Abstract
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 ED50 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.
Highlights
Migraine headaches are one of the most common debilitating chronic pain conditions, affecting more than ten percent of the global population (Woldeamanuel and Cowan, 2017)
To address the adequacy of nitroglycerin in rats as an acute model of human migraine headache this study evaluated the model pharmacologically in an operant assay using Orofacial Pain Assessment Devices (OPAD, Stoelting, Co.)
The data indicate that nitroglycerin reduced overall activity in the animals rather than producing mechanical hypersensitivity. This lack of hypersensitivity contrasts with previous reports on nitroglycerin in rodents (Di et al, 2016; Tipton et al, 2016; Farajdokht et al, 2018; Qin et al, 2018)
Summary
Migraine headaches are one of the most common debilitating chronic pain conditions, affecting more than ten percent of the global population (Woldeamanuel and Cowan, 2017). Botulinum toxin, calcitonin gene-related peptide (CGRP) antagonists and antibodies to CGRP and CGRP receptors have been developed for long term control of migraine headaches (Matak et al, 2011; Dodick et al, 2014a; Dodick et al, 2014b; Lupi et al, 2019) These therapies typically reduce the incidence of migraine by just a few attacks per month (Dodick et al, 2019; Urits et al, 2019), indicating that extended therapy for chronic migraine is still not satisfactory. A previous study by the same researchers, did indicated some degree of headache prevention when sumatriptan was given prior to nitroglycerin in healthy volunteers (Iversen and Olesen, 1996). These observations suggest that nitroglycerin in humans may not be an accurate model of migraine headache
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