Department of Neural and Pain Sciences, University of Maryland Baltimore, Baltimore, MD, United States.
Headache Group, Department of Basic and Clinical Neuroscience, Institute of Psychology, Psychiatry and Neuroscience, King's College London, London, United Kingdom.
Pain. 2021 May 1;162(5):1567-1577. doi: 10.1097/j.pain.0000000000002142.
Cranial hypersensitivity is a prominent symptom of migraine, exhibited as migraine headache exacerbated with physical activity, and cutaneous facial allodynia and hyperalgesia. The underlying mechanism is believed to be, in part, activation and sensitization of dural-responsive trigeminocervical neurons. Validated preclinical models that exhibit this phenotype have great utility for understanding putative mechanisms and as a tool to screen therapeutics. We have previously shown that nitroglycerin triggers cranial allodynia in association with migraine-like headache, and this translates to neuronal cranial hypersensitivity in rats. Furthermore, responses in both humans and rats are aborted by triptan administration, similar to responses in spontaneous migraine. Here, our objective was to study the nitroglycerin model examining the effects on therapeutic targets with newly approved treatments, specifically gepants and ditans, for the acute treatment of migraine. Using electrophysiological methods, we determined changes to ongoing firing and somatosensory-evoked cranial sensitivity, in response to nitroglycerin, followed by treatment with a calcitonin gene-related peptide receptor antagonist, gepant (olcegepant), a 5-HT1F receptor agonist, ditan (LY344864), and an NK1 receptor antagonist (GR205171). Nitroglycerin induced activation of migraine-like central trigeminocervical neurons, and intracranial and extracranial neuronal hypersensitivity. These responses were aborted by olcegepant and LY344864. However, GR205171, which failed in clinical trial for both abortive and preventive treatment of migraine, had no effect. These data support the nitroglycerin model as a valid approach to study cranial hypersensitivity and putative mechanisms involved in migraine and as a screen to dissect potentially efficacious migraine therapeutic targets.
颅敏感性是偏头痛的一个突出症状，表现为偏头痛性头痛在体力活动时加重，以及皮肤面部触诱发痛和痛觉过敏。其潜在机制部分归因于硬脑膜反应性三叉神经根颈神经元的激活和敏化。具有这种表型的经过验证的临床前模型对于理解推测的机制非常有用，并且可作为筛选治疗方法的工具。我们之前已经表明，硝化甘油会引发与偏头痛相关的颅部触诱发痛，并且这会在大鼠中转化为神经元颅部敏感性。此外，人类和大鼠的反应均通过曲坦类药物给药而终止，类似于自发性偏头痛的反应。在这里，我们的目的是研究硝化甘油模型，以研究新批准的治疗方法（特别是 gepants 和 ditans）对偏头痛急性治疗的治疗靶标。使用电生理方法，我们确定了硝化甘油对持续性放电和躯体感觉诱发的颅敏感性的影响，然后用降钙素基因相关肽受体拮抗剂（gepant（olcegepant））、5-HT1F 受体激动剂（ditans（LY344864））和 NK1 受体拮抗剂（GR205171）进行治疗。硝化甘油诱导偏头痛样中枢三叉神经根颈神经元的激活以及颅内和颅外神经元的敏感性增加。olcegepant 和 LY344864 可终止这些反应。但是，在偏头痛的发作和预防性治疗的临床试验中均失败的 GR205171 没有效果。这些数据支持硝化甘油模型作为研究偏头痛中颅敏感性和潜在机制的有效方法，以及作为筛选潜在有效的偏头痛治疗靶标的方法。
