maxillofacial Surgery, University of Florida, Gainesville, FL, United States.
Department of Orthodontics, University of Florida, Gainesville, FL, United States.
Front Pharmacol. 2020 Dec 3;11:527495. doi: 10.3389/fphar.2020.527495. eCollection 2020.
Rodent models of human disease can be valuable for understanding the mechanisms of a disease and for identifying novel therapies. However, it is critical that these models be vetted prior to committing resources to developing novel therapeutics. Failure to confirm the model can lead to significant losses in time and resources. One model used for migraine headache is to administer nitroglycerin to rodents. Nitroglycerin is known to produce migraine-like pain in humans and is presumed to do the same in rodents. It is not known, however, if the mechanism for nitroglycerin headaches involves the same pathological processes as migraine. In the absence of known mechanisms, it becomes imperative that the model not only translates into successful clinical trials but also successfully reverse translates by demonstrating efficacy of current therapeutics. In this study female rats were given nitroglycerin and nociception was evaluated in OPADs. Estrous was not monitored. Based on the ED of nitroglycerin a dose of 10 mg/kg was used for experiments. Sumatriptan, caffeine, buprenorphine and morphine were administered to evaluate the reverse translatability of the model. We found that nitroglycerin did not produce mechanical allodynia in the face of the rats, which is reported to be a consequence of migraine in humans. Nitroglycerin reduced the animals' participation in the assay. The reduced activity was verified using an assay to measure exploratory behavior. Furthermore, the effects of nitroglycerin were not reversed or prevented by agents that are effective acute therapies for migraine. Two interesting findings from this study, however, were that morphine and nitroglycerin interact to increase the rats' tolerance of mechanical stimuli on their faces, and they work in concert to slow down the central motor pattern generator for licking on the reward bottle. These interactions suggest that nitroglycerin generated nitric oxide and mu opioid receptors interact with the same neuronal circuits in an additive manner. The interaction of nitroglycerin and morphine on sensory and motor circuits deserves additional examination. In conclusion, based on the results of this study the use of nitroglycerin at these doses in naïve female rats is not recommended as a model for migraine headaches.
人类疾病的啮齿动物模型对于理解疾病机制和识别新疗法可能很有价值。然而，在投入资源开发新疗法之前，对这些模型进行审查至关重要。未能确认模型可能导致时间和资源的重大损失。一种用于偏头痛的模型是给啮齿动物施用硝酸甘油。已知硝酸甘油会在人类中产生类似偏头痛的疼痛，并且推测在啮齿动物中也是如此。然而，尚不清楚硝酸甘油性头痛的机制是否涉及与偏头痛相同的病理过程。在缺乏已知机制的情况下，当务之急是该模型不仅要转化为成功的临床试验，还要通过证明当前疗法的有效性成功反向转化。在这项研究中，给雌性大鼠施用硝酸甘油，并在口腔-面部撤离反射（OPADs）中评估伤害感受。未监测动情周期。根据硝酸甘油的半数有效量（ED），将10mg/kg的剂量用于实验。施用舒马曲坦、咖啡因、丁丙诺啡和吗啡以评估该模型的反向转化能力。我们发现，硝酸甘油并未在大鼠面部产生机械性异常性疼痛，而据报道这是人类偏头痛的一个后果。硝酸甘油降低了动物参与该试验的程度。使用测量探索行为的试验验证了活动减少的情况。此外，对偏头痛有效的急性治疗药物并未逆转或预防硝酸甘油的作用。然而，这项研究的两个有趣发现是，吗啡和硝酸甘油相互作用可增加大鼠对其面部机械刺激的耐受性，并且它们协同作用以减慢用于舔舐奖励瓶的中枢运动模式发生器的活动。这些相互作用表明，硝酸甘油产生的一氧化氮和μ阿片受体以相加的方式与相同的神经回路相互作用。硝酸甘油和吗啡在感觉和运动回路上的相互作用值得进一步研究。总之，基于这项研究的结果，不建议在未经处理的雌性大鼠中使用这些剂量的硝酸甘油作为偏头痛模型。
